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http://www.ncbi.nlm.nih.gov/pubmed/10391249
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1. Nature. 1999 Jun 24;399(6738):806-9. doi: 10.1038/21690.
The tyrosine kinase c-Abl regulates p73 in apoptotic response to
cisplatin-induced DNA damage.
Gong JG(1), Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, Wang JY.
Author information:
(1)Department of Biology, University of California, San Diego, La Jolla
92093-0322, USA.
Comment in
Nature. 1999 Jun 24;399(6738):734-5, 737. doi: 10.1038/21539.
Cancer chemotherapeutic agents such as cisplatin exert their cytotoxic effect by
inducing DNA damage and activating programmed cell death (apoptosis). The
tumour-suppressor protein p53 is an important activator of apoptosis. Although
p53-deficient cancer cells are less responsive to chemotherapy, their resistance
is not complete, which suggests that other apoptotic pathways may exist. A
p53-related gene, p73, which encodes several proteins as a result of alternative
splicing, can also induce apoptosis. Here we show that the amount of p73 protein
in the cell is increased by cisplatin. This induction of p73 is not seen in
cells unable to carry out mismatch repair and in which the nuclear enzyme c-Abl
tyrosine kinase is not activated by cisplatin. The half-life of p73 is prolonged
by cisplatin and by co-expression with c-Abl tyrosine kinase; the
apoptosis-inducing function of p73 is also enhanced by the c-Abl kinase. Mouse
embryo fibroblasts deficient in mismatch repair or in c-Abl do not upregulate
p73 and are more resistant to killing by cisplatin. Our results indicate that
c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway
which contributes to cisplatin-induced cytotoxicity.
DOI: 10.1038/21690
PMID: 10391249 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24563699
|
1. Commun Integr Biol. 2013 Nov 1;6(6):e25660. doi: 10.4161/cib.25660. Epub 2013
Jul 23.
Targeting secretion to the apical surface by mDia1-built actin tracks.
Geron E(1), Schejter ED(1), Shilo BZ(1).
Author information:
(1)Department of Molecular Genetics; Weizmann Institute of Science; Rehovot,
Israel.
The apical surface of secretory tubular epithelia is a dynamic cellular domain
where massive membrane turnover takes place during exocytosis and its subsequent
compensatory endocytosis. This extensive membrane flow poses a difficulty in
targeting secretory vesicles efficiently to a narrow apical domain. We have
studied how actin filaments mediate the secretory process in the murine exocrine
pancreas, which produces and secretes digestive enzymes that are deposited into
the intestine. We show that cargo-filled secretory vesicles move over bundles of
linear actin cables from their storage areas to the apical membrane of
pancreatic acinar cells. mDia1, a linear actin nucleator of the Formin family,
was identified as the generator of these structures. The active form of mDia1
localizes to the apical surface, and the microfilament bundles it forms emanate
from the apical surface and extend into the cytoplasm, generating polarized
secretion tracks. These bundles ensure orderly progression of exocytosis, since
the apical targeting of pancreatic vesicles is compromised in their absence, and
vesicles fuse with each other to generate compound, membrane-associated
secretory structures.
DOI: 10.4161/cib.25660
PMCID: PMC3917947
PMID: 24563699
|
http://www.ncbi.nlm.nih.gov/pubmed/19160018
|
1. Cancer Metastasis Rev. 2009 Jun;28(1-2):65-76. doi: 10.1007/s10555-008-9170-7.
Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion.
Narumiya S(1), Tanji M, Ishizaki T.
Author information:
(1)Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto,
606-8501, Japan. snaru@mfour.med.kyoto-u.ac.jp
The Rho subgroup of the Rho GTPases consisting of RhoA, RhoB and RhoC induces a
specific type of actin cytoskeleton and carry out a variety of functions in the
cell. mDia and ROCK are downstream effectors of Rho mediating Rho action on the
actin cytoskeleton; mDia produces actin filaments by nucleation and
polymerization and ROCK activate myosin to cross-link them for induction of
actomyosin bundles and contractility. mDia is potentially linked to Rac
activation and membrane ruffle formation through c-Src-induced phosphorylation
of focal adhesion proteins, and ROCK antagonizes this mDia action. Thus, cell
morphogenesis, adhesion, and motility can be determined by the balance between
mDia and ROCK activities. Though they are not oncogenes by themselves,
overexpression of RhoA and RhoC are often found in clinical cancers, and RhoC
has been repeatedly identified as a gene associated with metastasis. The
Rho-ROCK pathway is implicated in Ras-mediated transformation, the amoeboid
movement of tumor cells in the three-dimensional matrix, and transmigration of
tumor cells through the mesothelial monolayer. On the other hand, the Rho-mDia1
pathway is implicated in Src-mediated remodeling of focal adhesions and
migration of tumor cells. There is also an indication that the Rho pathway other
than ROCK is involved in Src-mediated induction of podosome and regulation of
matrix metalloproteases. Thus, Rho mediates various phenotypes of malignant
transformation by Ras and Src through its effectors, ROCK and mDia.
DOI: 10.1007/s10555-008-9170-7
PMID: 19160018 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26109050
|
1. Genes Dev. 2015 Jun 15;29(12):1271-84. doi: 10.1101/gad.262816.115.
A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.
Moroishi T(1), Park HW(1), Qin B(2), Chen Q(3), Meng Z(1), Plouffe SW(1),
Taniguchi K(4), Yu FX(5), Karin M(4), Pan D(3), Guan KL(1).
Author information:
(1)Department of Pharmacology, Moores Cancer Center, University of California at
San Diego, La Jolla, California 92093, USA;
(2)Department of Pharmacology, Moores Cancer Center, University of California at
San Diego, La Jolla, California 92093, USA; Department of Laboratory Medicine,
Shanghai Changzheng Hospital, Second Military Medical University, Shanghai
200003, China;
(3)Department of Molecular Biology and Genetics, Johns Hopkins University School
of Medicine, Baltimore, Maryland 21205, USA;
(4)Department of Pharmacology, University of California at San Diego, La Jolla,
California 92093, USA; Department of Pathology, University of California at San
Diego, La Jolla, California 92093, USA;
(5)Children's Hospital, Fudan University, Shanghai 200032, China; Institutes of
Biomedical Sciences, Fudan University, Shanghai 200032, China.
YAP (Yes-associated protein) and TAZ (transcriptional coactivator with
PDZ-binding motif) are major downstream effectors of the Hippo pathway that
influences tissue homeostasis, organ size, and cancer development. Aberrant
hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas
their inactivation impairs tissue development and regeneration. Dynamic and
precise control of YAP/TAZ activity is thus important to ensure proper
physiological regulation and homeostasis of the cells. Here, we show that
YAP/TAZ activation results in activation of their negative regulators, LATS1/2
(large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of
the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex
with the transcription factor TEAD (TEA domain family member) directly induce
LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of
LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is
responsible for the transient activation of YAP upon lysophosphatidic acid (LPA)
stimulation and the inhibition of YAP-induced cell migration. Thus, this
LATS-mediated feedback loop provides an efficient mechanism to establish the
robustness and homeostasis of YAP/TAZ regulation.
© 2015 Moroishi et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gad.262816.115
PMCID: PMC4495398
PMID: 26109050 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25109332
|
1. Oncogene. 2015 Jun 11;34(24):3095-106. doi: 10.1038/onc.2014.251. Epub 2014
Aug 11.
Geranylgeranylation signals to the Hippo pathway for breast cancer cell
proliferation and migration.
Mi W(1), Lin Q(2), Childress C(1), Sudol M(3), Robishaw J(1), Berlot CH(1),
Shabahang M(4), Yang W(1).
Author information:
(1)Weis Center for Research, Danville, PA, USA.
(2)1] Weis Center for Research, Danville, PA, USA [2] School of Medical Sciences
and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
(3)1] Weis Center for Research, Danville, PA, USA [2] Department of Medicine,
Mount Sinai Medical School, New York, NY, USA.
(4)Department of General Surgery, Geisinger Clinic, Danville, PA, USA.
Protein geranylgeranylation (GGylation) is an important biochemical process for
many cellular signaling molecules. Previous studies have shown that GGylation is
essential for cell survival in many types of cancer. However, the molecular
mechanism mediating the cell survival effect remains elusive. In this report, we
show that the Hippo pathway mediates GGylation-dependent cell proliferation and
migration in breast cancer cells. Blockade of GGylation enhanced phosphorylation
of Mst1/2 and Lats1, and inhibited YAP and TAZ activity and the Hippo-YAP/TAZ
pathway-dependent transcription. The effect of GGylation blockade on inhibition
of breast cancer cell proliferation and migration is dependent on the
Hippo-YAP/TAZ signaling, in which YAP appears to regulate cell proliferation and
TAZ to regulate cell migration. Furthermore, GGylation-dependent cell
proliferation is correlated with the activity of YAP/TAZ in breast cancer cells.
Finally, Gγ and RhoA are the GGylated proteins that may transduce GGylation
signals to the Hippo-YAP/TAZ pathway. Taken together, our studies have
demonstrated that the Hippo-YAP/TAZ pathway is essential for GGylation-dependent
cancer cell proliferation and migration.
DOI: 10.1038/onc.2014.251
PMID: 25109332 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16818632
|
1. Cancer Res. 2006 Jul 1;66(13):6598-605. doi: 10.1158/0008-5472.CAN-05-3115.
MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen
species.
Ray S(1), Atkuri KR, Deb-Basu D, Adler AS, Chang HY, Herzenberg LA, Felsher DW.
Author information:
(1)Division of Oncology, Department of Medicine and Pathology, Stanford
University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA.
MYC overexpression is thought to initiate tumorigenesis by inducing cellular
proliferation and growth and to be restrained from causing tumorigenesis by
inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show
that MYC can induce DNA breaks both in vitro and in vivo independent of
increased production of reactive oxygen species (ROS). We provide an insight
into the specific circumstances under which MYC generates ROS in vitro and
propose a possible mechanism. We found that MYC induces DNA double-strand breaks
(DSBs) independent of ROS production in murine lymphocytes in vivo as well as in
normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as
measured by gammaH2AX staining. However, NHFs cultured in vitro in low serum
(0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative
damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In
NHFs cultured in low versus normal serum, MYC induced increased expression of
CYP2C9, a gene product well known to be associated with ROS production. Specific
inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit
MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs
under some conditions, but generally induces widespread DSBs in vivo and in
vitro independent of ROS production.
DOI: 10.1158/0008-5472.CAN-05-3115
PMID: 16818632 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21930699
|
1. J Biol Chem. 2011 Nov 11;286(45):39236-46. doi: 10.1074/jbc.M111.253898. Epub
2011 Sep 19.
Unique structural and nucleotide exchange features of the Rho1 GTPase of
Entamoeba histolytica.
Bosch DE(1), Wittchen ES, Qiu C, Burridge K, Siderovski DP.
Author information:
(1)Department of Pharmacology, University of North Carolina, Chapel Hill, North
Carolina 27599-7365, USA.
The single-celled human parasite Entamoeba histolytica possesses a dynamic actin
cytoskeleton vital for its intestinal and systemic pathogenicity. The E.
histolytica genome encodes several Rho family GTPases known to regulate
cytoskeletal dynamics. EhRho1, the first family member identified, was reported
to be insensitive to the Rho GTPase-specific Clostridium botulinum C3 exoenzyme,
raising the possibility that it may be a misclassified Ras family member. Here,
we report the crystal structures of EhRho1 in both active and inactive states.
EhRho1 is activated by a conserved switch mechanism, but diverges from mammalian
Rho GTPases in lacking a signature Rho insert helix. EhRho1 engages a homolog of
mDia, EhFormin1, suggesting a role in mediating serum-stimulated actin
reorganization and microtubule formation during mitosis. EhRho1, but not a
constitutively active mutant, interacts with a newly identified EhRhoGDI in a
prenylation-dependent manner. Furthermore, constitutively active EhRho1 induces
actin stress fiber formation in mammalian fibroblasts, thereby identifying it as
a functional Rho family GTPase. EhRho1 exhibits a fast rate of nucleotide
exchange relative to mammalian Rho GTPases due to a distinctive switch one
isoleucine residue reminiscent of the constitutively active F28L mutation in
human Cdc42, which for the latter protein, is sufficient for cellular
transformation. Nonconserved, nucleotide-interacting residues within EhRho1,
revealed by the crystal structure models, were observed to contribute a
moderating influence on fast spontaneous nucleotide exchange. Collectively,
these observations indicate that EhRho1 is a bona fide member of the Rho GTPase
family, albeit with unique structural and functional aspects compared with
mammalian Rho GTPases.
DOI: 10.1074/jbc.M111.253898
PMCID: PMC3234748
PMID: 21930699 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14765113
|
1. EMBO J. 2004 Feb 25;23(4):760-71. doi: 10.1038/sj.emboj.7600095. Epub 2004 Feb
5.
DIP (mDia interacting protein) is a key molecule regulating Rho and Rac in a
Src-dependent manner.
Meng W(1), Numazaki M, Takeuchi K, Uchibori Y, Ando-Akatsuka Y, Tominaga M,
Tominaga T.
Author information:
(1)Department of Cellular and Molecular Physiology, Mie University School of
Medicine, Tsu, Japan.
Cell movement is driven by the coordinated regulation of cytoskeletal
reorganization through Rho GTPases downstream of integrin and growth-factor
receptor signaling. We have reported that mDia, a target protein of Rho,
interacts with Src and DIP. Here we show that DIP binds to p190RhoGAP and Vav2,
and that DIP is phosphorylated by Src and mediates the phosphorylation of
p190RhoGAP and Vav2 upon EGF stimulation. When endogenous DIP was inhibited by
expressing dominant-negative mutants of DIP or siRNA, phosphorylation of
p190RhoGAP and Vav2 upon EGF stimulation was diminished, and EGF-induced actin
organization, distribution of p190RhoGAP and Vav2, and cell movement were
affected. Therefore, DIP seems to transfer the complex of the three proteins
from cytosol to beneath the membrane, and the three proteins, in turn, can be
phosphorylated by Src. DIP inactivated Rho and activated Rac following EGF
stimulation in the membrane fraction. Thus, DIP acts as a regulatory molecule
causing Src kinase-dependent feedback modulation of Rho GTPases downstream of
Rho-mDia upon EGF stimulation, and plays an important role in cell motility.
DOI: 10.1038/sj.emboj.7600095
PMCID: PMC381003
PMID: 14765113 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8144827
|
1. J Am Geriatr Soc. 1994 Apr;42(4):413-9. doi:
10.1111/j.1532-5415.1994.tb07490.x.
The effects of the presence of a third person on the physician-older patient
medical interview.
Greene MG(1), Majerovitz SD, Adelman RD, Rizzo C.
Author information:
(1)Department of Health and Nutrition Sciences, Brooklyn College, New York.
OBJECTIVE: To compare communication in triadic (three-person) and dyadic
(two-person) older patient medical interviews and to determine the influence of
the presence of a third person on the physician-older patient relationship.
DESIGN: Matched sample of dyadic and triadic audiotaped outpatient medical
visits. Audiotapes were coded with the Multi-dimensional Interaction Analysis
(MDIA) system.
SETTING: Hospital-based medical primary care group practice in a major urban
teaching institution.
PARTICIPANTS: Patients 60 years and older who were making their first visit to
study physicians. In a sample of 96 audiotaped initial medical visits, 15
encounters involved three persons. These 15 cases were matched with 15 dyadic
interviews for gender and race of the patient and for gender and race of the
physician.
MAIN OUTCOME MEASURES: Content, interactional processes, and specific language
and communication behaviors of older patients, physicians, and third persons in
the medical encounter, as measured by the MDIA system.
RESULTS: The specific content and the quality of interactional processes of
physicians were not affected by the presence of a third person. However, older
patients raised fewer topics in all content areas (medical, personal habits,
psychosocial, and physician-patient relationship) in triads than in dyads.
Overall, patients were less responsive (ie, the quality of their questioning,
informing, and supportiveness was poorer) on patient-raised topics in triads
than in dyads. Patients were rated as less assertive and expressive, and there
was less joint decision-making and shared laughter in triads than in dyads.
Patients were frequently excluded from conversations in visits in which a third
person was present.
CONCLUSIONS: The presence of a third person in the medical encounter changes the
interactional dynamics of older patient medical interviews and may influence the
development of a trusting and effective physician-older patient relationship.
DOI: 10.1111/j.1532-5415.1994.tb07490.x
PMID: 8144827 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24242070
|
1. Cancer Res. 2013 Nov 15;73(22):6793-803. doi: 10.1158/0008-5472.CAN-13-1593.
Small-molecule intramimics of formin autoinhibition: a new strategy to target
the cytoskeletal remodeling machinery in cancer cells.
Lash LL(1), Wallar BJ, Turner JD, Vroegop SM, Kilkuskie RE, Kitchen-Goosen SM,
Xu HE, Alberts AS.
Author information:
(1)Authors' Affiliations: Laboratories of Cell Structure and Signal Integration
and Structural Sciences, Van Andel Research Institute; Grand Valley State
University, Grand Rapids; and Michigan High Throughput Screening Center,
Kalamazoo, Michigan.
Although the cancer cell cytoskeleton is a clinically validated target, few new
strategies have emerged for selectively targeting cell division by modulating
the cytoskeletal structure, particularly ways that could avoid the cardiotoxic
and neurotoxic effects of current agents such as taxanes. We address this gap by
describing a novel class of small-molecule agonists of the mammalian Diaphanous
(mDia)-related formins, which act downstream of Rho GTPases to assemble actin
filaments, and their organization with microfilaments to establish and maintain
cell polarity during migration and asymmetric division. GTP-bound Rho activates
mDia family members by disrupting the interaction between the DID and DAD
autoregulatory domains, which releases the FH2 domain to modulate actin and
microtubule dynamics. In screening for DID-DAD disruptors that activate mDia, we
identified two molecules called intramimics (IMM-01 and -02) that were
sufficient to trigger actin assembly and microtubule stabilization, serum
response factor-mediated gene expression, cell-cycle arrest, and apoptosis. In
vivo analysis of IMM-01 and -02 established their ability to slow tumor growth
in a mouse xenograft model of colon cancer. Taken together, our work establishes
the use of intramimics and mDia-related formins as a new general strategy for
therapeutic targeting of the cytoskeletal remodeling machinery of cancer cells.
©2013 AACR
DOI: 10.1158/0008-5472.CAN-13-1593
PMID: 24242070 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23740402
|
1. Commun Integr Biol. 2012 Nov 1;5(6):631-3. doi: 10.4161/cib.21686.
LIN7-IRSp53: A novel pathway for filopodia and neurite formation?
Ferrari I(1), Crespi A, Scita G, Pietrini G.
Author information:
(1)Department of BIOMETRA; Università degli Studi di Milano; CNR-Institute of
Neuroscience; Milan, Italy.
Filopodia are dynamic, actin-rich finger-like structures that protrude from the
cell membrane and play important roles in cell migration and neurite initiation
and outgrowth. The insulin receptor substrate protein of 53 kDa (IRSp53) and the
mammalian Diaphanous members of the formin family of proteins (mDia) are two key
players in the formation of filopodia and neurites. IRSp53 is an adaptor protein
that acts at the membrane:actin interface, coupling membrane deformation with
F-actin polymerization. mDia formin proteins, instead, can nucleate and
polymerize linear actin filaments. Emerging genetic and biochemical evidence
indicate that there are multiple and independent pathways leading to filopodium
and neurite formation, but the precise molecular components of these pathways
remain ill-defined. We recently identified the PDZ domain-containing protein
LIN7 as a novel regulator of IRSp53. We further showed that the association
between these two proteins is required to promote the formation of filopodia and
neurites independently from mDia formin proteins, highlighting novel mechanisms
of filopodia and neurite formation.
DOI: 10.4161/cib.21686
PMCID: PMC3541334
PMID: 23740402
|
http://www.ncbi.nlm.nih.gov/pubmed/10436006
|
1. Mol Biol Cell. 1999 Aug;10(8):2481-91. doi: 10.1091/mbc.10.8.2481.
Distinct actions and cooperative roles of ROCK and mDia in Rho small G
protein-induced reorganization of the actin cytoskeleton in Madin-Darby canine
kidney cells.
Nakano K(1), Takaishi K, Kodama A, Mammoto A, Shiozaki H, Monden M, Takai Y.
Author information:
(1)Department of Molecular Biology and Biochemistry, Osaka University Medical
School, Suita 565-0871, Japan.
Rho, a member of the Rho small G protein family, regulates the formation of
stress fibers and focal adhesions in various types of cultured cells. We
investigated here the actions of ROCK and mDia, both of which have been
identified to be putative downstream target molecules of Rho, in Madin-Darby
canine kidney cells. The dominant active mutant of RhoA induced the formation of
parallel stress fibers and focal adhesions, whereas the dominant active mutant
of ROCK induced the formation of stellate stress fibers and focal adhesions, and
the dominant active mutant of mDia induced the weak formation of parallel stress
fibers without affecting the formation of focal adhesions. In the presence of C3
ADP-ribosyltransferase for Rho, the dominant active mutant of ROCK induced the
formation of stellate stress fibers and focal adhesions, whereas the dominant
active mutant of mDia induced only the diffuse localization of actin filaments.
These results indicate that ROCK and mDia show distinct actions in
reorganization of the actin cytoskeleton. The dominant negative mutant of either
ROCK or mDia inhibited the formation of stress fibers and focal adhesions,
indicating that both ROCK and mDia are necessary for the formation of stress
fibers and focal adhesions. Moreover, inactivation and reactivation of both ROCK
and mDia were necessary for the 12-O-tetradecanoylphorbol-13-acetate-induced
disassembly and reassembly, respectively, of stress fibers and focal adhesions.
The morphologies of stress fibers and focal adhesions in the cells expressing
both the dominant active mutants of ROCK and mDia were not identical to those
induced by the dominant active mutant of Rho. These results indicate that at
least ROCK and mDia cooperatively act as downstream target molecules of Rho in
the Rho-induced reorganization of the actin cytoskeleton.
DOI: 10.1091/mbc.10.8.2481
PMCID: PMC25478
PMID: 10436006 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15371418
|
1. J Biol Chem. 2004 Nov 26;279(48):50250-6. doi: 10.1074/jbc.M404429200. Epub
2004 Sep 14.
Homo-oligomerization is essential for F-actin assembly by the formin family FH2
domain.
Copeland JW(1), Copeland SJ, Treisman R.
Author information:
(1)Transcription Laboratory, Cancer Research UK, London Research Institute,
Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London C2A 3PX,
United Kingdom. jcopelan@uottawa.ca
Formin proteins regulate the actin and microtubule cytoskeletons and also
control the activity of the SRF transcription factor through depletion of the
G-actin pool. Although the conserved formin homology 2 (FH2) domains of the
mDia1 and Bni1 formins can nucleate actin polymerization in vitro, the activity
of other FH2 domains and the relationship between actin polymerization and
microtubule reorganization have been controversial. We show that, similar to the
mDia1 FH2 domain, the FH2 domains of mDia2 and ld are sufficient for SRF
activation in vivo. We demonstrate that an mDia1 mutant defective for
microtubule rearrangement in vivo is also defective in SRF activation in vivo as
well as actin polymerization in vitro and that the mDia2 FH2 domain promotes
actin polymerization in vitro. Using co-immunoprecipitation, we show that mDia1
is oligomeric in its inactive autoinhibited state in vivo, that the active mDia1
and mDia2 FH2 domains form homo- but not hetero-oligomers in vivo, and that
oligomerization is abolished by inactivating FH2 deletion and point mutations.
Nevertheless, inactive mDia1 FH2 domain mutants retain the ability to interfere
with cellular mDia activity. Our results show that self-oligomerization is
essential for SRF activation in vivo and F-actin assembly in vitro and provide
strong support for recent structural models of the FH2 domain.
DOI: 10.1074/jbc.M404429200
PMID: 15371418 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18362183
|
1. J Cell Biol. 2008 Mar 24;180(6):1245-60. doi: 10.1083/jcb.200708123.
WASP family members and formin proteins coordinate regulation of cell
protrusions in carcinoma cells.
Sarmiento C(1), Wang W, Dovas A, Yamaguchi H, Sidani M, El-Sibai M, Desmarais V,
Holman HA, Kitchen S, Backer JM, Alberts A, Condeelis J.
Author information:
(1)Department of Anatomy and Structural Biology, Albert Einstein College of
Medicine, Yeshiva University, Bronx, NY 10461, USA. csarmien@aecom.yu.edu
We examined the role of the actin nucleation promoters neural Wiskott-Aldrich
syndrome protein (N-WASP) and WAVE2 in cell protrusion in response to epidermal
growth factor (EGF), a key regulator in carcinoma cell invasion. We found that
WAVE2 knockdown (KD) suppresses lamellipod formation and increases filopod
formation, whereas N-WASP KD has no effect. However, simultaneous KD of both
proteins results in the formation of large jagged protrusions with lamellar
properties and increased filopod formation. This suggests that another actin
nucleation activity is at work in carcinoma cells in response to EGF. A
mammalian Diaphanous-related formin, mDia1, localizes at the jagged protrusions
in double KD cells. Constitutively active mDia1 recapitulated the phenotype,
whereas inhibition of mDia1 blocked the formation of these protrusions.
Increased RhoA activity, which stimulates mDia1 nucleation, was observed in the
N-WASP/WAVE2 KD cells and was shown to be required for the N-WASP/WAVE2 KD
phenotype. These data show that coordinate regulation between the WASP family
and mDia proteins controls the balance between lamellar and lamellipodial
protrusion activity.
DOI: 10.1083/jcb.200708123
PMCID: PMC2290849
PMID: 18362183 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16361249
|
1. J Biol Chem. 2006 Feb 24;281(8):5084-93. doi: 10.1074/jbc.M509226200. Epub
2005 Dec 16.
Biochemical characterization of the diaphanous autoregulatory interaction in the
formin homology protein FHOD1.
Schönichen A(1), Alexander M, Gasteier JE, Cuesta FE, Fackler OT, Geyer M.
Author information:
(1)Max Planck Institute for Molecular Physiology, Department of Physical
Biochemistry, D-44227 Dortmund, Germany.
Diaphanous related formins (DRFs) are cytoskeleton remodeling proteins that
mediate specific upstream GTPase signals to regulate cellular processes such as
cytokinesis, cell polarity, and organelle motility. Previous work on the
Rho-interacting DRF mDia has established that the biological activity of DRFs is
regulated by an autoinhibitory interaction of a C-terminal diaphanous
autoregulatory domain (DAD) with the DRF N terminus. This autoinhibition is
released upon competitive binding of an activated GTPase to the N terminus of
the DRF. Analyzing autoregulation of the Rac1-interacting DRF FHOD1, we utilized
in vitro binding studies to identify a 60-amino acid DAD at the protein C
terminus that recognizes an N-terminal formin homology (FH) 3 domain.
Importantly, the FH3 domain of FHOD1 does not overlap with the proposed
Rac1-binding domain. The FHOD1 DAD was found to contain one functional
hydrophobic autoregulatory motif, while a previously uncharacterized basic
cluster that is conserved in all DRF family DADs also contributed to the FH3-DAD
interaction. Simultaneous mutation of both motifs efficiently released
autoinhibition of FHOD1 in NIH3T3 cells resulting in the formation of actin
stress fibers and increased serum response element transcription. A second
putative hydrophobic autoregulatory motif N-terminal of the DAD belongs to a
unique FHOD subdomain of yet undefined function. NMR structural analysis and
size exclusion chromatography experiments revealed that the FHOD1 DAD is
intrinsically unstructured with a tendency for a helical conformation in the
hydrophobic autoregulation motif. Together, these data suggest that in FHOD1,
DAD acts as signal sequence for binding to the well folded and monomeric FH3
domain and imply an activation mechanism that differs from competitive binding
of Rac1 and DAD to one interaction site.
DOI: 10.1074/jbc.M509226200
PMID: 16361249 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24068556
|
1. Nucleic Acids Res. 2014 Jan;42(1):128-36. doi: 10.1093/nar/gkt854. Epub 2013
Sep 24.
Nucleosome positioning and kinetics near transcription-start-site barriers are
controlled by interplay between active remodeling and DNA sequence.
Parmar JJ(1), Marko JF, Padinhateeri R.
Author information:
(1)Department of Biosciences and Bioengineering, Indian Institute of Technology
Bombay, Mumbai 400076, India, Department of Molecular Biosciences, Northwestern
University, Evanston, IL 60208, USA, Department of Physics and Astronomy,
Northwestern University, Evanston, IL 60208, USA and Wadhwani Research Centre
for Biosciences and Bioengineering, Indian Institute of Technology Bombay,
Mumbai 400076, India.
We investigate how DNA sequence, ATP-dependent chromatin remodeling and
nucleosome-depleted 'barriers' co-operate to determine the kinetics of
nucleosome organization, in a stochastic model of nucleosome positioning and
dynamics. We find that 'statistical' positioning of nucleosomes against
'barriers', hypothesized to control chromatin structure near transcription start
sites, requires active remodeling and therefore cannot be described using
equilibrium statistical mechanics. We show that, unlike steady-state occupancy,
DNA site exposure kinetics near a barrier is dominated by DNA sequence rather
than by proximity to the barrier itself. The timescale for formation of
positioning patterns near barriers is proportional to the timescale for active
nucleosome eviction. We also show that there are strong gene-to-gene variations
in nucleosome positioning near barriers, which are eliminated by averaging over
many genes. Our results suggest that measurement of nucleosome kinetics can
reveal information about sequence-dependent regulation that is not apparent in
steady-state nucleosome occupancy.
DOI: 10.1093/nar/gkt854
PMCID: PMC3874171
PMID: 24068556 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17198702
|
1. Exp Cell Res. 2007 Feb 1;313(3):560-71. doi: 10.1016/j.yexcr.2006.10.033. Epub
2006 Nov 11.
RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking.
Wallar BJ(1), Deward AD, Resau JH, Alberts AS.
Author information:
(1)Laboratory of Cell Structure and Signal Integration, Van Andel Research
Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
Rho GTPases and the dynamic assembly and disassembly of actin filaments have
been shown to have critical roles in both the internalization and trafficking of
growth factor receptors. While all three mammalian Diaphanous-related
(mDia1/2/3) formin GTPase effector proteins have been localized on endosomes, a
role for their actin nucleation, filament elongation, and/or bundling remains
poorly understood in the context of intracellular trafficking. In a study of a
functional relationship between RhoB, a GTPase known to associate with both
early- and late-endosomes, and the formin mDia2, we show that 1) RhoB and mDia2
interact on endosomes; 2) GTPase activity-the ability to hydrolyze GTP to GDP-is
required for the ability of RhoB to govern endosome dynamics; and 3) the actin
dynamics controlled by RhoB and mDia2 is necessary for vesicle trafficking.
These studies further suggest that Rho GTPases significantly influence the
activity of mDia family formins in driving cellular membrane remodeling through
the regulation of actin dynamics.
DOI: 10.1016/j.yexcr.2006.10.033
PMID: 17198702 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23060957
|
1. Commun Integr Biol. 2012 Jul 1;5(4):340-4. doi: 10.4161/cib.20214.
mDia1-3 in mammalian filopodia.
Goh WI(1), Ahmed S.
Author information:
(1)Institute of Medical Biology; Singapore; Immunos, Singapore.
mDia proteins are members of the formin family of actin nucleating proteins that
polymerize linear actin filaments. Such filaments form the core of thin,
tubular, membrane-bound cell surface protrusions known as filopodia, which are a
major feature of mammalian cell morphology. Filopodia are dynamic structures
that help cells sense environmental cues, and play a role in cell migration,
axon guidance, angiogenesis and other processes. RhoGTPases bind to and control
the activity of mDia proteins, and several other binding partners of the three
mDia1 isoforms-mDia1, mDia2 and mDia3-have been documented. Two independent
pathways controlling mammalian filopodium formation have emerged, with one
driven by the RhoGTPase Cdc42, and the other by Rif. While mDia2 has been the
main formin implicated in forming filopodia, mDia1 has recently surfaced as the
key formin utilized by both the Cdc42 and Rif pathways to drive filopodial
protrusion.
DOI: 10.4161/cib.20214
PMCID: PMC3460838
PMID: 23060957
|
http://www.ncbi.nlm.nih.gov/pubmed/18239683
|
1. EMBO J. 2008 Feb 20;27(4):618-28. doi: 10.1038/emboj.2008.7. Epub 2008 Jan 31.
The mammalian formin FHOD1 is activated through phosphorylation by ROCK and
mediates thrombin-induced stress fibre formation in endothelial cells.
Takeya R(1), Taniguchi K, Narumiya S, Sumimoto H.
Author information:
(1)Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Formin-family proteins, in the active state, form actin-based structures such as
stress fibres. Their activation mechanisms, however, are largely unknown except
that mDia and its closely related formins can be activated by direct binding of
the small GTPase Rho or Cdc42. Here we show that the Rho-dependent protein
kinase ROCK phosphorylates the C-terminal residues Ser1131, Ser1137, and Thr1141
of formin homology domain protein 1 (FHOD1), a major endothelial formin that is
normally autoinhibited by intramolecular interaction between the N- and
C-terminal regions. Phosphorylation of FHOD1 at the three residues fully
disrupts the autoinhibitory interaction, which culminates in formation of stress
fibres. We also demonstrate that, in vascular endothelial cells, thrombin, a
vasoactive substance leading to Rho activation, elicits both FHOD1
phosphorylation and stress fibre formation in a ROCK-dependent manner, and that
FHOD1 depletion by RNA interference impairs thrombin-induced stress fibre
formation. Based on these findings we propose a novel mechanism for activation
of formin-family proteins: ROCK, activated by G protein-coupled receptor ligands
such as thrombin, directly phosphorylates FHOD1 at the C-terminal region, which
renders this formin in the active form, leading to stress fibre formation.
DOI: 10.1038/emboj.2008.7
PMCID: PMC2262041
PMID: 18239683 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26366214
|
1. J Cancer. 2015 Aug 22;6(10):1005-10. doi: 10.7150/jca.12703. eCollection 2015.
Akt and Hippo Pathways in Ewing's Sarcoma Tumors and Their Prognostic
Significance.
Ahmed AA(1), Abedalthagafi M(1), Anwar AE(2), Bui MM(3).
Author information:
(1)1. Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia.
(2)2. Department of Epidemiology and Biostatistics, College of Public Health and
Health Informatics, King Saud Bin Abdulaziz University for Health Sciences,
Riyadh, Saudi Arabia.
(3)3. Department of Anatomic Pathology, Moffitt Cancer Center/University of
South Florida, Tampa, Florida, United States.
BACKGROUND: Ewing's sarcoma tumor is an aggressive malignancy of bone and soft
tissue in children and young adults. Despite advances in modern therapy,
metastasis occurs and results in high mortality. Intracellular molecules Yap,
Akt, mTOR, and Erk are signaling pathway members that regulate the proliferation
of tumor cells.
OBJECTIVE AND METHODS: We studied the immunohistochemical expression of these
proteins in 36 tumor samples from adult and pediatric patients with Ewing's
sarcoma tumors. Patients' age, sex, tumor site, tumor size, clinical stage and
survival (overall and disease-free survival) were collected. Tissue microarrays
slides were stained with antibodies against Yap, Akt, mTOR, and Erk proteins.
RESULTS: Tumors exhibited variable expression of Yap, Akt, mTOR, and Erk (from
negative, low to high), with high levels of expression present in 31%, 53%, 77%
and 0% respectively. Immunohistochemical expression of Akt was associated with
worse overall and disease-free survival (p<0.05). The other biomarkers did not
demonstrate any difference in survival between low versus high expression.
CONCLUSION: Although Yap, Akt, mTOR, and Erk protein are all expressed in
Ewing's sarcoma by immunohistochemistry, only Akt expression is associated with
worse prognosis. Larger studies are needed to verify these results and plan
targeted therapy, particularly against Akt.
DOI: 10.7150/jca.12703
PMCID: PMC4565850
PMID: 26366214
Conflict of interest statement: Conflicts of Interest: None.
|
http://www.ncbi.nlm.nih.gov/pubmed/18287523
|
1. Mol Biol Cell. 2008 May;19(5):2328-38. doi: 10.1091/mbc.e07-10-1086. Epub 2008
Feb 20.
mDia2 induces the actin scaffold for the contractile ring and stabilizes its
position during cytokinesis in NIH 3T3 cells.
Watanabe S(1), Ando Y, Yasuda S, Hosoya H, Watanabe N, Ishizaki T, Narumiya S.
Author information:
(1)Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto
606-8501, Japan.
mDia proteins are mammalian homologues of Drosophila diaphanous and belong to
the formin family proteins that catalyze actin nucleation and polymerization.
Although formin family proteins of nonmammalian species such as Drosophila
diaphanous are essential in cytokinesis, whether and how mDia proteins function
in cytokinesis remain unknown. Here we depleted each of the three mDia isoforms
in NIH 3T3 cells by RNA interference and examined this issue. Depletion of mDia2
selectively increased the number of binucleate cells, which was corrected by
coexpression of RNAi-resistant full-length mDia2. mDia2 accumulates in the
cleavage furrow during anaphase to telophase, and concentrates in the midbody at
the end of cytokinesis. Depletion of mDia2 induced contraction at aberrant sites
of dividing cells, where contractile ring components such as RhoA, myosin,
anillin, and phosphorylated ERM accumulated. Treatment with blebbistatin
suppressed abnormal contraction, corrected localization of the above components,
and revealed that the amount of F-actin at the equatorial region during
anaphase/telophase was significantly decreased with mDia2 RNAi. These results
demonstrate that mDia2 is essential in mammalian cell cytokinesis and that
mDia2-induced F-actin forms a scaffold for the contractile ring and maintains
its position in the middle of a dividing cell.
DOI: 10.1091/mbc.e07-10-1086
PMCID: PMC2366861
PMID: 18287523 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26039999
|
1. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7255-60. doi:
10.1073/pnas.1505917112. Epub 2015 May 26.
Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein
stability.
Qi Q(1), Li DY(2), Luo HR(3), Guan KL(4), Ye K(5).
Author information:
(1)Department of Pathology and Laboratory Medicine, Emory University School of
Medicine, Atlanta, GA 30322;
(2)Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84132;
(3)Department of Pathology and Lab Medicine, Harvard Medical School and
Children's Hospital Boston, Boston, MA 02115;
(4)Department of Pharmacology and Moores Cancer Center, University of California
at San Diego, La Jolla, CA 92037.
(5)Department of Pathology and Laboratory Medicine, Emory University School of
Medicine, Atlanta, GA 30322; kye@emory.edu.
Yes-associated protein (YAP), a transcription coactivator, is the major
downstream effector of the Hippo pathway, which plays a critical role in organ
size control and cancer development. However, how YAP is regulated by
extracellular stimuli in tumorigenesis remains incompletely understood.
Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity
in cancers. Nonetheless, the downstream signaling mediating its oncogenic
effects is not well defined. Here we show that netrin-1 via its transmembrane
receptors, deleted in colorectal cancer and uncoordinated-5 homolog,
up-regulates YAP expression, escalating YAP levels in the nucleus and promoting
cancer cell proliferation and migration. Inactivating netrin-1, deleted in
colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein
levels, abrogating cancer cell progression by netrin-1, whereas knockdown of
mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor
kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway,
has no effect in blocking netrin-1-induced up-regulation of YAP. Netrin-1
stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased
ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence,
our findings support that netrin-1 exerts oncogenic activity through YAP
signaling, providing a mechanism coupling extracellular signals to the nuclear
YAP oncogene.
DOI: 10.1073/pnas.1505917112
PMCID: PMC4466726
PMID: 26039999 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/20513433
|
1. Mol Cell. 2010 May 28;38(4):590-602. doi: 10.1016/j.molcel.2010.02.040.
SWI/SNF has intrinsic nucleosome disassembly activity that is dependent on
adjacent nucleosomes.
Dechassa ML(1), Sabri A, Pondugula S, Kassabov SR, Chatterjee N, Kladde MP,
Bartholomew B.
Author information:
(1)Department of Biochemistry and Molecular Biology, Southern Illinois
University School of Medicine, Carbondale, IL 62901-4413, USA.
Comment in
Mol Cell. 2010 May 28;38(4):484-6. doi: 10.1016/j.molcel.2010.05.005.
The ATP-dependent chromatin remodeling complex SWI/SNF regulates transcription
and has been implicated in promoter nucleosome eviction. Efficient nucleosome
disassembly by SWI/SNF alone in biochemical assays, however, has not been
directly observed. Employing a model system of dinucleosomes rather than
mononucleosomes, we demonstrate that remodeling leads to ordered and efficient
disassembly of one of the two nucleosomes. An H2A/H2B dimer is first rapidly
displaced, and then, in a slower reaction, an entire histone octamer is lost.
Nucleosome disassembly by SWI/SNF did not require additional factors such as
chaperones or acceptors of histones. Observations in single molecules as well as
bulk measurement suggest that a key intermediate in this process is one in which
a nucleosome is moved toward the adjacent nucleosome. SWI/SNF recruited by the
transcriptional activator Gal4-VP16 preferentially mobilizes the proximal
nucleosome and destabilizes the adjacent nucleosome.
Copyright 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2010.02.040
PMCID: PMC3161732
PMID: 20513433 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17235287
|
1. EMBO J. 2007 Feb 7;26(3):730-40. doi: 10.1038/sj.emboj.7601524. Epub 2007 Jan
18.
Activation domains drive nucleosome eviction by SWI/SNF.
Gutiérrez JL(1), Chandy M, Carrozza MJ, Workman JL.
Author information:
(1)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
ATP-dependent chromatin remodeling complexes play a critical role in chromatin
dynamics. A large number of in vitro studies have pointed towards nucleosome
sliding as the principal remodeling outcome of SWI/SNF action, whereas few have
described histone octamer transfer as the principal outcome. In contrast, recent
in vivo studies have linked the activity of SWI/SNF to histone eviction in trans
from gene promoters. In this study, we have found that the chimeric
transcription factor Gal4-VP16 can enhance SWI/SNF histone octamer transfer
activity, resulting in targeted histone eviction from a nucleosome probe. This
effect is dependent on the presence of the activation domain. We observed that
under conditions mimicking the in vivo relative abundance of SWI/SNF with
respect to the total number of nucleosomes in a cell nucleus, the accessibility
of the transcription factor binding site is the first determinant in the
sequence of events leading to nucleosome remodeling. We propose a model
mechanism for this transcription factor-mediated enhancement of SWI/SNF octamer
transfer activity.
DOI: 10.1038/sj.emboj.7601524
PMCID: PMC1794382
PMID: 17235287 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19470761
|
1. Mol Cell Biol. 2009 Aug;29(15):4220-34. doi: 10.1128/MCB.01882-08. Epub 2009
May 26.
An rtt109-independent role for vps75 in transcription-associated nucleosome
dynamics.
Selth LA(1), Lorch Y, Ocampo-Hafalla MT, Mitter R, Shales M, Krogan NJ, Kornberg
RD, Svejstrup JQ.
Author information:
(1)Clare Hall Laboratories, Cancer Research UK London Research Institute,
Blanche Lane, South Mimms, Hertfordshire, U.K.
The histone chaperone Vps75 forms a complex with, and stimulates the activity
of, the histone acetyltransferase Rtt109. However, Vps75 can also be isolated on
its own and might therefore possess Rtt109-independent functions. Analysis of
epistatic miniarray profiles showed that VPS75 genetically interacts with
factors involved in transcription regulation whereas RTT109 clusters with genes
linked to DNA replication/repair. Additional genetic and biochemical experiments
revealed a close relationship between Vps75 and RNA polymerase II. Furthermore,
Vps75 is recruited to activated genes in an Rtt109-independent manner, and its
genome-wide association with genes correlates with transcription rate.
Expression microarray analysis identified a number of genes whose normal
expression depends on VPS75. Interestingly, histone H2B dynamics at some of
these genes are consistent with a role for Vps75 in histone H2A/H2B
eviction/deposition during transcription. Indeed, reconstitution of nucleosome
disassembly using the ATP-dependent chromatin remodeler Rsc and Vps75 revealed
that these proteins can cooperate to remove H2A/H2B dimers from nucleosomes.
These results indicate a role for Vps75 in nucleosome dynamics during
transcription, and importantly, this function appears to be largely independent
of Rtt109.
DOI: 10.1128/MCB.01882-08
PMCID: PMC2715805
PMID: 19470761 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23150908
|
1. N Engl J Med. 2013 Jan 10;368(2):107-16. doi: 10.1056/NEJMoa1211103. Epub 2012
Nov 14.
Variant of TREM2 associated with the risk of Alzheimer's disease.
Jonsson T(1), Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J,
Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I,
Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A,
Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K.
Author information:
(1)deCODE Genetics, Reykjavik, Iceland.
Comment in
N Engl J Med. 2013 Jan 10;368(2):182-4. doi: 10.1056/NEJMe1213157.
Nat Rev Neurol. 2013 Jan;9(1):5. doi: 10.1038/nrneurol.2012.254.
Clin Genet. 2013 Jun;83(6):525-6. doi: 10.1111/cge.12108.
N Engl J Med. 2013 Oct 17;369(16):1568-9. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1564-5. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1565. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1568. doi: 10.1056/NEJMc1306509.
BACKGROUND: Sequence variants, including the ε4 allele of apolipoprotein E, have
been associated with the risk of the common late-onset form of Alzheimer's
disease. Few rare variants affecting the risk of late-onset Alzheimer's disease
have been found.
METHODS: We obtained the genome sequences of 2261 Icelanders and identified
sequence variants that were likely to affect protein function. We imputed these
variants into the genomes of patients with Alzheimer's disease and control
participants and then tested for an association with Alzheimer's disease. We
performed replication tests using case-control series from the United States,
Norway, The Netherlands, and Germany. We also tested for a genetic association
with cognitive function in a population of unaffected elderly persons.
RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the
triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to
result in an R47H substitution, was found to confer a significant risk of
Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI],
2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls
85 years of age or older. We observed the association in additional sample sets
(odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and
replication samples). We also found that carriers of rs75932628-T between the
ages of 80 and 100 years without Alzheimer's disease had poorer cognitive
function than noncarriers (P=0.003).
CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis
of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the
brain, the R47H substitution may lead to an increased predisposition to
Alzheimer's disease through impaired containment of inflammatory processes.
(Funded by the National Institute on Aging and others.).
DOI: 10.1056/NEJMoa1211103
PMCID: PMC3677583
PMID: 23150908 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17088018
|
1. Neurosci Lett. 2007 Jan 10;411(2):133-7. doi: 10.1016/j.neulet.2006.10.029.
Epub 2006 Nov 7.
Absence of TREM2 polymorphisms in patients with Alzheimer's disease and
Frontotemporal Lobar Degeneration.
Fenoglio C(1), Galimberti D, Piccio L, Scalabrini D, Panina P, Buonsanti C,
Venturelli E, Lovati C, Forloni G, Mariani C, Bresolin N, Scarpini E.
Author information:
(1)Department of Neurological Sciences, "Dino Ferrari" Center, University of
Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy.
Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a
genetic syndrome characterized by bone cysts and presenile dementia, named
Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of
frontal regions are features characterizing both NHD and other kinds of
neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD),
and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide
Polymorphisms (SNPs) in TREM2 coding region were screened by allelic
discrimination in a population of probable AD patients as well as FTLD patients
as compared with age-matched controls. In addition, mutation scanning of the
coding region of TREM2 gene was carried out in 7 patients with early onset AD
(EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either
in patients or controls. Moreover, mutation scanning of the five exons of TREM2
failed to detect the presence of novel polymorphisms. These data demonstrate
that TREM2 coding region is highly conserved, implying a crucial role of this
receptor. Further studies, including a functional analysis, are certainly
required to clarify the role of TREM2 in neurodegenerative processes.
DOI: 10.1016/j.neulet.2006.10.029
PMID: 17088018 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19029894
|
1. Nat Struct Mol Biol. 2008 Dec;15(12):1272-7. doi: 10.1038/nsmb.1524. Epub 2008
Nov 23.
Structure of a RSC-nucleosome complex and insights into chromatin remodeling.
Chaban Y(1), Ezeokonkwo C, Chung WH, Zhang F, Kornberg RD, Maier-Davis B, Lorch
Y, Asturias FJ.
Author information:
(1)Department of Cell Biology, The Scripps Research Institute, 10550 North
Torrey Pines Road, La Jolla, California 92037, USA.
ATP-dependent chromatin-remodeling complexes, such as RSC, can reposition, evict
or restructure nucleosomes. A structure of a RSC-nucleosome complex with a
nucleosome determined by cryo-EM shows the nucleosome bound in a central RSC
cavity. Extensive interaction of RSC with histones and DNA seems to destabilize
the nucleosome and lead to an overall ATP-independent rearrangement of its
structure. Nucleosomal DNA appears disordered and largely free to bulge out into
solution as required for remodeling, but the structure of the RSC-nucleosome
complex indicates that RSC is unlikely to displace the octamer from the
nucleosome to which it is bound. Consideration of the RSC-nucleosome structure
and published biochemical information suggests that ATP-dependent DNA
translocation by RSC may result in the eviction of histone octamers from
adjacent nucleosomes.
DOI: 10.1038/nsmb.1524
PMCID: PMC2659406
PMID: 19029894 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15046306
|
1. Syst Appl Microbiol. 2004 Mar;27(2):175-85. doi: 10.1078/072320204322881790.
Use of the genomic signature in bacterial classification and identification.
Coenye T(1), Vandamme P.
Author information:
(1)Laboratorium voor Microbiologie, Ghent University, Gent, Belgium.
Tom.Coenye@UGent.be
In this study we investigated the correlation between dinucleotide relative
abundance values (the genomic signature) obtained from bacterial whole-genome
sequences and two parameters widely used for bacterial classification, 16S rDNA
sequence similarity and DNA-DNA hybridisation values. Twenty-eight completely
sequenced bacterial genomes were included in the study. The correlation between
the genomic signature and DNA-DNA hybridisation values was high and taxa that
showed less than 30% DNA-DNA binding will in general not have dinucleotide
relative abundance dissimilarity (delta*) values below 40. On the other hand,
taxa showing more than 50% DNA-DNA binding will not have delta* values higher
than 17. Our data indicate that the overall correlation between genomic
signature and 16S rDNA sequence similarity is low, except for closely related
organisms (16S rDNA similarity >94%). Statistical analysis of delta* values
between different subgroups of the Proteobacteria indicate that the beta- and
gamma-Proteobacteria are more closely related to each other than to the other
subgroups of the Proteobacteria and that the alpha- and epsilon-Proteobacteria
form clearly separate subgroups. Using the genomic signature we have also
predicted DNA-DNA binding values for fastidious or unculturable endosymbionts
belonging to the genera Rickettsia, Wigglesworthia and Buchnera.
DOI: 10.1078/072320204322881790
PMID: 15046306 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9190805
|
1. J Bacteriol. 1997 Jun;179(12):3899-913. doi: 10.1128/jb.179.12.3899-3913.1997.
Compositional biases of bacterial genomes and evolutionary implications.
Karlin S(1), Mrázek J, Campbell AM.
Author information:
(1)Department of Mathematics, Stanford University, California 94305-2125, USA.
We compare and contrast genome-wide compositional biases and distributions of
short oligonucleotides across 15 diverse prokaryotes that have substantial
genomic sequence collections. These include seven complete genomes (Escherichia
coli, Haemophilus influenzae, Mycoplasma genitalium, Mycoplasma pneumoniae,
Synechocystis sp. strain PCC6803, Methanococcus jannaschii, and Pyrobaculum
aerophilum). A key observation concerns the constancy of the dinucleotide
relative abundance profiles over multiple 50-kb disjoint contigs within the same
genome. (The profile is rhoXY* = fXY*/fX*fY* for all XY, where fX* denotes the
frequency of the nucleotide X and fY* denotes the frequency of the dinucleotide
XY, both computed from the sequence concatenated with its inverted complementary
sequence.) On the basis of this constancy, we refer to the collection [rhoXY*]
as the genome signature. We establish that the differences between [rhoXY*]
vectors of 50-kb sample contigs of different genomes virtually always exceed the
differences between those of the same genomes. Various di- and tetranucleotide
biases are identified. In particular, we find that the dinucleotide CpG=CG is
underrepresented in many thermophiles (e.g., M. jannaschii, Sulfolobus sp., and
M. thermoautotrophicum) but overrepresented in halobacteria. TA is broadly
underrepresented in prokaryotes and eukaryotes, but normal counts appear in
Sulfolobus and P. aerophilum sequences. More than for any other bacterial
genome, palindromic tetranucleotides are underrepresented in H. influenzae. The
M. jannaschii sequence is unprecedented in its extreme underrepresentation of
CTAG tetranucleotides and in the anomalous distribution of CTAG sites around the
genome. Comparative analysis of numbers of long tetranucleotide microsatellites
distinguishes H. influenzae. Dinucleotide relative abundance differences between
bacterial sequences are compared. For example, in these assessments of
differences, the cyanobacteria Synechocystis, Synechococcus, and Anabaena do not
form a coherent group and are as far from each other as general gram-negative
sequences are from general gram-positive sequences. The difference of M.
jannaschii from low-G+C gram-positive proteobacteria is one-half of the
difference from gram-negative proteobacteria. Interpretations and hypotheses
center on the role of the genome signature in highlighting similarities and
dissimilarities across different classes of prokaryotic species, possible
mechanisms underlying the genome signature, the form and level of genome
compositional flux, the use of the genome signature as a chronometer of
molecular phylogeny, and implications with respect to the three putative
eubacterial, archaeal, and eukaryote domains of life and to the origin and early
evolution of eukaryotes.
DOI: 10.1128/jb.179.12.3899-3913.1997
PMCID: PMC179198
PMID: 9190805 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9294192
|
1. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10227-32. doi:
10.1073/pnas.94.19.10227.
Compositional differences within and between eukaryotic genomes.
Karlin S(1), Mrázek J.
Author information:
(1)Department of Mathematics, Stanford University, Stanford, CA 94305-2125, USA.
Eukaryotic genome similarity relationships are inferred using sequence
information derived from large aggregates of genomic sequences. Comparisons
within and between species sample sequences are based on the profile of
dinucleotide relative abundance values (The profile is rho*XY = f*XY/f*Xf*Y for
all XY, where f*X denotes the frequency of the nucleotide X and f*XY denotes the
frequency of the dinucleotide XY, both computed from the sequence concatenated
with its inverted complement). Previous studies with respect to prokaryotes and
this study document that profiles of different DNA sequence samples (sample size
>/=50 kb) from the same organism are generally much more similar to each other
than they are to profiles from other organisms, and that closely related
organisms generally have more similar profiles than do distantly related
organisms. On this basis we refer to the collection (rho*XY) as the genome
signature. This paper identifies rho*XY extremes and compares genome signature
differences for a diverse range of eukaryotic species. Interpretations on the
mechanisms maintaining these profile differences center on genome-wide
replication, repair, DNA structures, and context-dependent mutational biases. It
is also observed that mitochondrial genome signature differences between species
parallel the corresponding nuclear genome signature differences despite large
differences between corresponding mitochondrial and nuclear signatures. The
genome signature differences also have implications for contrasts between
rodents and other mammals, and between monocot and dicot plants, as well as
providing evidence for similarities among fungi and the diversity of protists.
DOI: 10.1073/pnas.94.19.10227
PMCID: PMC23344
PMID: 9294192 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15716010
|
1. Gene. 2005 Feb 14;346:173-85. doi: 10.1016/j.gene.2004.10.021.
The spectrum of genomic signatures: from dinucleotides to chaos game
representation.
Wang Y(1), Hill K, Singh S, Kari L.
Author information:
(1)Department of Computer Science, University of Western Ontario, London,
Ontario, Canada N6A 5B7. ywang@upei.ca
In the post genomic era, access to complete genome sequence data for numerous
diverse species has opened multiple avenues for examining and comparing primary
DNA sequence organization of entire genomes. Previously, the concept of a
genomic signature was introduced with the observation of species-type specific
Dinucleotide Relative Abundance Profiles (DRAPs); dinucleotides were identified
as the subsequences with the greatest bias in representation in a majority of
genomes. Herein, we demonstrate that DRAP is one particular genomic signature
contained within a broader spectrum of signatures. Within this spectrum, an
alternative genomic signature, Chaos Game Representation (CGR), provides a
unique visualization of patterns in sequence organization. A genomic signature
is associated with a particular integer order or subsequence length that
represents a measure of the resolution or granularity in the analysis of primary
DNA sequence organization. We quantitatively explore the organizational
information provided by genomic signatures of different orders through different
distance measures, including a novel Image Distance. The Image Distance and
other existing distance measures are evaluated by comparing the phylogenetic
trees they generate for 26 complete mitochondrial genomes from a diversity of
species. The phylogenetic tree generated by the Image Distance is compatible
with the known relatedness of species. Quantitative evaluation of the spectrum
of genomic signatures may be used to ultimately gain insight into the
determinants and biological relevance of the genome signatures.
DOI: 10.1016/j.gene.2004.10.021
PMID: 15716010 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12171605
|
1. BMC Genomics. 2002 Aug 9;3(1):23. doi: 10.1186/1471-2164-3-23.
Pervasive properties of the genomic signature.
Jernigan RW(1), Baran RH.
Author information:
(1)Department of Mathematics and Statistics, The American University,
Washington, DC 20016, USA. jernigan@american.edu
BACKGROUND: The dinucleotide relative abundance profile can be regarded as a
genomic signature because, despite diversity between species, it varies little
between 50 kilobase or longer windows on a given genome. Both the causes and the
functional significance of this phenomenon could be illuminated by determining
if it persists on smaller scales. The profile is computed from the base step
"odds ratios" that compare dinucleotide frequencies to those expected under the
assumption of stochastic equilibrium (thorough shuffling). Analysis is carried
out on 22 sequences, representing 19 species and comprised of about 53 million
bases all together, to assess stability of the signature in windows ranging in
size from 50 kilobases down to 125 bases.
RESULTS: Dinucleotide relative abundance distance from the global signature is
computed locally for all non-overlapping windows on each sequence. These
distances are log-normally distributed with nearly constant variance and with
means that tend to zero slower than reciprocal square root of window size. The
mean distance within genomes is larger for protist, plant, and human
chromosomes, and smaller for archaea, bacteria, and yeast, for any window size.
CONCLUSIONS: The imprint of the global signature is locally pervasive on all
scales considered in the sequences (either genomes or chromosomes) that were
scanned.
DOI: 10.1186/1471-2164-3-23
PMCID: PMC126251
PMID: 12171605
|
http://www.ncbi.nlm.nih.gov/pubmed/23407992
|
1. Mol Neurobiol. 2013 Aug;48(1):180-5. doi: 10.1007/s12035-013-8424-8. Epub 2013
Feb 14.
TREM2 in Alzheimer's disease.
Jiang T(1), Yu JT, Zhu XC, Tan L.
Author information:
(1)Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical
University, Nanjing, China.
Recent works have demonstrated a rare functional variant (R47H) in triggering
receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein,
increase susceptibility to late-onset Alzheimer's disease (AD), with an odds
ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of
TREM2 was speculated to be the main cause in the pathogenic effects of this risk
variant, and TREM2 is highly expressed in white matter, as well as in the
hippocampus and neocortex, which is partly consistent with the pathological
features reported in AD brain, indicating the possible involvement of TREM2 in
AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress
inflammatory response by repression of microglia-mediated cytokine production
and secretion, which may prevent inflammation-induced bystander damage of
neurons. TREM2 also participates in the regulation of phagocytic pathways that
are responsible for the removal of neuronal debris. In this article, we review
the recent epidemiological findings of TREM2 that related with late-onset AD and
speculate the possible roles of TREM2 in progression of this disease. Based on
the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2
might provide new opportunities for AD treatment.
DOI: 10.1007/s12035-013-8424-8
PMID: 23407992 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24008565
|
1. Nat Struct Mol Biol. 2013 Sep;20(9):1026-32. doi: 10.1038/nsmb.2648.
Nucleosome sliding mechanisms: new twists in a looped history.
Mueller-Planitz F(1), Klinker H, Becker PB.
Author information:
(1)1] Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität, Munich,
Germany. [2] Center for Integrated Protein Science Munich,
Ludwig-Maximilians-Universität, Munich, Germany.
Nucleosomes, the basic organizational units of chromatin, package and regulate
eukaryotic genomes. ATP-dependent nucleosome-remodeling factors endow chromatin
with structural flexibility by promoting assembly or disruption of nucleosomes
and the exchange of histone variants. Furthermore, most remodeling factors
induce nucleosome movements through sliding of histone octamers on DNA. We
summarize recent progress toward unraveling the basic nucleosome sliding
mechanism and the interplay of the remodelers' DNA translocases with accessory
domains. Such domains optimize and regulate the basic sliding reaction and
exploit sliding to achieve diverse structural effects, such as nucleosome
positioning or eviction, or the regular spacing of nucleosomes in chromatin.
DOI: 10.1038/nsmb.2648
PMID: 24008565 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10430918
|
1. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9190-5. doi:
10.1073/pnas.96.16.9190.
A chimeric prokaryotic ancestry of mitochondria and primitive eukaryotes.
Karlin S(1), Brocchieri L, Mrázek J, Campbell AM, Spormann AM.
Author information:
(1)Department of Mathematics, Stanford University, Stanford, CA 94305-2125, USA.
We provide data and analysis to support the hypothesis that the ancestor of
animal mitochondria (Mt) and many primitive amitochondrial (a-Mt) eukaryotes was
a fusion microbe composed of a Clostridium-like eubacterium and a
Sulfolobus-like archaebacterium. The analysis is based on several observations:
(i) The genome signatures (dinucleotide relative abundance values) of
Clostridium and Sulfolobus are compatible (sufficiently similar) and each has
significantly more similarity in genome signatures with animal Mt sequences than
do all other available prokaryotes. That stable fusions may require
compatibility in genome signatures is suggested by the compatibility of plasmids
and hosts. (ii) The expanded energy metabolism of the fusion organism was
strongly selective for cementing such a fusion. (iii) The molecular apparatus of
endospore formation in Clostridium serves as raw material for the development of
the nucleus and cytoplasm of the eukaryotic cell.
DOI: 10.1073/pnas.96.16.9190
PMCID: PMC17755
PMID: 10430918 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18953039
|
1. Nucleic Acids Res. 2008 Dec;36(22):e147. doi: 10.1093/nar/gkn753. Epub 2008
Oct 25.
Using Mahalanobis distance to compare genomic signatures between bacterial
plasmids and chromosomes.
Suzuki H(1), Sota M, Brown CJ, Top EM.
Author information:
(1)Department of Biological Sciences, University of Idaho, Moscow, ID 83844,
USA.
Plasmids are ubiquitous mobile elements that serve as a pool of many host
beneficial traits such as antibiotic resistance in bacterial communities. To
understand the importance of plasmids in horizontal gene transfer, we need to
gain insight into the 'evolutionary history' of these plasmids, i.e. the range
of hosts in which they have evolved. Since extensive data support the proposal
that foreign DNA acquires the host's nucleotide composition during long-term
residence, comparison of nucleotide composition of plasmids and chromosomes
could shed light on a plasmid's evolutionary history. The average absolute
dinucleotide relative abundance difference, termed delta-distance, has been
commonly used to measure differences in dinucleotide composition, or 'genomic
signature', between bacterial chromosomes and plasmids. Here, we introduce the
Mahalanobis distance, which takes into account the variance-covariance structure
of the chromosome signatures. We demonstrate that the Mahalanobis distance is
better than the delta-distance at measuring genomic signature differences
between plasmids and chromosomes of potential hosts. We illustrate the
usefulness of this metric for proposing candidate long-term hosts for plasmids,
focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from
Escherichia coli O157:H7, as well as the broad host range multi-drug resistance
plasmid pB10 from an unknown host.
DOI: 10.1093/nar/gkn753
PMCID: PMC2602791
PMID: 18953039 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7809131
|
1. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12837-41. doi:
10.1073/pnas.91.26.12837.
Heterogeneity of genomes: measures and values.
Karlin S(1), Ladunga I, Blaisdell BE.
Author information:
(1)Department of Mathematics, Stanford University, CA 94305-2125.
Genomic homogeneity is investigated for a broad base of DNA sequences in terms
of dinucleotide relative abundance distances (abbreviated delta-distances) and
of oligonucleotide compositional extremes. It is shown that delta-distances
between different genomic sequences in the same species are low, only about 2 or
3 times the distance found in random DNA, and are generally smaller than the
between-species delta-distances. Extremes in short oligonucleotides include
underrepresentation of TpA and overrepresentation of GpC in most temperate
bacteriophage sequences; underrepresentation of CTAG in most eubacterial
genomes; underrepresentation of GATC in most bacteriophage; CpG suppression in
vertebrates, in all animal mitochondrial genomes, and in many thermophilic
bacterial sequences; and overrepresentation of GpG/CpC in all animal
mitochondrial sets and chloroplast genomes. Interpretations center on DNA
structures (dinucleotide stacking energies, DNA curvature and superhelicity,
nucleosome organization), context-dependent mutational events, methylation
effects, and processes of replication and repair.
DOI: 10.1073/pnas.91.26.12837
PMCID: PMC45535
PMID: 7809131 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10066522
|
1. Curr Opin Microbiol. 1998 Oct;1(5):598-610. doi:
10.1016/s1369-5274(98)80095-7.
Global dinucleotide signatures and analysis of genomic heterogeneity.
Karlin S(1).
Author information:
(1)Department of Mathematics, Stanford University, Stanford, CA 94305-2125, USA.
Early biochemical experiments measuring nearest neighbor frequencies established
that the set of dinucleotide relative abundance values (dinucleotide biases) is
a remarkably stable property of the DNA of an organism. Analyses of currently
available genomic sequence data have extended these earlier results, showing
that the dinucleotide biases evaluated for successive 50 kb segments of a genome
are significantly more similar to each other than to those of sequences from
more distant organisms. From this perspective, the set of dinucleotide biases
constitutes a 'genomic signature' that can discriminate sequences from different
organisms. The dinucleotide biases appear to reflect species-specific properties
of DNA stacking energies, modification, replication, and repair mechanisms. The
genomic signature is useful for detecting pathogenicity islands in bacterial
genomes.
DOI: 10.1016/s1369-5274(98)80095-7
PMID: 10066522 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19933844
|
1. Mol Cell Biol. 2010 Feb;30(3):657-74. doi: 10.1128/MCB.01117-09. Epub 2009 Nov
23.
Fission yeast Iec1-ino80-mediated nucleosome eviction regulates nucleotide and
phosphate metabolism.
Hogan CJ(1), Aligianni S, Durand-Dubief M, Persson J, Will WR, Webster J,
Wheeler L, Mathews CK, Elderkin S, Oxley D, Ekwall K, Varga-Weisz PD.
Author information:
(1)Chromatin and Gene Expression, Babraham Institute, Babraham, Cambridge CB22
3AT, UK.
Ino80 is an ATP-dependent nucleosome-remodeling enzyme involved in
transcription, replication, and the DNA damage response. Here, we characterize
the fission yeast Ino80 and find that it is essential for cell viability. We
show that the Ino80 complex from fission yeast mediates ATP-dependent nucleosome
remodeling in vitro. The purification of the Ino80-associated complex identified
a highly conserved complex and the presence of a novel zinc finger protein with
similarities to the mammalian transcriptional regulator Yin Yang 1 (YY1) and
other members of the GLI-Krüppel family of proteins. Deletion of this Iec1
protein or the Ino80 complex subunit arp8, ies6, or ies2 causes defects in DNA
damage repair, the response to replication stress, and nucleotide metabolism. We
show that Iec1 is important for the correct expression of genes involved in
nucleotide metabolism, including the ribonucleotide reductase subunit cdc22 and
phosphate- and adenine-responsive genes. We find that Ino80 is recruited to a
large number of promoter regions on phosphate starvation, including those of
phosphate- and adenine-responsive genes that depend on Iec1 for correct
expression. Iec1 is required for the binding of Ino80 to target genes and
subsequent histone loss at the promoter and throughout the body of these genes
on phosphate starvation. This suggests that the Iec1-Ino80 complex promotes
transcription through nucleosome eviction.
DOI: 10.1128/MCB.01117-09
PMCID: PMC2812234
PMID: 19933844 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18836177
|
1. Mol Cell Proteomics. 2009 Feb;8(2):258-72. doi: 10.1074/mcp.M800060-MCP200.
Epub 2008 Oct 3.
Analysis of protein processing by N-terminal proteomics reveals novel
species-specific substrate determinants of granzyme B orthologs.
Van Damme P(1), Maurer-Stroh S, Plasman K, Van Durme J, Colaert N, Timmerman E,
De Bock PJ, Goethals M, Rousseau F, Schymkowitz J, Vandekerckhove J, Gevaert K.
Author information:
(1)Department of Medical Protein Research, Flanders Institute for Biotechnology
(VIB), Ghent, Belgium.
Using a targeted peptide-centric proteomics approach, we performed in vitro
protease substrate profiling of the apoptotic serine protease granzyme B
resulting in the delineation of more than 800 cleavage sites in 322 human and
282 mouse substrates, encompassing the known substrates Bid, caspase-7, lupus La
protein, and fibrillarin. Triple SILAC (stable isotope labeling by amino acids
in cell culture) further permitted intra-experimental evaluation of
species-specific variations in substrate selection by the mouse or human
granzyme B ortholog. For the first time granzyme B substrate specificities were
directly mapped on a proteomic scale and revealed unknown cleavage
specificities, uncharacterized extended specificity profiles, and macromolecular
determinants in substrate selection that were confirmed by molecular modeling.
We further tackled a substrate hunt in an in vivo setup of natural killer
cell-mediated cell death confirming in vitro characterized granzyme B cleavages
next to several other unique and hitherto unreported proteolytic events in
target cells.
DOI: 10.1074/mcp.M800060-MCP200
PMID: 18836177 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23294434
|
1. Curr Comput Aided Drug Des. 2013 Mar;9(1):108-17.
Biomedical data integration in computational drug design and bioinformatics.
Seoane JA(1), Aguiar-Pulido V, Munteanu CR, Rivero D, Rabunal JR, Dorado J,
Pazos A.
Author information:
(1)Department of Information and Communication Technologies, Computer Science
School, University of A Coruña, Spain.
In recent years, in the post genomic era, more and more data is being generated
by biological high throughput technologies, such as proteomics and
transcriptomics. This omics data can be very useful, but the real challenge is
to analyze all this data, as a whole, after integrating it. Biomedical data
integration enables making queries to different, heterogeneous and distributed
biomedical data sources. Data integration solutions can be very useful not only
in the context of drug design, but also in biomedical information retrieval,
clinical diagnosis, system biology, etc. In this review, we analyze the most
common approaches to biomedical data integration, such as federated databases,
data warehousing, multi-agent systems and semantic technology, as well as the
solutions developed using these approaches in the past few years.
PMID: 23294434 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23964590
|
1. J Proteome Res. 2013 Sep 6;12(9):3823-30. doi: 10.1021/pr400435d. Epub 2013
Aug 21.
Novel highly sensitive, specific, and straightforward strategy for comprehensive
N-terminal proteomics reveals unknown substrates of the mitochondrial peptidase
Icp55.
Venne AS(1), Vögtle FN, Meisinger C, Sickmann A, Zahedi RP.
Author information:
(1)Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
We present a novel straightforward method for enrichment of N-terminal peptides,
utilizing charge-based fractional diagonal chromatography (ChaFRADIC). Our
method is robust, easy to operate, fast, specific, and more sensitive than
existing methods, enabling the differential quantitation of 1459 nonredundant
N-terminal peptides between two S. cerevisiae samples within 10 h of LC-MS,
starting from only 50 μg of protein per condition and analyzing only 40% of the
obtained fractions. Using ChaFRADIC we compared mitochondrial proteins from
wild-type and icp55Δ yeast (30 μg each). Icp55 is an intermediate cleaving
peptidase, which, following mitochondrial processing peptidase (MPP)-dependent
cleavage of signal sequences, removes a single amino acid from a specific set of
proteins according to the N-end rule. Using ChaFRADIC we identified 36 icp55
substrates, 14 of which were previously unknown, expanding the set of known
icp55 substrates to a total of 52 proteins. Interestingly, a novel substrate,
Isa2, is likely processed by Icp55 in two consecutive steps and thus might
represent the first example of a triple processing event in a mitochondrial
precursor protein. Thus, ChaFRADIC is a powerful and practicable tool for
protease and peptidase research, providing the sensitivity to characterize even
samples that can be obtained only in small quantities.
DOI: 10.1021/pr400435d
PMID: 23964590 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23287290
|
1. Curr Opin Chem Biol. 2013 Feb;17(1):34-40. doi: 10.1016/j.cbpa.2012.12.007.
Epub 2013 Jan 1.
Glycomics meets genomics, epigenomics and other high throughput omics for system
biology studies.
Zoldoš V(1), Horvat T, Lauc G.
Author information:
(1)University of Zagreb, Faculty of Science, Zagreb, Croatia.
Majority of eukaryotic proteins are glycosylated and their glycan moieties have
numerous important structural, functional and regulatory roles. Because of
structural complexity of glycans and technological limitations glycomics, and
particularly glycoproteomics was not able to follow rapid progress in genomics
and proteomics over last 30 years. However, the field of glycan has been
progressing rapidly and first large-scale studies of the glycome have been
completed recently. These studies have revealed significant differences in
glycome composition between individuals, which may contribute to the human
phenotypic variability. The current state-of-the-art in high-throughput
glycomics and its integration with genomics, epigenomics and lipidomics is
reviewed in this article.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cbpa.2012.12.007
PMID: 23287290 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26199863
|
1. FEBS Open Bio. 2015 Jun 22;5:542-9. doi: 10.1016/j.fob.2015.06.007.
eCollection 2015.
Small molecules inhibiting the nuclear localization of YAP/TAZ for
chemotherapeutics and chemosensitizers against breast cancers.
Oku Y(1), Nishiya N(1), Shito T(1), Yamamoto R(1), Yamamoto Y(1), Oyama C(1),
Uehara Y(1).
Author information:
(1)Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical
University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho,
Shiwa-gun, Iwate 028-3694, Japan.
YAP and TAZ oncoproteins confer malignancy and drug resistance to various cancer
types. We screened for small molecules that inhibit the nuclear localization of
YAP/TAZ. Dasatinib, statins and pazopanib inhibited the nuclear localization and
target gene expression of YAP and TAZ. All three drugs induced phosphorylation
of YAP and TAZ, and pazopanib induced proteasomal degradation of YAP/TAZ. The
sensitivities to these drugs are correlated with dependence on YAP/TAZ in breast
cancer cell lines. Combinations of these compounds with each other or with other
anti-cancer drugs efficiently reduced cell proliferation of YAP/TAZ-dependent
breast cancer cells. These results suggest that these drugs can be therapeutics
and chemosensitizers for YAP/TAZ-dependent breast cancers.
DOI: 10.1016/j.fob.2015.06.007
PMCID: PMC4506957
PMID: 26199863
|
http://www.ncbi.nlm.nih.gov/pubmed/23745983
|
1. J Proteome Res. 2013 Jul 5;12(7):3277-87. doi: 10.1021/pr400127j. Epub 2013
Jun 19.
Improved N(α)-acetylated peptide enrichment following dimethyl labeling and SCX.
Chen SH(1), Chen CR, Chen SH, Li DT, Hsu JL.
Author information:
(1)Department of Biological Science and Technology, National Pingtung University
of Science and Technology, Pingtung, Taiwan.
Protein N-terminal acetylation is one of the most common modifications occurring
co- and post-translationally on either eukaryote or prokaryote proteins.
However, compared to other protein modifications, the physiological role of
protein N-terminal acetylation is relatively unclear. To explore the biological
functions of protein N-terminal acetylation, a robust and large-scale method for
qualitative and quantitative analysis of this modification is required.
Enrichment of N(α)-acetylated peptides or depletion of the free N-terminal and
internal tryptic peptides prior to analysis by mass spectrometry are necessary
based on current technologies. This study demonstrated a simple strong cation
exchange (SCX) fractionation method to selectively enrich N(α)-acetylated
tryptic peptides via dimethyl labeling without the need for tedious protective
labeling and depleting procedures. This method was introduced for the
comprehensive analysis of N-terminal acetylated proteins from HepG2 cells.
Several hundred N-terminal acetylation sites were readily identified in a single
SCX flow-through fraction. Moreover, the N(α)-acetylated peptides of some
protein isoforms were simultaneously observed in the SCX flow-through fraction,
which indicated that this approach can be utilized to discriminate protein
isoforms with very similar full sequences but different N-terminal sequences,
such as β-actin/γ-actin, ERK1/ERK2, α-centractin/β-centractin, and ADP/ATP
translocase 2 and 3. Compared to other methods, this method is relatively simple
and can be directly implemented in a two-dimensional separation (SCX-RP)-mass
spectrometry scheme for quantitative N-terminal proteomics using stable-isotope
dimethyl labeling.
DOI: 10.1021/pr400127j
PMID: 23745983 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20627866
|
1. Mol Cell Proteomics. 2010 Oct;9(10):2327-33. doi: 10.1074/mcp.M110.001271.
Epub 2010 Jul 13.
A quantitative proteomics design for systematic identification of protease
cleavage events.
Impens F(1), Colaert N, Helsens K, Ghesquière B, Timmerman E, De Bock PJ, Chain
BM, Vandekerckhove J, Gevaert K.
Author information:
(1)Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium.
We present here a novel proteomics design for systematic identification of
protease cleavage events by quantitative N-terminal proteomics, circumventing
the need for time-consuming manual validation. We bypass the singleton detection
problem of protease-generated neo-N-terminal peptides by introducing
differential isotopic proteome labeling such that these substrate reporter
peptides are readily distinguished from all other N-terminal peptides. Our
approach was validated using the canonical human caspase-3 protease and further
applied to mouse cathepsin D and E substrate processing in a mouse dendritic
cell proteome, identifying the largest set of protein protease substrates ever
reported and gaining novel insight into substrate specificity differences of
these cathepsins.
DOI: 10.1074/mcp.M110.001271
PMCID: PMC2953924
PMID: 20627866 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26557869
|
1. Evid Based Complement Alternat Med. 2015;2015:983139. doi:
10.1155/2015/983139. Epub 2015 Oct 19.
Recent Advance in Applications of Proteomics Technologies on Traditional Chinese
Medicine Research.
Ji Q(1), Zhu F(2), Liu X(3), Li Q(3), Su SB(4).
Author information:
(1)Research Center for Traditional Chinese Medicine Complexity System, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China ; Department
of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional
Chinese Medicine, Shanghai 201203, China.
(2)Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028,
China.
(3)Department of Medical Oncology, Shuguang Hospital, Shanghai University of
Traditional Chinese Medicine, Shanghai 201203, China.
(4)Research Center for Traditional Chinese Medicine Complexity System, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China.
Proteomics technology, a major component of system biology, has gained
comprehensive attention in the area of medical diagnosis, drug development, and
mechanism research. On the holistic and systemic theory, proteomics has a
convergence with traditional Chinese medicine (TCM). In this review, we
discussed the applications of proteomic technologies in diseases-TCM syndrome
combination researches. We also introduced the proteomic studies on the in vivo
and in vitro effects and underlying mechanisms of TCM treatments using Chinese
herbal medicine (CHM), Chinese herbal formula (CHF), and acupuncture.
Furthermore, the combined studies of proteomics with other "-omics" technologies
in TCM were also discussed. In summary, this report presents an overview of the
recent advances in the application of proteomic technologies in TCM studies and
sheds a light on the future global and further research on TCM.
DOI: 10.1155/2015/983139
PMCID: PMC4629032
PMID: 26557869
|
http://www.ncbi.nlm.nih.gov/pubmed/23137709
|
1. J Proteomics. 2013 Jan 14;78:558-77. doi: 10.1016/j.jprot.2012.10.023. Epub
2012 Nov 6.
Meat science: From proteomics to integrated omics towards system biology.
D'Alessandro A(1), Zolla L.
Author information:
(1)Department of Ecological and Biological Sciences, University of Tuscia, Largo
dell'Università, snc, 01100 Viterbo, Italy.
Since the main ultimate goal of farm animal raising is the production of
proteins for human consumption, research tools to investigate proteins play a
major role in farm animal and meat science. Indeed, proteomics has been applied
to the field of farm animal science to monitor in vivo performances of livestock
animals (growth performances, fertility, milk quality etc.), but also to further
our understanding of the molecular processes at the basis of meat quality, which
are largely dependent on the post mortem biochemistry of the muscle, often in a
species-specific way. Post mortem alterations to the muscle proteome reflect the
biological complexity of the process of "muscle to meat conversion," a process
that, despite decades of advancements, is all but fully understood. This is
mainly due to the enormous amounts of variables affecting meat tenderness per
se, including biological factors, such as animal species, breed
specific-characteristic, muscle under investigation. However, it is rapidly
emerging that the tender meat phenotype is not only tied to genetics (livestock
breeding selection), but also to extrinsic factors, such as the rearing
environment, feeding conditions, physical activity, administration of hormonal
growth promotants, pre-slaughter handling and stress, post mortem handling. From
this intricate scenario, biochemical approaches and systems-wide integrated
investigations (metabolomics, transcriptomics, interactomics, phosphoproteomics,
mathematical modeling), which have emerged as complementary tools to proteomics,
have helped establishing a few milestones in our understanding of the events
leading from muscle to meat conversion. The growing integration of omics
disciplines in the field of systems biology will soon contribute to take further
steps forward.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jprot.2012.10.023
PMID: 23137709 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23369275
|
1. J Biosci Bioeng. 2013 Jun;115(6):579-89. doi: 10.1016/j.jbiosc.2012.12.007.
Epub 2013 Jan 29.
Current metabolomics: practical applications.
Putri SP(1), Nakayama Y, Matsuda F, Uchikata T, Kobayashi S, Matsubara A,
Fukusaki E.
Author information:
(1)Department of Biotechnology, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
The field of metabolomics continues to grow rapidly over the last decade and has
been proven to be a powerful technology in predicting and explaining complex
phenotypes in diverse biological systems. Metabolomics complements other omics,
such as transcriptomics and proteomics and since it is a 'downstream' result of
gene expression, changes in the metabolome is considered to best reflect the
activities of the cell at a functional level. Thus far, metabolomics might be
the sole technology capable of detecting complex, biologically essential
changes. As one of the omics technology, metabolomics has exciting applications
in varied fields, including medical science, synthetic biology, medicine, and
predictive modeling of plant, animal and microbial systems. In addition,
integrated applications with genomics, transcriptomics, and proteomics provide
greater understanding of global system biology. In this review, we discuss
recent applications of metabolomics in microbiology, plant, animal, food, and
medical science.
Copyright © 2013. Published by Elsevier B.V.
DOI: 10.1016/j.jbiosc.2012.12.007
PMID: 23369275 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24957891
|
1. Metabolites. 2013 Feb 4;3(1):72-100. doi: 10.3390/metabo3010072.
Recent applications of metabolomics toward cyanobacteria.
Schwarz D(1), Orf I(2), Kopka J(3), Hagemann M(4).
Author information:
(1)Institut Biowissenschaften, Pflanzenphysiologie, Universität Rostock,
Albert-Einstein-Str. 3, D-18059 Rostock, Germany. doreen.schwarz@uni-rostock.de.
(2)Max-Planck-Institut für Molekulare Pflanzenphysiologie, Am Mühlenberg 1,
14476 Golm, Germany. orf@mpimp-golm.mpg.de.
(3)Max-Planck-Institut für Molekulare Pflanzenphysiologie, Am Mühlenberg 1,
14476 Golm, Germany. kopka@mpimp-golm.mpg.de.
(4)Institut Biowissenschaften, Pflanzenphysiologie, Universität Rostock,
Albert-Einstein-Str. 3, D-18059 Rostock, Germany.
martin.hagemann@uni-rostock.de.
Our knowledge on cyanobacterial molecular biology increased tremendously by the
application of the "omics" techniques. Only recently, metabolomics was applied
systematically to model cyanobacteria. Metabolomics, the quantitative estimation
of ideally the complete set of cellular metabolites, is particularly well suited
to mirror cellular metabolism and its flexibility under diverse conditions.
Traditionally, small sets of metabolites are quantified in targeted metabolome
approaches. The development of separation technologies coupled to
mass-spectroscopy- or nuclear-magnetic-resonance-based identification of low
molecular mass molecules presently allows the profiling of hundreds of
metabolites of diverse chemical nature. Metabolome analysis was applied to
characterize changes in the cyanobacterial primary metabolism under diverse
environmental conditions or in defined mutants. The resulting lists of
metabolites and their steady state concentrations in combination with
transcriptomics can be used in system biology approaches. The application of
stable isotopes in fluxomics, i.e. the quantitative estimation of carbon and
nitrogen fluxes through the biochemical network, has only rarely been applied to
cyanobacteria, but particularly this technique will allow the making of kinetic
models of cyanobacterial systems. The further application of metabolomics in the
concert of other "omics" technologies will not only broaden our knowledge, but
will also certainly strengthen the base for the biotechnological application of
cyanobacteria.
DOI: 10.3390/metabo3010072
PMCID: PMC3901253
PMID: 24957891
|
http://www.ncbi.nlm.nih.gov/pubmed/11509578
|
1. J Biol Chem. 2001 Oct 19;276(42):39290-4. doi: 10.1074/jbc.M107026200. Epub
2001 Aug 16.
mDia-interacting protein acts downstream of Rho-mDia and modifies Src activation
and stress fiber formation.
Satoh S(1), Tominaga T.
Author information:
(1)Department of Molecular and Cell Biology, Dokkyo University School of
Medicine, Tochigi 321-0293, Japan.
The formin homology protein mDia is a Rho GTPase effector protein that
participates in stress fiber formation, cytokinesis, and transcriptional
activation of the serum response factor. Although the function of another
effector of Rho, Rho-associated kinase, is well established, relatively little
is known about the functional mechanism and the downstream targets of mDia. Our
recent report of a Rho-mDia-Src-tyrosine kinase pathway suggested an important
role for mDia in cell adhesion turnover. We identified a new mDia-interacting
protein which is expressed ubiquitously. The new protein mainly binds to the
proline-rich region of mDia through its Src homology 3 domain and also binds to
Grb2 through its proline-rich domain. The protein is localized at the cell
periphery and membrane ruffles and co-localizes with mDia. Co-expression of vSrc
and the mDia-interacting protein induces significant morphological changes at
focal contacts and activation of vSrc. Furthermore, we found that the
mDia-interacting protein plays an important role in stress fiber formation
induced by active mDia1. Our results suggest that this new protein regulates
actin polymerization and cell adhesion turnover in the downstream portion of the
Rho-mDia pathway by interacting with Grb2 and Src.
DOI: 10.1074/jbc.M107026200
PMID: 11509578 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16361707
|
1. J Biol Chem. 2006 Feb 17;281(7):4300-7. doi: 10.1074/jbc.M510277200. Epub 2005
Dec 18.
The basic region of the diaphanous-autoregulatory domain (DAD) is required for
autoregulatory interactions with the diaphanous-related formin inhibitory
domain.
Wallar BJ(1), Stropich BN, Schoenherr JA, Holman HA, Kitchen SM, Alberts AS.
Author information:
(1)Chemistry Department and Cell and Molecular Biology Program, Grand Valley
State University, Allendale, Michigan 49401-9403, USA.
Mammalian diaphanous-related (mDia) formins act as Rho GTPase effectors during
cytoskeletal remodeling. Rho binding to mDia amino-terminal GTPase-binding
domains (GBDs) causes the adjacent Dia-inhibitory domain (DID) to release the
carboxyl-terminal Dia-autoregulatory (DAD) domain that flanks the formin
homology-2 (FH2) domain. The release of DAD allows the FH2 domain to then
nucleate and elongate nonbranched actin filaments. DAD, initially discovered as
a region of homology shared between a phylogenetically divergent set of formin
proteins, is comprised of a core motif, MDXLLXL, and an adjacent region is
comprised of numerous basic residues, typically RRKR in the mDia family. Here,
we show that these specific amino acids within the basic region of DAD
contribute to the binding of DID and therefore the maintenance of the mDia
autoregulatory mechanism. In addition, expression of full-length versions of
mDia2 containing amino acid substitutions in either the DAD core or basic
regions causes profound changes in the F-actin architecture, including the
formation of filopodia-like structures that rapidly elongate from the cell edge.
These studies further refine our understanding of the molecular contribution of
DAD to mDia control and the role of mDia2 in the assembly of membrane
protrusions.
DOI: 10.1074/jbc.M510277200
PMID: 16361707 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10629846
|
1. Nihon Yakurigaku Zasshi. 1999 Oct;114 Suppl 1:1P-5P. doi:
10.1254/fpj.114.supplement_1.
[Cellular functions & pharmacological manipulations of the small GTPase Rho &
Rho effectors].
[Article in Japanese]
Narumiya S(1).
Author information:
(1)Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
Rho is a member of the Ras-related family of small molecular weight GTP-binding
proteins, and works as a molecular switch by shuttling between the GDP-bound
inactive form and the GTP-bound active form. Cellular functions of Rho have been
studied by two ways; one is to express or microinject constitutively active Rho
mutants in cells to identify the active phenotype of Rho, and the other is to
use botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho
in cells to find out phenotypes of Rho inactivation. These analyses have
revealed that Rho is involved in cell to substratum adhesion and motility, cell
contraction and cytokinesis through the reorganization of the actincytoskeleton
and modulation of its activity. These actions of Rho are mediated by downstream
Rho effectors. Several putative Rho effectors have been isolated on the basis of
their selective binding to the GTP-bound form of Rho. Among them, the ROCK
family of Rho-associated serine/threonine protein kinases inactivates cofilin
and myosin phosphatase to induce stabilization of filamentous actin and increase
in the actomyosin-based contractility. mDia binds profilin likely to promote
actin polymerization. Thus, these effectors in combination are supposed to work
in organization of various forms of the actin cytoskeleton. Furthermore,
analyses using a ROCK specific inhibitor Y-27632 have suggested that the
Rho-ROCK pathway works in contractions of vascular and bronchial smooth muscles
under various pathological conditions and is involved in malignant cell
transformation and tumor invasion and metastasis.
DOI: 10.1254/fpj.114.supplement_1
PMID: 10629846 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23256674
|
1. Expert Rev Proteomics. 2012 Dec;9(6):635-48. doi: 10.1586/epr.12.61.
Deciphering the single-cell omic: innovative application for translational
medicine.
Mannello F(1), Ligi D, Magnani M.
Author information:
(1)Department of Biomolecular Sciences, Section of Clinical Biochemistry, Unit
of Cell Biology, University Carlo Bo, Via O Ubaldini 7, 61029 Urbino (PU),
Italy. ferdinando.mannello@uniurb.it
Traditional technologies to investigate system biology are limited by the
detection of parameters resulting from the averages of large populations of
cells, missing cells produced in small numbers, and attempting to uniform the
heterogeneity. The advent of proteomics and genomics at a single-cell level has
set the basis for an outstanding improvement in analytical technology and data
acquisition. It has been well demonstrated that cellular heterogeneity is
closely related to numerous stochastic transcriptional events leading to
variations in patterns of expression among single genetically identical cells.
The new-generation technology of single-cell analysis is able to better
characterize a cell's population, identifying and differentiating outlier cells,
in order to provide both a single-cell experiment and a corresponding bulk
measurement, through the identification, quantification and characterization of
all system biology aspects (genomics, transcriptomics, proteomics, metabolomics,
degradomics and fluxomics). The movement of omics into single-cell analysis
represents a significant and outstanding shift.
DOI: 10.1586/epr.12.61
PMID: 23256674 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22309662
|
1. Expert Rev Vaccines. 2012 Feb;11(2):133-44. doi: 10.1586/erv.11.177.
Targeting EGF receptor variant III: tumor-specific peptide vaccination for
malignant gliomas.
Del Vecchio CA(1), Li G, Wong AJ.
Author information:
(1)Stanford University, 1201 Welch Road, MSLS P105, Stanford, CA 94305, USA.
Glioblastoma multiforme (GBM) is the most common and deadly of the human brain
cancers. The EGF receptor is often amplified in GBM and provides a potential
therapeutic target. However, targeting the normal receptor is complicated by its
nearly ubiquitous and high level of expression in certain tissues. A naturally
occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively
active variant originally identified in a high percentage of brain cancer cases,
and more importantly is rarely found in normal tissue. A peptide vaccine,
rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon
1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy
in preclinical models. Recent Phase II clinical trials in patients with newly
diagnosed GBM have shown EGFRvIII-specific immune responses and significantly
increased time to progression and overall survival in those receiving vaccine
therapy, as compared with published results for standard of care. Rindopepimut
therefore represents a very promising therapy for patients with GBM.
DOI: 10.1586/erv.11.177
PMID: 22309662 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21154166
|
1. Curr Opin Mol Ther. 2010 Dec;12(6):741-54.
Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the
potential treatment of glioblastoma multiforme.
Del Vecchio CA(1), Wong AJ.
Author information:
(1)Stanford University, 300 Pasteur Drive, Edwards R213, Stanford, CA 94305,
USA.
Celldex Therapeutics is developing rindopepimut (CDX-110), a 14-mer injectable
peptide vaccine for the potential treatment of glioblastoma multiforme (GBM).
Rindopepimut specifically targets a novel junctional epitope of the EGFR
deletion mutant EGFRvIII, which is a constitutively active receptor that is
expressed in approximately 60 to 70% of patients with GBM. EGFRvIII expression
is correlated with worse prognosis and reduced overall survival. Importantly,
EGFRvIII is not expressed in normal brain tissue, making it an excellent
therapeutic target. Preclinical studies demonstrated lasting tumor regression
and increased survival times, as well as efficient generation of
EGFRvIII-specific humoral and cellular immune responses, in animals expressing
EGFRvIII and vaccinated with rindopepimut. Phase I and II clinical trials in
patients with GBM demonstrated significantly increased median time to
progression and overall survival time in those vaccinated with rindopepimut
compared with matched historical controls. Only limited side effects have been
observed in patients. Given these results, rindopepimut is an extremely
promising therapy for patients with GBM. Phase I and II clinical trials in
patients with GBM were ongoing at the time of publication. In the future, it may
be beneficial to combine rindopepimut with other treatment modalities to further
prolong survival.
PMID: 21154166 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18159245
|
1. PLoS One. 2007 Dec 26;2(12):e1362. doi: 10.1371/journal.pone.0001362.
Noncompaction of the ventricular myocardium is associated with a de novo
mutation in the beta-myosin heavy chain gene.
Budde BS(1), Binner P, Waldmüller S, Höhne W, Blankenfeldt W, Hassfeld S,
Brömsen J, Dermintzoglou A, Wieczorek M, May E, Kirst E, Selignow C, Rackebrandt
K, Müller M, Goody RS, Vosberg HP, Nürnberg P, Scheffold T.
Author information:
(1)Cologne Center for Genomics and Institute for Genetics, University of
Cologne, Cologne, Germany.
Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark
of a rare familial or sporadic unclassified heart disease of heterogeneous
origin. NVM results presumably from a congenital developmental error and has
been traced back to single point mutations in various genes. The objective of
this study was to determine the underlying genetic defect in a large German
family suffering from NVM. Twenty four family members were clinically assessed
using advanced imaging techniques. For molecular characterization, a genome-wide
linkage analysis was undertaken and the disease locus was mapped to chromosome
14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7
(encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced,
leading to the identification of a previously unknown de novo missense mutation,
c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid
in the myosin subfragment-1 (R281T). In silico simulations suggest that the
mutation R281T prevents the formation of a salt bridge between residues R281 and
D325, thereby destabilizing the myosin head. The mutation was exclusively
present in morphologically affected family members. A few members of the family
displayed NVM in combination with other heart defects, such as dislocation of
the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A
high degree of clinical variability was observed, ranging from the absence of
symptoms in childhood to cardiac death in the third decade of life. The data
presented in this report provide first evidence that a mutation in a sarcomeric
protein can cause noncompaction of the ventricular myocardium.
DOI: 10.1371/journal.pone.0001362
PMCID: PMC2137931
PMID: 18159245 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/8389710
|
1. Eur Heart J. 1993 May;14(5):629-33. doi: 10.1093/eurheartj/14.5.629.
Triiodothyronine therapy in open-heart surgery: from hope to disappointment.
Teiger E(1), Menasché P, Mansier P, Chevalier B, Lajeunie E, Bloch G, Piwnica A.
Author information:
(1)Department of Cardiovascular Surgery, Hopital Lariboisière, Paris, France.
A controversy persists as to whether cardiopulmonary bypass (CPB) decreases
plasma levels of triiodothyronine (T3), thereby justifying peri-operative
administration of T3 to improve haemodynamic recovery. To examine the effects of
T3 therapy on post-CPB haemodynamics and to determine whether the potential
inotropic effects of T3 are mediated by an increase in beta-adrenergic
responsiveness, a prospective, randomized, double-blind, placebo-controlled
study was performed in 20 patients undergoing cardiac surgery with CPB. T3 or
placebo solution (10 patients in each group) was given intravenously at the time
of aortic unclamping and 4, 8, 12 and 20 h thereafter. End points included (1)
thyroid hormone levels measured by radioimmunoassay (2) standard haemodynamic
parameters (3) the density of lymphocyte beta-adrenoceptors measured by a
radioligand (125I-iodocyanopindolol) binding technique. Post-CPB values (cross
clamp removal) of T3 (pg.ml-1) were not significantly decreased compared with
pre-CPB values: 3.3 +/- 0.2 vs 3.1 +/- 0.2 in controls and 3.3 +/- 0.4 vs 3.7
+/- 0.6 in T3-treated patients, respectively. The haemodynamic parameters were
no different between the two groups at any postoperative time point. Likewise,
density and affinity of lymphocyte beta-adrenoceptors were not significantly
different from pre-operative values in either group. Thus, there seems to be no
sound justification for a routine use of T3 in patients undergoing open-heart
procedures.
DOI: 10.1093/eurheartj/14.5.629
PMID: 8389710 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8594265
|
1. JAMA. 1996 Mar 6;275(9):687-92.
Cardiovascular effects of intravenous triiodothyronine in patients undergoing
coronary artery bypass graft surgery. A randomized, double-blind, placebo-
controlled trial. Duke T3 study group.
Bennett-Guerrero E(1), Jimenez JL, White WD, D'Amico EB, Baldwin BI, Schwinn DA.
Author information:
(1)Department of Anesthesiology, Duke University Medical Center, Durham, NC,
USA.
Comment in
JAMA. 1996 Mar 6;275(9):723-4.
JAMA. 1996 Jul 10;276(2):100-1.
OBJECTIVE: To test the hypothesis that triiodothyronine (T(3)) administration
improves hemodynamic variables and decreases inotropic drug requirements in
cardiac surgery patients.
DESIGN: Prospective, randomized, double-blind, placebo-controlled trial.
SETTING: Tertiary care medical center.
PATIENTS: A total of 211 patients undergoing coronary artery surgery at high
risk for requiring inotropic drug support.
INTERVENTION: At release of aortic cross-clamp, patients were randomized to an
intravenous infusion of T(3) (0.8 microg/kg followed by 0.12 microg.kg(-1).h(-1)
for 6 hours), dopamine (positive control, 5 microg.kg(-1).min(-1) for 6 hours)
or placebo.
MAIN OUTCOME MEASURES: Perioperative hemodynamic variables, inotropic support
requirements, and serum T(3) concentrations.
RESULTS: Mean+/-SEM free T(3) serum concentrations decreased significantly
during cardiopulmonary bypass in all groups (from 0.0035+/-0.0001 nmol/L
[0.23+/-0.01 ng/dL] to 0.001+/-0.0001 nmol/L [0.7+/- 0.00 ng/dL]; P=.001) and
increased to 0.0133+/-0.0004 nmol/L [0.87+/-0.03 ng/dL] (twice normal range;
P<.001) following initiation of intravenous T(3). Intravenous T(3) did not
change hemodynamic variables or inotropic drug requirements; however, heart rate
increased (P<.001), and a trend toward decreased use of inotropic agents was
demonstrated in the dopamine group.
CONCLUSIONS: Triiodothyronine administration prevents decreases in serum thyroid
hormone concentrations associated with cardiopulmonary bypass. Intravenous T(3)
does not have dramatic effects on hemodynamic variables in this setting as has
been previously suggested. Although mild effects on myocardial performance may
exist, we cannot recommend at this time the routine use of intravenous T(3) as
an inotropic agent in patients undergoing coronary artery bypass graft surgery.
PMID: 8594265 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23319591
|
1. J Biol Chem. 2013 Mar 22;288(12):8380-8390. doi: 10.1074/jbc.M112.359935. Epub
2013 Jan 14.
Methylation of histone H3 on lysine 4 by the lysine methyltransferase SET1
protein is needed for normal clock gene expression.
Raduwan H(1), Isola AL(1), Belden WJ(2).
Author information:
(1)Department of Biochemistry and Microbiology, Rutgers, The State University of
New Jersey, New Brunswick, New Jersey 08901.
(2)Department of Biochemistry and Microbiology, Rutgers, The State University of
New Jersey, New Brunswick, New Jersey 08901. Electronic address:
belden@aesop.rutgers.edu.
The circadian oscillator controls time-of-day gene expression by a network of
interconnected feedback loops and is reset by light. The requisite for chromatin
regulation in eukaryotic transcription necessitates temporal regulation of
histone-modifying and chromatin-remodeling enzymes for proper clock function.
CHD1 is known to bind H3K4me3 in mammalian cells, and Neurospora CHD1 is
required for proper regulation of the frequency (frq) gene. Based on this, we
examined a strain lacking SET1 to determine the role of H3K4 methylation in
clock- and light-mediated frq regulation. Expression of frq was altered in
strains lacking set1 under both circadian- and light-regulated gene expression.
There is a delay in the phasing of H3K4me3 relative to the peak in frq
expression. White Collar 2 (WC-2) association with the frq promoter persists
longer in Δset1, suggesting a more permissible chromatin state. Surprisingly,
SET1 is required for DNA methylation in the frq promoter, indicating a
dependence on H3K4me for DNA methylation. The data support a model where SET1 is
needed for proper regulation by modulating chromatin at frq.
DOI: 10.1074/jbc.M112.359935
PMCID: PMC3605655
PMID: 23319591 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21285074
|
1. Eur Heart J. 2011 Jun;32(12):1446-56. doi: 10.1093/eurheartj/ehq508. Epub 2011
Jan 31.
Left ventricular non-compaction revisited: a distinct phenotype with genetic
heterogeneity?
Oechslin E(1), Jenni R.
Author information:
(1)Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre,
University Health Network/Toronto General Hospital, Toronto, Ontario, Canada.
erwin.oechslin@uhn.on.ca
Non-compaction of the left ventricular myocardium (LVNC) has gained increasing
recognition during the last 25 years. There is a morphological trait of the
myocardial structure with a spectrum from normal variants to the pathological
phenotype of LVNC, which reflects the embryogenic structure of the human heart
due to an arrest in the compaction process during the first trimester. It must
be cautioned not to overdiagnose LVNC: the morphological spectrum of
trabeculations, from normal variants to pathological trabeculations with the
morphological feature of LVNC must be carefully considered. The classical triad
of complications are heart failure, arrhythmias, including sudden cardiac death,
and systemic embolic events. Non-compaction of the left ventricular myocardium
can occur in isolation or in association with congenital heart defects (CHDs),
genetic syndromes, and neuromuscular disorders among others. The clinical
spectrum is wide and the outcome is more favourable than in previously described
populations with a negative selection bias. Familial occurrence is frequent with
autosomal dominant and X-linked transmissions. Different mutations in sarcomere
protein genes were identified and there seems to be a shared molecular aetiology
of different cardiomyopathic phenotypes, including LVNC, hypertrophic and
dilated cardiomyopathies. Thus, genetic heterogeneity, with an overlap of
different phenotypes, and the variability of hereditary patterns, raise the
questions whether there is a morphological trait from dilated/hypertrophic
cardiomyopathy to LVNC and what are the triggers and modifiers to develop either
dilated, hypertrophic cardiomyopathy, or LVNC in patients with the same
mutation. The variety in clinical presentation, the genetic heterogeneity, and
the phenotype of the first transgenetic animal model of an LVNC-associated
mutation question the hypothesis that LVNC be a distinct cardiomyopathy: it
seems to be rather a distinct phenotype or phenotypic, morphological expression
of different underlying diseases than a distinct cardiomyopathy.
DOI: 10.1093/eurheartj/ehq508
PMID: 21285074 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12857739
|
1. J Biol Chem. 2003 Oct 3;278(40):38902-12. doi: 10.1074/jbc.M306229200. Epub
2003 Jul 10.
Activation of the Rac-binding partner FHOD1 induces actin stress fibers via a
ROCK-dependent mechanism.
Gasteier JE(1), Madrid R, Krautkrämer E, Schröder S, Muranyi W, Benichou S,
Fackler OT.
Author information:
(1)Institute for Hygiene, Department of Virology, University of Heidelberg,
69120 Heidelberg, Germany.
Diaphanous related formins (DRFs) are part of the formin protein family that
control morphogenesis, embryonic differentiation, cytokinesis, and cell
polarity. DRFs organize the cytoskeleton in eukaryotic cells via the interaction
with specific members of the Rho family of small GTPases including Rho, Rac, and
Cdc42. This is best understood for Rho, which transmits signals to the actin
cytoskeleton through the cooperation of its DRF effector mDia with ROCK
(Rho-associated kinase). Here, we show that a constitutive active form of the
Rac-interacting DRF FHOD1 (formin homology 2 domain containing 1) associates
with F-actin in NIH3T3 cells, resulting in the formation of thick actin fibers.
Cytoskeletal changes induced by FHOD1 correlated with the induction of serum
response element transcription and were mediated by formin homology domains 1
and 2 of FHOD1. FHOD1-induced effects required the activity of the Rho-ROCK
cascade that is targeted at a level downstream of Rho by the DRF. However, when
the functional interaction of FHOD1 with individual GTPases was addressed, Rac
but not Rho or Cdc42 bound to FHOD1 in cells and induced its recruitment to
actin filaments and lamellipodia/membrane ruffles. Furthermore, activated FHOD1
interfered with lamellipodia formation. These results indicate that FHOD1 acts
as an effector of Rac in actin rearrangements and transcriptional regulation and
may provide a link for the Rac-dependent activation of the Rho cascade.
DOI: 10.1074/jbc.M306229200
PMID: 12857739 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20083571
|
1. Cardiovasc Res. 2010 Jun 1;86(3):452-60. doi: 10.1093/cvr/cvq009. Epub 2010
Jan 18.
Severe familial left ventricular non-compaction cardiomyopathy due to a novel
troponin T (TNNT2) mutation.
Luedde M(1), Ehlermann P, Weichenhan D, Will R, Zeller R, Rupp S, Müller A,
Steen H, Ivandic BT, Ulmer HE, Kern M, Katus HA, Frey N.
Author information:
(1)Department of Internal Medicine III, University of Heidelberg, 69120
Heidelberg, Germany.
AIMS: Left ventricular non-compaction (LVNC) is caused by mutations in multiple
genes. It is still unclear whether LVNC is the primary determinant of
cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte
dysfunction being the actual cause of the disease. Here, we describe a family
with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T
gene (TNNT2).
METHODS AND RESULTS: The novel mutation was identified in the index patient and
all affected relatives, but not in 430 healthy control individuals. Mutations in
known LVNC-associated genes were excluded. To investigate the pathophysiological
implications of the mutation, we generated transgenic mice expressing human
wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut
cTNT). Animals were characterized by echocardiography, histology, and gene
expression analysis. Mut cTNT mice displayed an impaired left ventricular
function and induction of marker genes of heart failure. Remarkably, left
ventricular non-compaction was not observed.
CONCLUSION: Familial co-segregation and the cardiomyopathy phenotype of mut cTNT
mice strongly support a causal relationship of the pE96K mutation and disease in
our index patient. In addition, our data suggest that a non-compaction phenotype
is not required for the development of cardiomyopathy in this specific TNNT2
mutation leading to LVNC.
DOI: 10.1093/cvr/cvq009
PMID: 20083571 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7477166
|
1. N Engl J Med. 1995 Dec 7;333(23):1522-7. doi: 10.1056/NEJM199512073332302.
Thyroid hormone treatment after coronary-artery bypass surgery.
Klemperer JD(1), Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW,
Krieger K.
Author information:
(1)Department of Cardiothoracic Surgery, New York Hospital-Cornell University
Medical College, New York 10021, USA.
Comment in
N Engl J Med. 1995 Dec 7;333(23):1562-3. doi: 10.1056/NEJM199512073332310.
BACKGROUND: Thyroid hormone has many effects on the cardiovascular system.
During and after cardiopulmonary bypass, serum triiodothyronine concentrations
decline transiently, which may contribute to postoperative hemodynamic
dysfunction. We investigated whether the perioperative administration of
triiodothyronine (liothyronine sodium) enhances cardiovascular performance in
high-risk patients undergoing coronary-artery bypass surgery.
METHODS: We administered triiodothyronine or placebo to 142 patients with
coronary artery disease and depressed left ventricular function. The hormone was
administered as an intravenous bolus of 0.8 microgram per kilogram of body
weight when the aortic cross-clamp was removed after the completion of bypass
surgery and then as an infusion of 0.113 microgram per kilogram per hour for six
hours. Clinical and hemodynamic responses were serially recorded, as was any
need for inotropic or vasodilator drugs.
RESULTS: The patients' preoperative serum triiodothyronine concentrations were
normal (mean [+/- SD] value, 81 +/- 22 ng per deciliter [1.2 +/- 0.3 nmol per
liter]), and they decreased by 40 percent (P < 0.001) 30 minutes after the onset
of cardiopulmonary bypass. The concentrations in patients given intravenous
triiodothyronine became supranormal and were significantly higher than those in
patients given placebo (P < 0.001). However, the concentrations were once again
similar in the two groups 24 hours after surgery. The mean postoperative cardiac
index was higher in the triiodothyronine group (2.97 +/- 0.72 vs. 2.67 +/- 0.61
liters per minute per square meter of body-surface area, P = 0.007), and
systemic vascular resistance was lower (1073 +/- 314 vs. 1235 +/- 387
dyn.sec.cm-5, P = 0.003). The two groups did not differ significantly in the
incidence of arrhythmia or the need for therapy with inotropic and vasodilator
drugs during the 24 hours after surgery, or in perioperative mortality and
morbidity.
CONCLUSIONS: Raising serum triiodothyronine concentrations in patients
undergoing coronary-artery bypass surgery increases cardiac output and lowers
systemic vascular resistance, but does not change outcome or alter the need for
standard postoperative therapy.
DOI: 10.1056/NEJM199512073332302
PMID: 7477166 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22221061
|
1. Comb Chem High Throughput Screen. 2012 May 1;15(4):286-98. doi:
10.2174/138620712799361852.
Integrative system biology strategies for disease biomarker discovery.
Zhang H(1), Hu H, Deng C, Chun Y, Zhou S, Huang F, Zhou Q.
Author information:
(1)Medical School, Yangtze University, Jingzhou Hubei 434000, People's Republic
of China. zhanghaiyuan1972@hotmail.com
Biomarkers are currently widely used to diagnose diseases, monitor treatments,
and evaluate potential drug candidates. Research of differential Omics
accelerate the advancements of biomarkers' discovery. By extracting biological
knowledge from the 'omics' through integration, integrative system biology
creates predictive models of cells, organs, biochemical processes and complete
organisms, in addition to identifying human disease biomarkers. Recent
development in high-throughput methods enables analysis of genome,
transcriptome, proteome, and metabolome at an unprecedented scale, thus
contributing to the deluge of experimental data in numerous public databases.
Several integrative system biology approaches have been developed and applied to
the discovery of disease biomarkers from databases. In this review, we highlight
several of these approaches and identify future steps in the context of the
field of integrative system biology.
DOI: 10.2174/138620712799361852
PMID: 22221061 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18395448
|
1. Neuromuscul Disord. 2008 Apr;18(4):331-3. doi: 10.1016/j.nmd.2007.11.012.
Left ventricular non-compaction in a patient with myotonic dystrophy type 2.
Wahbi K(1), Meune C, Bassez G, Laforêt P, Vignaux O, Marmursztejn J, Bécane HM,
Eymard B, Duboc D.
Author information:
(1)Department of Cardiology, Cochin Hospital, Assistance Publique Hôpitaux de
Paris, René Descartes University, 27 rue du Fg St-Jacques, 75014 Paris, France.
karim.wahbi@cch.aphp.fr
Cardiac involvement is frequent in myotonic dystrophy type 2 (DM2) with dilated
cardiomyopathy and severe arrhythmias having been reported. Left ventricular
non-compaction is a cardiomyopathy often associated with neuromuscular
disorders. We report the case of a 61-year-old man with DM2 treated for 5 years
for a suspected dilated cardiomyopathy. Echocardiography showed left ventricular
non-compaction typical pattern, with prominent apical trabeculations and
intertrabecular spaces perfused from ventricular cavity. MRI confirmed the
diagnosis. Physicians should be aware of the risk of severe cardiac
complications in DM2 patients. Left ventricular non-compaction diagnosis is
often overlooked. Neurological examination should be performed in all patients
with left ventricular non-compaction.
DOI: 10.1016/j.nmd.2007.11.012
PMID: 18395448 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17101628
|
1. Europace. 2006 Dec;8(12):1064-7. doi: 10.1093/europace/eul125. Epub 2006 Nov
13.
Isolated ventricular non-compaction: clinical study and genetic review.
Markiewicz-Loskot G(1), Moric-Janiszewska E, Loskot M, Szydlowski L, Weglarz L,
Hollek A.
Author information:
(1)Department of Pediatric Cardiology, Medical University of Silesia, Medyków
16, 40-752 Katowice, Poland. ejaniszewska@slam.katowice.pl
Comment in
Europace. 2007 May;9(5):333. doi: 10.1093/europace/eum012.
Isolated non-compaction of the ventricular myocardium (INVM), sometimes referred
to as 'spongy myocardium', is a congenital and exceedingly rare cardiomyopathy.
Isolated ventricular non-compaction occurs in the absence of other structural
heart diseases and, hypothetically, it is due to the arrest of myocardial
morphogenesis. Isolated non-compaction of the ventricular myocardium may
manifest itself from infancy to young adulthood with a high mortality rate. Both
sexes are affected. In our study, we present a case of INVM (left and right
ventricles) in a 3-year-old girl, diagnosed by two-dimensional echocardiography.
The anomaly presented as a restrictive cardiomyopathy. The girl was admitted to
our hospital with heart failure, when she was 10 months old. She was treated
with dopamine, digoxin, furosemide, spironolactone, and acenocoumarol and her
condition improved. Presently, the girl remains asymptomatic and for 3 years of
follow-up, her development has been almost normal. We here describe the genetic
background of this disorder (based on a literature review).
DOI: 10.1093/europace/eul125
PMID: 17101628 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19478006
|
1. Bioinformatics. 2009 Jun 15;25(12):i321-9. doi: 10.1093/bioinformatics/btp230.
DISCOVER: a feature-based discriminative method for motif search in complex
genomes.
Fu W(1), Ray P, Xing EP.
Author information:
(1)School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213,
USA.
MOTIVATION: Identifying transcription factor binding sites (TFBSs) encoding
complex regulatory signals in metazoan genomes remains a challenging problem in
computational genomics. Due to degeneracy of nucleotide content among binding
site instances or motifs, and intricate 'grammatical organization' of motifs
within cis-regulatory modules (CRMs), extant pattern matching-based in silico
motif search methods often suffer from impractically high false positive rates,
especially in the context of analyzing large genomic datasets, and noisy
position weight matrices which characterize binding sites. Here, we try to
address this problem by using a framework to maximally utilize the information
content of the genomic DNA in the region of query, taking cues from values of
various biologically meaningful genetic and epigenetic factors in the query
region such as clade-specific evolutionary parameters, presence/absence of
nearby coding regions, etc. We present a new method for TFBS prediction in
metazoan genomes that utilizes both the CRM architecture of sequences and a
variety of features of individual motifs. Our proposed approach is based on a
discriminative probabilistic model known as conditional random fields that
explicitly optimizes the predictive probability of motif presence in large
sequences, based on the joint effect of all such features.
RESULTS: This model overcomes weaknesses in earlier methods based on less
effective statistical formalisms that are sensitive to spurious signals in the
data. We evaluate our method on both simulated CRMs and real Drosophila
sequences in comparison with a wide spectrum of existing models, and outperform
the state of the art by 22% in F1 score.
AVAILABILITY AND IMPLEMENTATION: The code is publicly available at
http://www.sailing.cs.cmu.edu/discover.html.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
DOI: 10.1093/bioinformatics/btp230
PMCID: PMC2687984
PMID: 19478006 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16895927
|
1. Bioinformatics. 2006 Oct 15;22(20):2562-4. doi: 10.1093/bioinformatics/btl428.
Epub 2006 Aug 7.
HiRes--a tool for comprehensive assessment and interpretation of metabolomic
data.
Zhao Q(1), Stoyanova R, Du S, Sajda P, Brown TR.
Author information:
(1)Hatch Center for MR Research, Department of Radiology, Columbia University,
New York, NY 10032 USA. qz2106@columbia.edu
The increasing role of metabolomics in system biology is driving the development
of tools for comprehensive analysis of high-resolution NMR spectral datasets.
This task is quite challenging since unlike the datasets resulting from other
'omics', a substantial preprocessing of the data is needed to allow successful
identification of spectral patterns associated with relevant biological
variability. HiRes is a unique stand-alone software tool that combines standard
NMR spectral processing functionalities with techniques for multi-spectral
dataset analysis, such as principal component analysis and non-negative matrix
factorization. In addition, HiRes contains extensive abilities for data
cleansing, such as baseline correction, solvent peak suppression, removal of
frequency shifts owing to experimental conditions as well as auxiliary
information management. Integration of these components together with
multivariate analytical procedures makes HiRes very capable of addressing the
challenges for assessment and interpretation of large metabolomic datasets,
greatly simplifying this otherwise lengthy and difficult process and assuring
optimal information retrieval.
AVAILABILITY: HiRes is freely available for research purposes at
http://hatch.cpmc.columbia.edu/highresmrs.html
DOI: 10.1093/bioinformatics/btl428
PMID: 16895927 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19438153
|
1. Rev Port Cardiol. 2009 Feb;28(2):185-94.
Left ventricular non-compaction: a new mutation predisposing to reverse
remodeling?
[Article in English, Portuguese]
Cortez-Dias N(1), Varela MG, Sargento L, Brito D, Almeida A, Cerqueira R, Lança
V, Fernandes AR, Tavares P, Pereira RA, Fernandes A, Madeira H.
Author information:
(1)Serviço de Cardiologia, Hospital de Santa Maria, Lisboa, Portugal.
Left ventricular non-compaction (LVNC) is a rare disorder of endomyocardial
morphogenesis that results in multiple trabeculations and deep intertrabecular
recesses filled with direct blood flow from the left ventricular cavity. LVNC is
attracting increasing interest as a model for the study of cardiomyopathies,
since it is a genetically heterogeneous disorder which varies greatly in
clinical presentation and age of onset. The authors present the case of a young
black male with progressive congestive heart failure of 2-3 years' evolution.
The investigation, which included transthoracic echocardiography (contrast and
3D), transesophageal echocardiography and cardiac magnetic resonance imaging,
showed LVNC and severe aortic regurgitation, with severe left ventricular
systolic dysfunction. The family history was suggestive of genetically
transmitted disease and genetic study of the TAZ gene at locus Xq28 identified
the mutation p.Phe128Ser (c.383T>C), the first description of this mutation in a
patient with LVNC. The patient underwent aortic valve replacement, with
excellent clinical evolution, regression of left ventricular dimensions and
global systolic functio Aortic regurgitation (not related to LVNC) was the
determining factor in the clinical expression. However, the excellent reverse
remodeling that occurred after surgery highlights the heterogeneity of
myocardial behavior in LVNC patients.
PMID: 19438153 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21604106
|
1. Neth Heart J. 2013 Mar;21(3):113-7. doi: 10.1007/s12471-011-0141-1.
Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7.
van Engelen K(1), Postma AV, van de Meerakker JB, Roos-Hesselink JW,
Helderman-van den Enden AT, Vliegen HW, Rahman T, Baars MJ, Sels JW, Bauer U,
Pickardt T, Sperling SR, Moorman AF, Keavney B, Goodship J, Klaassen S, Mulder
BJ.
Author information:
(1)Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ,
Amsterdam, the Netherlands.
Ebstein's anomaly is a rare congenital heart malformation characterised by
adherence of the septal and posterior leaflets of the tricuspid valve to the
underlying myocardium. Associated abnormalities of left ventricular morphology
and function including left ventricular noncompaction (LVNC) have been observed.
An association between Ebstein's anomaly with LVNC and mutations in the
sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by
recent studies. This might represent a specific subtype of Ebstein's anomaly
with a Mendelian inheritance pattern. In this review we discuss the association
of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the
clinical care for patients and their family members.
DOI: 10.1007/s12471-011-0141-1
PMCID: PMC3578524
PMID: 21604106
|
http://www.ncbi.nlm.nih.gov/pubmed/15883375
|
1. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7079-84. doi:
10.1073/pnas.0408743102. Epub 2005 May 9.
De novo cis-regulatory module elicitation for eukaryotic genomes.
Gupta M(1), Liu JS.
Author information:
(1)Department of Biostatistics, University of North Carolina, Chapel Hill, NC
27599, USA. gupta@bios.unc.edu
Transcription regulation is controlled by coordinated binding of one or more
transcription factors in the promoter regions of genes. In many species,
especially higher eukaryotes, transcription factor binding sites tend to occur
as homotypic or heterotypic clusters, also known as cis-regulatory modules. The
number of sites and distances between the sites, however, vary greatly in a
module. We propose a statistical model to describe the underlying cluster
structure as well as individual motif conservation and develop a Monte Carlo
motif screening strategy for predicting novel regulatory modules in upstream
sequences of coregulated genes. We demonstrate the power of the method with
examples ranging from bacterial to insect and human genomes.
DOI: 10.1073/pnas.0408743102
PMCID: PMC1129096
PMID: 15883375 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22619057
|
1. J Neurol. 2012 Jul;259(7):1494-6. doi: 10.1007/s00415-012-6543-1. Epub 2012
May 23.
ZASPopathy with childhood-onset distal myopathy.
Strach K(1), Reimann J, Thomas D, Naehle CP, Kress W, Kornblum C.
Author information:
(1)Department of Radiology, University of Bonn, Bonn, Germany.
katharina.strach@med.ovgu.de
We report on a German family presenting with a predominantly distal myopathy
primarily affecting anterior compartments of lower legs in childhood. Proximal
lower limb and hip girdle weakness developed later in early adulthood in the
female index patient and likewise in her mother. Consecutive muscle biopsy
findings were first attributed to a mild congenital myopathy and later on
interpreted as neurogenic changes without clear signs of a myopathy. Molecular
genetic analysis was performed because of the clinical impression of a distal
myopathy combined with dominant inheritance. The heterozygous mutation c.349G>A
(p.D117N) in the ZASP gene could be found. This mutation had been previously
associated with an adult-onset, isolated, dilated left ventricular
non-compaction cardiomyopathy (OMIM*605906.0007), which was not present in our
patients. Our data show that this mutation can be associated with an isolated
skeletal muscle phenotype. Second, mutation analysis of the ZASP gene is
suggested for distal myopathies of any age, even in cases of uncharacteristic
muscle biopsy findings on routine analysis.
DOI: 10.1007/s00415-012-6543-1
PMID: 22619057 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25268582
|
1. PLoS One. 2014 Sep 30;9(9):e108065. doi: 10.1371/journal.pone.0108065.
eCollection 2014.
CisMiner: genome-wide in-silico cis-regulatory module prediction by fuzzy
itemset mining.
Navarro C(1), Lopez FJ(2), Cano C(1), Garcia-Alcalde F(3), Blanco A(1).
Author information:
(1)Department of Computer Science and AI, University of Granada, Granada, Spain.
(2)Andalusian Human Genome Sequencing Centre (CASEGH), Medical Genome Project
(MGP), Sevilla, Spain.
(3)Max Planck Institute for Infection Biology, Berlin, Germany.
Eukaryotic gene control regions are known to be spread throughout non-coding DNA
sequences which may appear distant from the gene promoter. Transcription factors
are proteins that coordinately bind to these regions at transcription factor
binding sites to regulate gene expression. Several tools allow to detect
significant co-occurrences of closely located binding sites (cis-regulatory
modules, CRMs). However, these tools present at least one of the following
limitations: 1) scope limited to promoter or conserved regions of the genome; 2)
do not allow to identify combinations involving more than two motifs; 3) require
prior information about target motifs. In this work we present CisMiner, a novel
methodology to detect putative CRMs by means of a fuzzy itemset mining approach
able to operate at genome-wide scale. CisMiner allows to perform a blind search
of CRMs without any prior information about target CRMs nor limitation in the
number of motifs. CisMiner tackles the combinatorial complexity of genome-wide
cis-regulatory module extraction using a natural representation of motif
combinations as itemsets and applying the Top-Down Fuzzy Frequent- Pattern Tree
algorithm to identify significant itemsets. Fuzzy technology allows CisMiner to
better handle the imprecision and noise inherent to regulatory processes.
Results obtained for a set of well-known binding sites in the S. cerevisiae
genome show that our method yields highly reliable predictions. Furthermore,
CisMiner was also applied to putative in-silico predicted transcription factor
binding sites to identify significant combinations in S. cerevisiae and D.
melanogaster, proving that our approach can be further applied genome-wide to
more complex genomes. CisMiner is freely accesible at:
http://genome2.ugr.es/cisminer. CisMiner can be queried for the results
presented in this work and can also perform a customized cis-regulatory module
prediction on a query set of transcription factor binding sites provided by the
user.
DOI: 10.1371/journal.pone.0108065
PMCID: PMC4182448
PMID: 25268582 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/21152003
|
1. PLoS Comput Biol. 2010 Dec 2;6(12):e1001020. doi:
10.1371/journal.pcbi.1001020.
Assessing computational methods of cis-regulatory module prediction.
Su J(1), Teichmann SA, Down TA.
Author information:
(1)MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
Computational methods attempting to identify instances of cis-regulatory modules
(CRMs) in the genome face a challenging problem of searching for potentially
interacting transcription factor binding sites while knowledge of the specific
interactions involved remains limited. Without a comprehensive comparison of
their performance, the reliability and accuracy of these tools remains unclear.
Faced with a large number of different tools that address this problem, we
summarized and categorized them based on search strategy and input data
requirements. Twelve representative methods were chosen and applied to predict
CRMs from the Drosophila CRM database REDfly, and across the human ENCODE
regions. Our results show that the optimal choice of method varies depending on
species and composition of the sequences in question. When discriminating CRMs
from non-coding regions, those methods considering evolutionary conservation
have a stronger predictive power than methods designed to be run on a single
genome. Different CRM representations and search strategies rely on different
CRM properties, and different methods can complement one another. For example,
some favour homotypical clusters of binding sites, while others perform best on
short CRMs. Furthermore, most methods appear to be sensitive to the composition
and structure of the genome to which they are applied. We analyze the principal
features that distinguish the methods that performed well, identify weaknesses
leading to poor performance, and provide a guide for users. We also propose key
considerations for the development and evaluation of future CRM-prediction
methods.
DOI: 10.1371/journal.pcbi.1001020
PMCID: PMC2996316
PMID: 21152003 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/12702576
|
1. Cancer Res. 2003 Apr 15;63(8):1871-5.
SCCA2-like serpins mediate genetic predisposition to skin tumors.
Gariboldi M(1), Peissel B, Fabbri A, Saran A, Zaffaroni D, Falvella FS, Spinola
M, Tanuma J, Pazzaglia S, Mancuso MT, Maurichi A, Bartoli C, Cataltepe S,
Silverman GA, Pilotti S, Hayashizaki Y, Okazaki Y, Dragani TA.
Author information:
(1)Department of Experimental Oncology, Istituto Nazionale Tumori 20133, Milan,
Italy.
Reasons for early onset skin cancer are poorly understood. Microarray analysis
revealed overexpression of the Scca2 gene in the
12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-S mice, or line
phenotypically selected for high susceptibility to two-stage skin
carcinogenesis, as compared with 12-O-tetradecanoylphorbol-13-acetate-treated
skin of Car-R mice, which is resistant. A human skin squamous cell carcinoma
cell line (NCI-H520) transfected with mouse Scca2 or a related gene, Scca2-rs1,
both expressed in the skin, showed significantly increased tumor growth as
compared with controls when injected in nude mice. Immunohistochemical analysis
of samples from two independent series of Italian and Korean patients with
squamous cell carcinoma of the skin indicated a significant association between
SCCA2 protein expression and younger age at tumor onset. These findings provide
evidence that SCCA2-like serpins mediate genetic predisposition to skin cancer
in a mouse model and in humans.
PMID: 12702576 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14965369
|
1. Cancer Sci. 2004 Feb;95(2):176-80. doi: 10.1111/j.1349-7006.2004.tb03200.x.
Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small
cell lung cancer cells via the JNK/c-Jun/AP-1 signaling.
Yang Y(1), Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H.
Author information:
(1)Department of Internal Medicine, Kochi Medical School, Kochi 783-8505, Japan.
Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple
myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some
objective responses in individuals with relapsed, refractory MM. However, the
activity of PS-341 against non-hematological malignancies remains to be fully
elucidated. In this study, we found that PS-341 induced growth arrest and
apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in
conjunction with markedly up-regulated levels of p21(waf1) and p53, and
down-regulation of bcl-2 protein in these cells. Also, PS-341 caused
phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun, and enhanced
AP-1/DNA binding activities in these cells as measured by western blotting and
enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the
JNK/c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the
ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the
levels of p21(waf1) in these cells was blunted, but the expression of p53 was
sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway
might mediate the anti-lung cancer effects of PS-341, with p21(waf1) playing the
central role. Thus, PS-341 might be useful for the treatment of individuals with
NSCLC.
DOI: 10.1111/j.1349-7006.2004.tb03200.x
PMCID: PMC11160053
PMID: 14965369 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14662268
|
1. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. doi: 10.1016/j.jacc.2003.10.021.
Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left
ventricular non-compaction.
Vatta M(1), Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G,
Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA,
Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA.
Author information:
(1)Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston,
Texas, USA.
Comment in
J Am Coll Cardiol. 2004 Sep 1;44(5):1139; author reply 1139-40. doi:
10.1016/j.jacc.2004.06.007.
OBJECTIVES: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated
cardiomyopathy (DCM) with or without isolated non-compaction of the left
ventricular myocardium (INLVM).
BACKGROUND: Dilated cardiomyopathy, characterized by left ventricular dilation
and systolic dysfunction with signs of heart failure, is genetically transmitted
in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations
in multiple cytoskeletal and sarcomeric genes causing the phenotype. In
addition, INLVM with a hypertrophic dilated left ventricle, ventricular
dysfunction, and deep trabeculations, is also inherited, and the genes
identified to date differ from those causing DCM. Cypher/ZASP is a newly
identified gene encoding a protein that is a component of the Z-line in both
skeletal and cardiac muscle.
METHODS: Diagnosis of DCM was performed by echocardiogram, electrocardiogram,
and physical examination. In addition, levels of the muscular isoform of
creatine kinase were measured to evaluate for skeletal muscle involvement.
Cypher/ZASP was screened by denaturing high performance liquid chromatography
(DHPLC) and direct deoxyribonucleic acid sequencing.
RESULTS: We identified and screened 100 probands with left ventricular
dysfunction. Five mutations in six probands (6% of cases) were identified in
patients with familial or sporadic DCM or INLVM. In vitro studies showed
cytoskeleton disarray in cells transfected with mutated Cypher/ZASP.
CONCLUSIONS: These data suggest that mutated Cypher/ZASP can cause DCM and INLVM
and identify a mechanistic basis.
DOI: 10.1016/j.jacc.2003.10.021
PMID: 14662268 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15750352
|
1. Mol Cells. 2005 Feb 28;19(1):143-8.
Combined effect of heptaplatin and ionizing radiation on human squamous
carcinoma cell lines.
Ryu MR(1), Paik SY, Chung SM.
Author information:
(1)Department of Radiation Oncology, College of Medicine, The Catholic
University of Korea, Seoul 137-701, Korea.
Heptaplatin, cis-malonato [(4R,5R)-4,5-bis
(amino-methyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI-2053R, Sunpla) is a
new platinum derivative with anti-tumor activity comparable to cisplatin on
various cancer cell lines. Preclinical studies suggest that it is less
nephrotoxic than cisplatin. This study was undertaken to examine the combined
effect of heptaplatin and ionizing radiation on two established human squamous
carcinoma cell lines (NCI-H520, SQ20B). The cytotoxic activity of heptaplatin
was concentration-dependent in both cell lines. When low dose heptaplatin was
combined with high dose ionizing radiation, there was an additive cytotoxic
effect on NCI-H520 cells (P < 0.05), while a moderate dose of heptaplatin and a
low dose of ionizing radiation had an additive cytotoxic effect on the growth of
SQ20B cells (P < 0.05). FACS analysis and DAPI staining showed that their
additive cytotoxic effects were correlated with the induction of apoptosis.
Further studies are warranted using heptaplatin and ionizing radiation in
squamous cell carcinoma as a substitute for cisplatin.
PMID: 15750352 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23800289
|
1. Orphanet J Rare Dis. 2013 Jun 21;8:91. doi: 10.1186/1750-1172-8-91.
Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy
chain 7B genes causes congenital myopathy with left ventricular non-compact
cardiomyopathy.
Esposito T(1), Sampaolo S, Limongelli G, Varone A, Formicola D, Diodato D,
Farina O, Napolitano F, Pacileo G, Gianfrancesco F, Di Iorio G.
Author information:
(1)Institute of Genetics and Biophysics, National Research Council of Italy,
Naples, Italy. teresa.esposito@igb.cnr.it
Comment in
Orphanet J Rare Dis. 2013 Nov 20;8:183. doi: 10.1186/1750-1172-8-183.
BACKGROUND: We report an Italian family in which the proband showed a severe
phenotype characterized by the association of congenital fiber type
disproportion (CFTD) with a left ventricular non-compaction cardiomyopathy
(LVNC). This study was focused on the identification of the responsible gene/s.
METHODS AND RESULTS: Using the whole-exome sequencing approach, we identified
the proband homozygous missense mutations in two genes, the myosin heavy chain
7B (MYH7B) and the integrin alpha 7 (ITGA7). Both genes are expressed in heart
and muscle tissues, and both mutations were predicted to be deleterious and were
not found in the healthy population.The R890C mutation in the MYH7B gene
segregated with the LVNC phenotype in the examined family. It was also found in
one unrelated patient affected by LVNC, confirming a causative role in
cardiomyopathy.The E882K mutation in the ITGA7 gene, a key component of the
basal lamina of muscle fibers, was found only in the proband, suggesting a role
in CFTD.
CONCLUSIONS: This study identifies two novel disease genes. Mutation in MYH7B
causes a classical LVNC phenotype, whereas mutation in ITGA7 causes CFTD. Both
phenotypes represent alterations of skeletal and cardiac muscle maturation and
are usually not severe. The severe phenotype of the proband is most likely due
to a synergic effect of these two mutations.This study provides new insights
into the genetics underlying Mendelian traits and demonstrates a role for
digenic inheritance in complex phenotypes.
DOI: 10.1186/1750-1172-8-91
PMCID: PMC3695851
PMID: 23800289 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19467449
|
1. Trends Cardiovasc Med. 2009 Jan;19(1):17-21. doi: 10.1016/j.tcm.2009.03.003.
Sarcomere mutations in cardiogenesis and ventricular noncompaction.
McNally E(1), Dellefave L.
Author information:
(1)Department of Medicine, Section of Cardiology, The University of Chicago,
Chicago, IL 60637, USA. emcnally@uchicago.edu
Ventricular noncompaction is a form of cardiomyopathy where increased
trabeculation is present frequently affecting the left ventricle and resembling
an embryonic state of heart development. Clinically, left ventricular
noncompaction may manifest as congestive heart failure, arrhythmias, and/or
thromboembolic events. There are multiple genes linked to noncompaction, but
recently, sarcomere gene mutations were found in both familial and sporadic
cases of noncompaction. The association of noncompaction with sarcomere
mutations supports the classification of ventricular noncompaction as
cardiomyopathy and raises interesting questions regarding the continuum of
hypertrophic cardiomyopathy, dilated cardiomyopathy, and noncompaction. The
mutational spectrum of sarcomere genes in these disorders highlights the
importance of the MYH7 gene encoding beta-myosin heavy chain and ACTC1 encoding
the cardiac actin gene. Intriguingly, these mutations also share a low but
definitive incidence of congenital heart malformations including septal defects.
These human genetic findings support that normal myocardial and sarcomere
function are required for proper compaction and septation and that these
mutations also portend a high risk of developing heart failure in later life.
DOI: 10.1016/j.tcm.2009.03.003
PMID: 19467449 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20142034
|
1. Chem Biol. 2010 Jan 29;17(1):6-8. doi: 10.1016/j.chembiol.2010.01.002.
Mechanism-based neddylation inhibitor.
Petroski MD(1).
Author information:
(1)Signal Transduction Program, NCI Cancer Center, Burnham Institute for Medical
Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
petroski@burnham.org
Brownell et al. (2010) elucidate the mechanism of action of MLN4924, a
NEDD8-activating enzyme inhibitor. MLN4924 requires the activity of the enzyme
to generate a NEDD8-adenylate analog that potently and selectively shuts down
this posttranslational modification system.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2010.01.002
PMID: 20142034
|
http://www.ncbi.nlm.nih.gov/pubmed/20542340
|
1. Int J Cardiol. 2010 Nov 19;145(2):405-407. doi: 10.1016/j.ijcard.2010.04.032.
Epub 2010 Jun 14.
The R820W mutation in the MYBPC3 gene, associated with hypertrophic
cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular
non-compaction in humans.
Ripoll Vera T(1), Monserrat Iglesias L(2), Hermida Prieto M(2), Ortiz M(2),
Rodriguez Garcia I(2), Govea Callizo N(3), Gómez Navarro C(4), Rosell Andreo
J(3), Gámez Martínez JM(5), Pons Lladó G(6), Cremer Luengos D(5), Torres Marqués
J(5).
Author information:
(1)Cardiology Department, Hospital Son Llatzer, Palma de Mallorca, Spain.
Electronic address: tripoll@hsll.es.
(2)Instituto de Investigación Biomédica de A Coruña, Spain.
(3)Genetics Unit, Hospital Son Dureta, Palma de Mallorca, Spain.
(4)Cardiology Department, Hospital de Torrecárdenas, Almería, Spain.
(5)Cardiology Department, Hospital Son Llatzer, Palma de Mallorca, Spain.
(6)Cardiology Department, Clínica Palmaplanas, Palma de Mallorca, Spain.
BACKGROUND: The R820W mutation in the MYBPC3 gene has been associated with the
development of hypertrophic cardiomyopathy (HCM) in rag-doll cats, but had not
been described in humans.
AIMS: To describe the phenotype associated with the R820W mutation identified in
a human family.
METHODS: The R820W was identified by direct sequencing of the MYBPC3 gene in a
47 year old woman with HCM and left ventricular non-compaction (LVNC). Clinical
and genetic studies of the R820W mutation were performed in her family.
RESULTS: The index patient was homozygous for the mutation and had no additional
mutations in the main sarcomeric genes (MYH7, TNNT2, TNNI3, and TPM1). She had
HCM with LVNC and normal systolic function. One brother had died suddenly at age
43 years. Another brother diagnosed of LVNC with severe systolic dysfunction and
a cardiac arrest was also homozygous for the mutation. One heterozygous 31 year
old sister, and three heterozygous sons of the index (ages 14, 20 and 23 years
old) were clinically unaffected. The father of the index was apparently healthy
and her mother had atrial fibrillation and an electrocardiographic diagnosis of
left ventricular hypertrophy at age 86 years.
CONCLUSION: The R820W mutation in the MYBPC3 gene, previously associated with
HCM in rag-doll cats, causes both HCM and LVNC in homozygous human carriers,
with mild or null clinical expression in heterozygous carriers.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ijcard.2010.04.032
PMID: 20542340 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25388161
|
1. Clin Cancer Res. 2015 Jan 15;21(2):439-47. doi: 10.1158/1078-0432.CCR-14-1960.
Epub 2014 Nov 11.
The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and
augments the efficacy of cytarabine.
Nawrocki ST(1), Kelly KR(2), Smith PG(3), Keaton M(4), Carraway H(5), Sekeres
MA(5), Maciejewski JP(5), Carew JS(6).
Author information:
(1)Division of Hematology/Oncology, CTRC, The University of Texas Health Science
Center, San Antonio, Texas.
(2)USC Norris Comprehensive Cancer Center, Pasadena, California.
(3)Millennium Pharmaceuticals, Cambridge, Massachusetts. H3 Biomedicine,
Cambridge, Massachusetts.
(4)Metabolon, Inc., Durham, North Carolina. Duke University, Durham, North
Carolina.
(5)Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
(6)Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. carewj@ccf.org.
PURPOSE: New therapies are urgently needed for patients with acute myelogenous
leukemia (AML). The novel NEDDylation inhibitor MLN4924 (pevonedistat) has
demonstrated significant preclinical antileukemic activity and preliminary
efficacy in patients with AML in a phase I trial. On the basis of its
antimyeloid and DNA-damaging properties, we investigated the ability of MLN4924
to augment conventional cytarabine (ara-C) therapy.
EXPERIMENTAL DESIGN: The effects of MLN4924/ara-C on viability, clonogenic
survival, apoptosis, DNA damage, and relevant pharmacodynamic targets were
determined. The efficacy and pharmacodynamics of MLN4924/ara-C were assessed in
an AML xenograft model.
RESULTS: Cotreatment of AML cell lines and primary patient specimens with
MLN4924 and ara-C led to diminished clonogenic survival, increased apoptosis,
and synergistic levels of DNA damage. RNAi demonstrated that stabilization of
CDT-1, an event previously shown to mediate the DNA-damaging effects of MLN4924,
was not a key regulator of sensitivity to the MLN4924/ara-C combination. Global
metabolic profiling revealed that MLN4924 disrupts nucleotide metabolism and
depletes intracellular nucleotide pools in AML cells. Subsequent experiments
showed that MLN4924 promoted increased incorporation of ara-C into the DNA of
AML cells. This effect as well as the therapeutic benefit of the MLN4924/ara-C
combination was antagonized by supplementation with the nucleotide building
block ribose. Coadministration of MLN4924 and ara-C to mice bearing FLT3-ITD(+)
AML xenografts stably inhibited disease progression and increased DNA damage in
vivo.
CONCLUSIONS: Our findings provide strong rationale for clinical investigation of
the MLN4924/ara-C combination and establish a new link between therapeutic
inhibition of NEDDylation and alterations in nucleotide metabolism. Clin Cancer
Res; 21(2); 439-47. ©2014 AACR.
©2014 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-14-1960
PMCID: PMC4297545
PMID: 25388161 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of conflicts of interest: PGS is a
former employee of Millennium Pharmaceuticals, Inc.
|
http://www.ncbi.nlm.nih.gov/pubmed/23147248
|
1. Biochim Biophys Acta. 2013 Apr;1833(4):833-9. doi:
10.1016/j.bbamcr.2012.11.003. Epub 2012 Nov 9.
A novel alpha-tropomyosin mutation associates with dilated and non-compaction
cardiomyopathy and diminishes actin binding.
van de Meerakker JB(1), Christiaans I, Barnett P, Lekanne Deprez RH, Ilgun A,
Mook OR, Mannens MM, Lam J, Wilde AA, Moorman AF, Postma AV.
Author information:
(1)Department of Anatomy, Embryology & Physiology, Academic Medical Center,
Amsterdam, The Netherlands.
BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by idiopathic
dilatation and systolic contractile dysfunction of the ventricle(s) leading to
an impaired systolic function. The origin of DCM is heterogeneous, but genetic
transmission of the disease accounts for up to 50% of the cases. Mutations in
alpha-tropomyosin (TPM1), a thin filament protein involved in structural and
regulatory roles in muscle cells, are associated with hypertrophic
cardiomyopathy (HCM) and very rarely with DCM.
METHODS AND RESULTS: Here we present a large four-generation family in which DCM
is inherited as an autosomal dominant trait. Six family members have a
cardiomyopathy with the age of diagnosis ranging from 5 months to 52 years. The
youngest affected was diagnosed with dilated and non-compaction cardiomyopathy
(NCCM) and died at the age of five. Three additional children died young of
suspected heart problems. We mapped the phenotype to chromosome 15 and
subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino
acid substitution. In addition we sequenced 23 HCM/DCM genes using next
generation sequencing. The TPM1 p.D84N was the only mutation identified. The
mutation co-segregates with all clinically affected family members and
significantly weakens the binding of tropomyosin to actin by 25%.
CONCLUSIONS: We show that a mutation in TPM1 is associated with DCM and a
lethal, early onset form of NCCM, probably as a result of diminished actin
binding caused by weakened charge-charge interactions. Consequently, the
screening of TPM1 in patients and families with DCM and/or (severe, early onset
forms of) NCCM is warranted. This article is part of a Special Issue entitled:
Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and
Contraction.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2012.11.003
PMID: 23147248 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23715514
|
1. Oncotarget. 2013 May;4(5):739-50. doi: 10.18632/oncotarget.1034.
Musashi1 as a potential therapeutic target and diagnostic marker for lung
cancer.
Wang XY(1), Yu H, Linnoila RI, Li L, Li D, Mo B, Okano H, Penalva LO, Glazer RI.
Author information:
(1)Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA.
Lung cancer remains one of the leading causes of cancer-related deaths worldwide
with a 5-year survival rate of less than 20%. One approach to improving survival
is the identification of biomarkers to detect early stage disease. In this
study, we investigated the potential of the stem cell and progenitor cell
marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target
for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and
NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in
spheroid cultures of tumor cells and in the CD133+ cell population.
Downregulation of Msi1 by lentivirus-mediated expression of an Msi1 shRNA
reduced spheroid colony proliferation. Growth inhibition was associated with
reduced nuclear localization of β-catenin and inhibition of the processing of
intracellular Notch. In primary lung cancer, Msi1 protein expression was
elevated in 86% of 202 tissue microarray specimens, and Msi1 mRNA was increased
in 80% of 118 bronchoscopic biopsies, including metastatic disease, but was
rarely detected in adjacent normal lung tissue and in non-malignant diseased
tissue. Msi1 was expressed in a diffuse pattern in most tumor subtypes, except
in squamous cell carcinomas, where it appeared in a focal pattern in 50% of
specimens. Thus, Msi1 is a sensitive and specific diagnostic marker for all lung
cancer subtypes.
DOI: 10.18632/oncotarget.1034
PMCID: PMC3742834
PMID: 23715514 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11830536
|
1. Cancer Res. 2002 Feb 1;62(3):801-8.
The CLN3 gene is a novel molecular target for cancer drug discovery.
Rylova SN(1), Amalfitano A, Persaud-Sawin DA, Guo WX, Chang J, Jansen PJ, Proia
AD, Boustany RM.
Author information:
(1)Department of Pediatrics, Duke University Medical Center, Durham, North
Carolina 27710, USA.
Juvenile Batten disease is a neurodegenerative disease caused by accelerated
apoptotic death of photoreceptors and neurons attributable to defects in the
CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor
cells. CLN3 negatively modulates endogenous ceramide levels in NT2 cells and
acts upstream of ceramide generation. Because defects in regulation of apoptosis
are involved in the development of cancer, we evaluated the expression of CLN3
on both mRNA and protein levels in a variety of cancer cell lines and solid
colon cancer tissue. We also observed the effect of the blocking of CLN3 protein
expression on cancer cell growth, survival, ceramide production, and apoptosis
by using an adenovirus-bearing antisense CLN3 construct. We show that CLN3 mRNA
and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma
(IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3,
SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480,
and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung
(A-549 and NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse
melanoma and breast carcinoma cancer cell lines. We found CLN3 expression is
22-330% higher than in corresponding normal colon control tissue in 8 of 10
solid colon tumors. An adenovirus-expressing antisense CLN3 (Ad-AS-CLN3) blocks
CLN3 protein expression in DU-145, BT-20, SW1116, and T98g cancer cell lines as
seen by Western blot. Blocking of CLN3 expression using Ad-AS-CLN3 inhibits
growth and viability of cancer cells. It also causes elevation in endogenous
ceramide production through de novo ceramide synthesis and results in increased
apoptosis as shown by propidium iodide and JC-1 staining. This suggests that
Ad-AS-CLN3 may be an option for therapy in some cancers. More importantly these
results suggest that CLN3 is a novel molecular target for cancer drug discovery.
PMID: 11830536 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7482779
|
1. Trends Genet. 1995 Jul;11(7):283-90. doi: 10.1016/s0168-9525(00)89076-9.
Dinucleotide relative abundance extremes: a genomic signature.
Karlin S(1), Burge C.
Author information:
(1)Department of Mathematics, Stanford University, CA 94305-2125, USA.
Early biochemical experiments established that the set of dinucleotide odds
ratios or 'general design' is a remarkably stable property of the DNA of an
organism, which is essentially the same in protein-coding DNA, bulk genomic DNA,
and in different renaturation rate and density gradient fractions of genomic DNA
in many organisms. Analysis of currently available genomic sequence data has
extended these earlier results, showing that the general designs of disjoint
samples of a genome are substantially more similar to each other than to those
of sequences from other organisms and that closely related organisms have
similar general designs. From this perspective, the set of dinucleotide odds
ratio (relative abundance) values constitute a signature of each DNA genome,
which can discriminate between sequences from different organisms.
Dinucleotide-odds ratio values appear to reflect not only the chemistry of
dinucleotide stacking energies and base-step conformational preferences, but
also the species-specific properties of DNA modification, replication and repair
mechanisms.
DOI: 10.1016/s0168-9525(00)89076-9
PMID: 7482779 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19968287
|
1. J Med Chem. 2010 Jan 14;53(1):139-46. doi: 10.1021/jm900803q.
In vivo positron emission tomography (PET) imaging of mesenchymal-epithelial
transition (MET) receptor.
Wu C(1), Tang Z, Fan W, Zhu W, Wang C, Somoza E, Owino N, Li R, Ma PC, Wang Y.
Author information:
(1)Division of Radiopharmaceutical Science, Case Center for Imaging Research,
Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106,
USA.
We report the radiosynthesis and evaluation of
3-[3,5-dimethyl-4-(4-[11C]methylpiperazinecarbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic
acid (3-chlorophenyl)methylamide, termed [11C]SU11274 ([11C]14) for in vivo
imaging of mesenchymal-epithelial transition (MET) receptor by positron emission
tomography (PET). Following the synthesis of the precursor (13) that was
achieved in 10 steps with a total yield of 9.7%, [11C]14 was obtained through
radiomethylation in a range of 5-10% radiochemical yield and over 95%
radiochemical purity. For in vivo PET studies, two human lung cancer xenograft
models were established using MET-positive NCI-H1975 and MET-negative NCI-H520
cell lines. Quantitative [11C]14-PET studies showed that the tumor uptake of
[11C]14 in the NCI-H1975 xenografts was significantly higher than that in the
NCI-H520 xenografts, which is consistent with their corresponding
immunohistochemical tissue staining patterns of MET receptors from the same
animals. These studies demonstrated that [11C]14-PET is an appropriate imaging
marker for quantification of MET receptor in vivo, which can facilitate efficacy
evaluation in the clinical development of MET-targeted cancer therapeutics.
DOI: 10.1021/jm900803q
PMID: 19968287 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17947214
|
1. Eur Heart J. 2007 Nov;28(22):2732-7. doi: 10.1093/eurheartj/ehm429. Epub 2007
Oct 17.
Cardiac beta-myosin heavy chain defects in two families with non-compaction
cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated
cardiomyopathies.
Hoedemaekers YM(1), Caliskan K, Majoor-Krakauer D, van de Laar I, Michels M,
Witsenburg M, ten Cate FJ, Simoons ML, Dooijes D.
Author information:
(1)Department of Clinical Genetics, Erasmus Medical Centre, Dr Molewaterplein
50, 3015GE Rotterdam, The Netherlands.
Comment in
Eur Heart J. 2008 Apr;29(7):949-50; author reply 950-1. doi:
10.1093/eurheartj/ehn029.
Cardiomyopathies are classified according to distinct morphological
characteristics. They occur relatively frequent and are an important cause of
mortality and morbidity. Isolated ventricular non-compaction or non-compaction
cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial
layer with deep intertrabecular recesses, reminiscent of the myocardium during
early embryogenesis. Aims Autosomal-dominant as well as X-linked inheritance for
NCCM has been described and several loci have been associated with the disease.
Nevertheless, a major genetic cause for familial NCCM remains to be identified.
Methods and Results We describe, in two separate autosomal-dominant NCCM
families, the identification of mutations in the sarcomeric cardiac beta-myosin
heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy
(HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM).
Conclusion These results confirm the genetic heterogeneity of NCCM and suggest
that the molecular classification of cardiomyopathies includes an
MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.
DOI: 10.1093/eurheartj/ehm429
PMID: 17947214 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24129315
|
1. Mol Cell Proteomics. 2014 Jan;13(1):372-87. doi: 10.1074/mcp.O113.027870. Epub
2013 Oct 15.
Immunoaffinity enrichment and mass spectrometry analysis of protein methylation.
Guo A(1), Gu H, Zhou J, Mulhern D, Wang Y, Lee KA, Yang V, Aguiar M, Kornhauser
J, Jia X, Ren J, Beausoleil SA, Silva JC, Vemulapalli V, Bedford MT, Comb MJ.
Author information:
(1)Cell Signaling Technology Inc., 3 Trask Lane, Danvers, Massachusetts 01923;
Protein methylation is a common posttranslational modification that mostly
occurs on arginine and lysine residues. Arginine methylation has been reported
to regulate RNA processing, gene transcription, DNA damage repair, protein
translocation, and signal transduction. Lysine methylation is best known to
regulate histone function and is involved in epigenetic regulation of gene
transcription. To better study protein methylation, we have developed highly
specific antibodies against monomethyl arginine; asymmetric dimethyl arginine;
and monomethyl, dimethyl, and trimethyl lysine motifs. These antibodies were
used to perform immunoaffinity purification of methyl peptides followed by
LC-MS/MS analysis to identify and quantify arginine and lysine methylation sites
in several model studies. Overall, we identified over 1000 arginine methylation
sites in human cell line and mouse tissues, and ∼160 lysine methylation sites in
human cell line HCT116. The number of methylation sites identified in this study
exceeds those found in the literature to date. Detailed analysis of
arginine-methylated proteins observed in mouse brain compared with those found
in mouse embryo shows a tissue-specific distribution of arginine methylation,
and extends the types of proteins that are known to be arginine methylated to
include many new protein types. Many arginine-methylated proteins that we
identified from the brain, including receptors, ion channels, transporters, and
vesicle proteins, are involved in synaptic transmission, whereas the most
abundant methylated proteins identified from mouse embryo are transcriptional
regulators and RNA processing proteins.
DOI: 10.1074/mcp.O113.027870
PMCID: PMC3879628
PMID: 24129315 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11857738
|
1. Hum Mutat. 2002 Mar;19(3):225-33. doi: 10.1002/humu.10044.
HbVar: A relational database of human hemoglobin variants and thalassemia
mutations at the globin gene server.
Hardison RC(1), Chui DH, Giardine B, Riemer C, Patrinos GP, Anagnou N, Miller W,
Wajcman H.
Author information:
(1)Department of Biochemistry and Molecular Biology, Pennsylvania State
University, University Park, Pennsylvania, USA.
We have constructed a relational database of hemoglobin variants and thalassemia
mutations, called HbVar, which can be accessed on the web at
http://globin.cse.psu.edu. Extensive information is recorded for each variant
and mutation, including a description of the variant and associated pathology,
hematology, electrophoretic mobility, methods of isolation, stability
information, ethnic occurrence, structure studies, functional studies, and
references. The initial information was derived from books by Dr. Titus Huisman
and colleagues [Huisman et al., 1996, 1997, 1998]. The current database is
updated regularly with the addition of new data and corrections to previous
data. Queries can be formulated based on fields in the database. Tables of
common categories of variants, such as all those involving the alpha1-globin
gene (HBA1) or all those that result in high oxygen affinity, are maintained by
automated queries on the database. Users can formulate more precise queries,
such as identifying "all beta-globin variants associated with instability and
found in Scottish populations." This new database should be useful for clinical
diagnosis as well as in fundamental studies of hemoglobin biochemistry, globin
gene regulation, and human sequence variation at these loci.
Copyright 2002 Wiley-Liss, Inc.
DOI: 10.1002/humu.10044
PMID: 11857738 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16798224
|
1. Ann Thorac Surg. 2006 Jul;82(1):249-53. doi: 10.1016/j.athoracsur.2006.02.033.
Inhibition of retinoblastoma tumor suppressor activity by RNA interference in
lung cancer lines.
Reed MF(1), Zagorski WA, Howington JA, Zilfou JT, Knudsen ES.
Author information:
(1)Division of Thoracic Surgery, Department of Surgery, University of Cincinnati
College of Medicine, Cincinnati, Ohio 45267-0558, USA. michael.reed@uc.edu
BACKGROUND: Inactivation of retinoblastoma (RB) tumor suppressor function occurs
frequently in lung cancer. Short-hairpin RNA can be constructed to target
specific sequences and efficiently knock down protein expression. We developed a
short-hairpin RNA approach to specifically target Rb in lung cancer cells to
determine the influence of RB knockdown on proliferation.
METHODS: NCI-H520 human lung cancer cells (wild-type Rb) were transfected with
pMSCVpuro-Rb3C, a plasmid containing a short-hairpin sequence targeted to human
Rb. Transfectants harboring the construct were selected with puromycin. Loss of
RB expression in selected cell populations was determined by immunoblotting.
Proliferating cells were counted to establish growth rates.
Retinoblastoma-proficient and RB-deficient tumor growth was monitored in nude
mice.
RESULTS: Transfection with pMSCVpuro-Rb3C dramatically diminished RB expression
and led to aberrant expression of RB-regulated genes. Cells harboring
pMSCVpuro-Rb3C grew at an increased rate compared with control cells: 480.6 +/-
37.7 versus 159.4 +/- 36.2 (relative cell count at 12 days). Tumor growth in
nude mice also increased with RB knockdown compared with control mice: 135.2 +/-
73.6 mm3 versus 40.0 +/- 17.0 mm3 (tumor volume at 10 days).
CONCLUSIONS: Inhibition of RB expression is efficiently achieved in lung cancer
cells with short-hairpin RNA. Genetic targets of RB are deregulated with RB
knockdown. Retinoblastoma depletion increases growth in vitro and in murine
xenografts. These studies indicate that even in the context of an established
tumor cell line, RB limits tumorigenic proliferation. Additionally, this model
will serve as an ideal system to evaluate the role of RB activity on therapeutic
response.
DOI: 10.1016/j.athoracsur.2006.02.033
PMID: 16798224 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22562359
|
1. Mol Cells. 2012 Jun;33(6):553-62. doi: 10.1007/s10059-012-2269-2. Epub 2012
May 4.
Lentiviral vector-mediated shRNA against AIMP2-DX2 suppresses lung cancer cell
growth through blocking glucose uptake.
Chang SH(1), Chung YS, Hwang SK, Kwon JT, Minai-Tehrani A, Kim S, Park SB, Kim
YS, Cho MH.
Author information:
(1)Laboratory of Toxicology, College of Veterinary Medicine, Seoul National
University, Seoul 151-742, Korea.
Aminoacyl-tRNA synthetases [ARS]-interacting multifunctional protein 2 (AIMP2)
has been implicated in the control of cell fate and lung cell differentiation. A
variant of AIMP2 lacking exon 2 (AIMP2-DX2) is expressed in different cancer
cells. We previously studied the expression level of AIMP2-DX2 in several lung
cell lines and reported elevated expression levels of AIMP2-DX2 in NCI-H460 and
NCI-H520. Here, we report that the suppression of AIMP2-DX2 by lentivirus
mediated short hairpin (sh)RNA (sh-DX2) decreased the rate of glucose uptake and
glucose transporters (Gluts) in NCI-H460 cells. Down-regulation of AIMP2-DX2
reduced glycosyltransferase (GnT)-V in the Golgi apparatus, while inducing the
GnT-V antagonist GnT-III. Down-regulation of AIMP2-DX2 also suppressed the
epidermal growth factor receptor/mitogen activated protein kinase (EGFR/MAPK)
signaling pathway, leading to the decrease of the proliferation marker Ki-67
expression in nuclei. Furthermore, dual luciferase activity reduced capdependent
protein translation in cells infected with sh-DX2. These results suggest that
AIMP2-DX2 may be a relevant therapeutic target for lung cancer, and that the
sh-DX2 lentiviral system can be an appropriate method for lung cancer therapy.
DOI: 10.1007/s10059-012-2269-2
PMCID: PMC3887752
PMID: 22562359 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14586397
|
1. Oncogene. 2003 Oct 30;22(49):7711-5. doi: 10.1038/sj.onc.1207088.
Allele-specific patterns of the mouse parathyroid hormone-related protein:
influences on cell adhesion and migration.
Benelli R(1), Peissel B, Manenti G, Gariboldi M, Vanzetto C, Albini A, Dragani
TA.
Author information:
(1)Molecular Biology Laboratory, Istituto Nazionale per la Ricerca sul Cancro,
Genoa, Italy.
The mouse parathyroid hormone-like hormone Pthlh(Pro) and Pthlh(Thr) variants
are linked with susceptibility and resistance to skin carcinogenesis of Car-S
and Car-R mice, respectively, and with in vitro effects (Oncogene, 19:
5324-5328, 2000). We have identified an additional Pthlh variant, consisting of
Thr and three amino-acid changes in the C-terminus (Pthlh(SerAspTyr)), carried
by an evolutionarily distant Mus spretus (SPRET/Ei) inbred strain. When
transfected into NCI-H520 tumor cells, this Pthlh(SerAspTyr) variant did not
stimulate tumor growth in nude mice. Analysis of cell adhesion, migration, and
invasion patterns of Pthlh(Pro)-, Pthlh(Thr)-, and Pthlh(SerAspTyr)-transfected
NCI-H520 cells revealed a 1.5-fold decrease in adhesion efficiency on both
collagen type I and Matrigel, and a 5-6-fold increase in migration capability in
Pthlh(Pro) transfectants as compared to nontransfected, vector-transfected,
Pthlh(Thr)-, or Pthlh(SerAspTyr)-transfected cells. These findings suggest that
the cancer modifier effects of the mouse Pthlh gene are mediated by differential
cell adhesion and migration effects of PTHrP variants.
DOI: 10.1038/sj.onc.1207088
PMID: 14586397 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22328940
|
1. PLoS One. 2012;7(2):e31605. doi: 10.1371/journal.pone.0031605. Epub 2012 Feb
6.
TET2 mutations are associated with specific 5-methylcytosine and
5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic
leukemia.
Pérez C(1), Martínez-Calle N, Martín-Subero JI, Segura V, Delabesse E,
Fernandez-Mercado M, Garate L, Alvarez S, Rifon J, Varea S, Boultwood J,
Wainscoat JS, Cruz Cigudosa J, Calasanz MJ, Cross NC, Prósper F, Agirre X.
Author information:
(1)Laboratory of Myeloproliferative Syndromes, Oncology Area, University of
Navarra, Pamplona, Spain.
Chronic myelomonocytic leukemia (CMML) has recently been associated with a high
incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated
in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays
and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24
patients with CMML. 249 genes were differentially methylated between CMML
patients and controls. Using Ingenuity pathway analysis, we identified
enrichment in a gene network centered around PLC, JNK and ERK suggesting that
these pathways, whose deregulation has been recently described in CMML, are
affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found
in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no
mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients
with wild type TET2 clustered separately from patients with TET2 mutations,
showed a higher degree of hypermethylation and were associated with higher risk
karyotypes. Our results demonstrate the presence of aberrant DNA methylation in
CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype
with a different epigenetic profile.
DOI: 10.1371/journal.pone.0031605
PMCID: PMC3273467
PMID: 22328940 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/9099905
|
1. Mol Cell Endocrinol. 1997 Mar 14;127(1):99-108. doi:
10.1016/s0303-7207(96)03994-9.
The noncalcemic vitamin D analogues EB1089 and 22-oxacalcitriol interact with
the vitamin D receptor and suppress parathyroid hormone-related peptide gene
expression.
Falzon M(1).
Author information:
(1)Department of Pharmacology and Toxicology, and Sealy Center for Molecular
Science, The University of Texas Medical Branch, Galveston 77555, USA.
Humoral hypercalcemia of malignancy, a frequent complication of squamous cell
carcinomas of the lung, is mediated by the parathyroid hormone-related peptide
(PTHrP). This study was undertaken to determine whether 1,25-dihydroxyvitamin
D(3) [1,25(OH)(2)D(3)] and two nonhypercalcemic analogues. EB1089 and
22-oxa-1,25(OH)(2)D(3) (OCT), suppress PTHrP gene expression in a human lung
squamous cancer cell line, NCI H520. All three compounds (1) decreased
steady-state PTHrP mRNA and secreted peptide levels via a transcriptional
mechanism; (2) modulated promoter activity of 1,25(OH)(2)D(3)-responsive DNA
sequences; and (3) activated the vitamin D receptor (VDR) both in vitro and in
vivo. Thus, EB1089 and OCT inhibit PTHrP gene expression in NCI H520 cells and
modulate gene expression through the same mechanism as 1,25(OH)(2)D(3), namely,
activation of the VDR. 1,25(OH)(2)D(3) is hypercalcemic in vivo. However, the
noncalcemic analogues EB1089 and OCT have a therapeutic potential through
suppression of PTHrP gene transcription.
DOI: 10.1016/s0303-7207(96)03994-9
PMID: 9099905 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16462760
|
1. Oncogene. 2006 Jun 29;25(28):3934-8. doi: 10.1038/sj.onc.1209422. Epub 2006
Feb 6.
Identification of RASSF8 as a candidate lung tumor suppressor gene.
Falvella FS(1), Manenti G, Spinola M, Pignatiello C, Conti B, Pastorino U,
Dragani TA.
Author information:
(1)Department of Experimental Oncology and Laboratories, Istituto Nazionale
Tumori, Milan, Italy.
The RASSF8 gene, which maps close to the KRAS2 gene, contains a RAS-associated
domain and encodes a protein that is evolutionarily conserved from fish to
humans. Analysis of the RASSF8 transcript revealed a complex expression pattern
of 5'-UTR mRNA isoforms in normal lung and in lung adenocarcinomas (ADCAs), with
no apparent differences. However, RASSF8 gene transcript levels were
approximately seven-fold-lower in lung ADCAs as compared to normal lung tissue.
Expression of RASSF8 protein by transfected lung cancer cells led to inhibition
of anchorage-independent growth in soft agar in A549 cells and reduction of
clonogenic activity in NCI-H520 cells. These results raise the possibility
protein encoded by RASSF8 is a novel tumor suppressor for lung cancer.
DOI: 10.1038/sj.onc.1209422
PMID: 16462760 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12964003
|
1. Int J Oncol. 2003 Oct;23(4):1187-93.
Oridonin induces growth inhibition and apoptosis of a variety of human cancer
cells.
Ikezoe T(1), Chen SS, Tong XJ, Heber D, Taguchi H, Koeffler HP.
Author information:
(1)Department of Internal Medicine, Kochi Medical School, Nankoku, Kochi
783-8505, Japan. ikezoet@med.kochi-ms.ac.jp
PC-SPES is an eight herbal mixture that was shown to have activity against
prostate cancer. Recently, we purified oridonin from Rabdosia rubescens, one
component of PC-SPES, by high performance liquid chromatography (HPLC). The
ability of oridonin to inhibit the proliferation of cancer cells was examined by
MTT assay. Oridonin effectively inhibited the proliferation of a wide variety of
cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7,
MDA-MB231), non-small cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers,
acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138)
with ED50s ranging from 1.8 to 7.5 micro g/ml. TUNEL assay and cell cycle
analysis showed that oridonin induced apoptosis and G0/G1 cell cycle arrest in
LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in
LNCaP and NCI-H520 cells in a p53-dependent manner. Interestingly, when p53 was
suppressed by over-expression of E6 from human papilloma virus type 16 (HPV-16),
these cells lost their sensitivity to oridonin-induced growth inhibition and
apoptosis. Taken together, oridonin inhibited the proliferation of cancer cells
via apoptosis and cell cycle arrest with p53 playing a central role in several
cancer types which express the wild-type p53 gene. Oridonin may be a novel,
adjunctive therapy for a large variety of malignancies and probably represents
one of the major, active components of PC-SPES.
PMID: 12964003 [Indexed for MEDLINE]
|
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