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10.1038/sj.bjp.0702634 | 124,464,216 | In the present study, we have observed the development of an inflammatory reaction in the rat hindpaw, following the injection of specific agonists of PAR 2 (two PAR 2 activating peptides). This inflammation was characterized by oedema and granulocyte infiltration. Two selective PAR 2 activating peptides, SLGRL‐NH 2 an... | 10.1038/nrd3615 | This study first established a role for PAR2 in regulating peripheral inflammation. |
10.1038/sj.bjp.0702408 | 39,997,621 | Thrombin has well characterized pro‐inflammatory actions that have recently been suggested to occur via activation of its receptor, proteinase‐activated receptor‐1 (PAR 1 ). In the present study, we have compared the effects of thrombin to those of two peptides that selectively activate the PAR 1 receptor, in a rat hin... | 10.1038/nrd3615 | This study first established a role for PAR1 in regulating peripheral inflammation. |
10.1126/science.1071699 | 60,428,211 | The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 ... | 10.1038/nrd3615 | This was the first study to demonstrate that biased PAR1 signalling by APC is distinct from thrombin-stimulated signalling, implying a role for APC–PAR1 signalling in sepsis. |
10.4049/jimmunol.170.5.2638 | 110,257,775 | Abstract Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is activated by thrombin and is implicated in the pathogenesis of inflammation. Although PAR-1 is expressed on immunocompetent cells within the brain such as astrocytes, little is known about its role in the pathogenesis of inflammato... | 10.1038/nrd3615 | This was one of the first studies to show that PAR1 can be involved in CNS neurotoxicity. |
10.1073/pnas.1017091108 | 27,011,124 | Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays a key role in a number of acute and chronic inflammatory diseases of the joints, lungs, brain, gastrointestinal tract, and vascular systems. Despite considerable effort by the pharmaceutical industry, PAR2 has proven recalci... | 10.1038/nrd3615 | This was one of the first studies to provide proof of concept that PAR2 pepducin antagonists are able to inhibit inflammatory responses in vivo |
10.1073/pnas.96.22.12257 | 58,875,015 | Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease α-thrombin, is expressed in va... | 10.1038/nrd3615 | This study reported the first successful synthesis and use of a PAR1-targeted peptidomimetic antagonist. |
10.1086/519201 | 15,852,852 | Objective. To compare the effects of hospital cleaning agents and germicides on the survival of epidemic Clostridium difficile strains. Methods. We compared the activity of and effects of exposure to 5 cleaning agents and/or germicides (3 containing chlorine, 1 containing only detergent, and 1 containing hydrogen perox... | 10.1038/nrmicro2164 | Quantification of the activity of detergents and disinfectants against C. difficile and the potential for some of these products to promote sporulation. |
10.2337/diabetes.53.7.1643 | 83,183,259 | The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear, and it has been suggested that an unidentified “work factor” exists that influences the contraction-induced increase in endogenous glucose production (EGP). The cytokine interleukin (IL)-6 is release... | 10.1038/nrd.2016.153 | A significant finding in the identification of IL-6 as a secreted product of skeletal muscle that carries out endocrine functions. |
10.1002/bies.20085 | 82,472,432 | Abstract Poly(ADP‐ribosyl)ation is an immediate DNA‐damage‐dependent post‐translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP‐ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and d... | 10.1038/nrd1718 | A recent and comprehensive review on the various PARP isoforms. |
10.1073/pnas.94.14.7303 | 84,497,601 | Poly(ADP-ribose) polymerase [PARP; NAD + ADP-ribosyltransferase; NAD + : poly(adenosine-diphosphate- d -ribosyl)-acceptor ADP- d -ribosyltransferase, EC 2.4.2.30 ] is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents. To determine its biological function, we hav... | 10.1038/nrd1718 | A definitive study showing the different radiosensitivity of PARP1-deficient and wild-type mice. |
10.1073/pnas.052712399 | 18,523,533 | Poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30 ), a nuclear enzyme activated by DNA strand breaks, physiologically participates in DNA repair. Excessive activation of PARP-1 by cellular insults depletes its substrate β-nicotinamide adenine dinucleotide and ATP, leading to cell death. PARP-1-deficient (PARP-1 −/− ) ... | 10.1038/nrd1718 | This report shows that PARP regulates signal transduction and gene expression in immunostimulated cells. |
10.1046/j.1365-2567.1998.00534.x | 58,526,797 | The mechanisms by which immature thymocyte apoptosis is induced during negative selection are poorly defined. Reports demonstrated that cross‐linking of T‐cell receptor leads to stromal cell activation, expression of inducible nitric oxide synthase (iNOS) and, subsequently, to thymocyte apoptosis. Therefore we examined... | 10.1038/nrd1718 | This was the first definitive report showing that PARP activation promotes cell necrosis. |
10.1126/science.8080500 | 105,428,726 | Poly(adenosine 5′-diphosphoribose) synthetase (PARS) is a nuclear enzyme which, when activated by DNA strand breaks, adds up to 100 adenosine 5′-diphosphoribose (ADP-ribose) units to nuclear proteins such as histones and PARS itself. This activation can lead to cell death through depletion of β-nicotinamide adenine din... | 10.1038/nrd1718 | A seminal report linking NO overproduction, PARP activation and neurotoxicity. |
10.1073/pnas.93.5.1753 | 18,810,523 | The free radicals nitric oxide and superoxide anion react to form peroxynitrite (ONOO-), a highly toxic oxidant species. In vivo formation of ONOO- has been demonstrated in shock and inflammation. Herein we provide evidence that cytotoxicity in cells exposed to ONOO- is mediated by DNA strand breakage and the subsequen... | 10.1038/nrd1718 | This report describes the identification of peroxynitrite (the reaction product of NO and superoxide) as an endogenous trigger of DNA single-strand breakage and PARP activation. |
10.1073/pnas.93.15.7481 | 84,497,608 | The crystal structures of the catalytic fragment of chicken poly(ADP-ribose) polymerase [NAD+ ADP-ribosyltransferase; NAD+:poly(adenosine-diphosphate-D-ribosyl)-acceptor ADP-D-ribosyltransferase, EC 2.4.2.30] with and without a nicotinamide-analogue inhibitor have been elucidated. Because this enzyme is involved in the... | 10.1038/nrd1718 | This paper describes the characterization of the catalytic site of PARP. |
10.1126/science.1125703 | 18,702,816 | In contrast to naïve T cells that recognize short antigen-derived peptides displayed by specialized antigen-presenting cells, immunoglobulin receptors of B lymphocytes primarily recognize intact proteins. How and where within a lymph node such unprocessed antigens become available for naïve B cell recognition is not ... | 10.1038/nri3469 | References 8 and 9use two-photon microscopy to visualize in vivo how B cells capture antigen from FDCs in primary follicles or from DCs upon entry to the lymph nodes. |
10.1126/science.1123940 | 18,937,211 | B cells recognize foreign antigens by virtue of cell surface immunoglobulin receptors and are most effectively activated by membrane-bound ligands. Here, we show that in the early stages of this process, B cells exhibit a two-phase response in which they first spread over the antigen-bearing membrane and then contract,... | 10.1038/nri3469 | This paper describes the two-phase spreading and contraction response exerted by B cells that are in contact with membrane-bound antigens. This response promotes antigen gathering into a central cluster at the synapse. |
10.4049/jimmunol.1101527 | 36,559,242 | Abstract Binding of Ag by B cells leads to signal transduction downstream of the BCR and to delivery of the internalized Ag–BCR complex to lysosomes where the Ag is processed and presented on MHC class II molecules. T cells that recognize the peptide–MHC complexes provide cognate help to B cells in the form of costimul... | 10.1038/nri3469 | This paper shows that BCR signalling that is initiated at the plasma membrane continues in intracellular compartments, initiating a sequential phosphorylation of kinases. |
10.1126/science.1213495 | 20,040,005 | Stochastic or Asymmetric Fate Determination? During an adaptive immune response, B lymphocytes rapidly divide and differentiate into effector cell populations, including antibody-secreting plasmablasts and memory B cells. Many also change the class of antibody they secrete, through a process called isotype switching. D... | 10.1038/nri3469 | This study describes how, following cell division, germinal centre B cells asymmetrically segregate molecules that are involved in B cell fate, as well as the ancestral polarity protein PKCζ,to generate unequal daughter cells. |
10.1126/science.1080944 | 123,204,080 | Cell polarization can occur in the absence of any spatial cues. To investigate the mechanism of spontaneous cell polarization, we used an assay in yeast where expression of an activated form of Cdc42, a Rho-type guanosine triphosphatase (GTPase) required for cell polarization, could generate cell polarity without any r... | 10.1038/nri3469 | This is an important paper, showing the role of CDC42 in cell polarity. In this paper, experiments that are corroborated by a mathematical model show that a stable axis of polarity arises in yeast from a positive feedback mechanism that amplifies a random concentration of activated CDC42. This work suggests that sponta... |
10.1101/gad.251903 | 44,904,993 | We investigated the translational regulation of SCL protein expression and its role in hematopoietic lineage choice. We show that the expression of different SCL protein isoforms is regulated by signal transduction pathways that modulate translation initiation factor (eIF) function. A conserved small upstream open read... | 10.1038/nri2024 | References 84 and 85 show another mechanism for transcription factor tuning; through varying protein isoform expression, as controlled by small sequence motifs in the untranslated upstream open-reading frames. |
10.1182/blood.v93.6.1817.406k36_1817_1824 | 123,257,554 | The AML1 gene encoding the DNA-binding -subunit in the Runt domain family of heterodimeric transcription factors has been noted for its frequent involvement in chromosomal translocations associated with leukemia. Using reverse transcriptase-polymerase chain reaction (RT-PCR) combined with nonisotopic RNase cleavage as... | 10.1038/nri2024 | This study shows that RUNX1 could be involved in the pathogenesis of AML through a mechanism other than translocation, and that RUNX1 mutations were associated with a distinct differentiation subtype of AML. |
10.1073/pnas.1115634109 | 82,781,581 | Although many types of ancient bacteria and archea rely on hydrogen sulfide (H 2 S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H 2 S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to cop... | 10.1038/nrd4433 | This study shows that increases in intracellular calcium promote translocation of CSE to the mitochondrion, leading to increased mitochondrial H 2 S production and improved ATP production under hypoxic conditions. |
10.1126/scisignal.2000464 | 62,607,345 | The gaseous messenger hydrogen sulfide regulates target proteins through S-sulfhydration of cysteine residues. | 10.1038/nrd4433 | This paper identifies the original discovery of the chemical interaction of H 2 S with proteins (that is, protein S -sulfhydration). |
10.1161/atvbaha.110.209783 | 123,205,336 | Objective— Recent studies have demonstrated that hydrogen sulfide (H 2 S) is produced within the vessel wall from l -cysteine regulating several aspects of vascular homeostasis. H 2 S generated from cystathione γ-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing eff... | 10.1038/nrd4433 | This paper reports the original discovery that H 2 S activates cGMP signalling via the inhibition of PDE, which contributes to the vasorelaxant and anti-inflammatory effects of H 2 S. |
10.1126/science.1162667 | 104,326,574 | Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H 2 S) is now receiving increasing attention. Here we show that H 2 S is physiological... | 10.1038/nrd4433 | This study provides direct evidence for the physiological importance of endogenous H 2 S (mice deficient in CSE displayed significant elevations of blood pressure). |
10.1152/ajpheart.00013.2002 | 19,492,290 | H 2 S is endogenously generated in vascular smooth muscle cells. The signal transduction pathways involved in the vascular effects of H 2 S have been unclear and were investigated in the present study. H 2 S induced a concentration-dependent relaxation of rat aortic tissues that was not affected by vascular denervation... | 10.1038/nrd4433 | This paper reveals some of the mechanisms underlying H 2 S-induced vasodilation, including the contributions of Ca 2+ and the vascular endothelium. |
10.1073/pnas.1105121108 | 103,911,480 | The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H 2 S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro “hyperglycemia”) induced the mitochondrial formation ... | 10.1038/nrd4433 | This paper shows that endogenous or exogenous H 2 S can prevent hyperglycaemia-associated damage to the vascular endothelium, indicating the therapeutic potential of H 2 S in the prevention of diabetes-associated vasculopathy. |
10.1073/pnas.0705891104 | 83,268,385 | The recent discovery that hydrogen sulfide (H 2 S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H 2 S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H 2... | 10.1038/nrd4433 | In this study, the potent cardioprotective effects of H 2 S were demonstrated in experimental myocardial infarction, and shown to be largely attributable to the preservation of myocardial mitochondrial function and reduced production of reactive oxygen species. |
10.4049/jimmunol.170.7.3528 | 42,578,804 | Abstract Abs of the IgG isotype are efficiently transported from mother to neonate and have an extended serum t1/2 compared with Abs of other isotypes. Circumstantial evidence suggests that the MHC class I-related protein, the neonatal FcR (FcRn), is the FcR responsible for both in vivo functions. To understand the phe... | 10.1038/nri2155 | A description of the FcRn-deficient mouse, which confirms the contribution of FcRn to the phenotypes of defective neonatal IgG transfer and shortened serum IgG half-life that were observed in β 2 m-deficient mice. |
10.1126/science.1079293 | 17,729,425 | The proteasome plays a central role in the degradation of regulatory and misfolded proteins. Current models suggest that substrates access the internal catalytic sites by processively threading their termini through the gated substrate channel. Here, we found that latent (closed) and activated (open) proteasomes degrad... | 10.1038/nrm1336 | Provides some of the clearest evidence that proteasome proteolysis can begin at an internal loop of the polypeptide chain of the substrate. |
10.1210/jc.2005-0987 | 82,933,497 | Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients,... | 10.1038/nrc3431 | This is the first comprehensive multicentre study that shows the association of BRAF mutation with aggressive behaviours of PTC, including aggressive pathological features, disease recurrence, loss of radioiodine avidity of the tumour and treatment failure. |
10.1002/cncr.26500 | 83,182,565 | Abstract BACKGROUND: The effects of the BRAF V600E mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta‐analysis to assess the strength of associations between these conditions and the BRAF V600E mutation. ME... | 10.1038/nrc3431 | This is a large meta-analysis on the relationship of BRAF mutation with clinicopathological behaviours of PTC. |
10.1210/jc.2008-0273 | 104,125,884 | Abstract Context: Genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways have not been fully defined in anaplastic and follicular thyroid cancers [anaplastic thyroid cancer (ATC), follicular thyroid cancer (FTC)]. Objective: The objective of the study was ... | 10.1038/nrc3431 | This study demonstrates a high prevalence of genetic alterations that can activate both the MAPK and PI3K–AKT pathways in aggressive thyroid cancer, thus providing a strong genetic basis for the joint role of the two pathways in the progression and aggressiveness of thyroid cancer. |
10.1126/science.290.5489.138 | 80,681,683 | Rearrangements involving the RET gene are common in radiation-associated papillary thyroid cancer (PTC). The RET /PTC1 type of rearrangement is an inversion of chromosome 10 mediated by illegitimate recombination between the RET and the H4 genes, which are 30 megabases apart. Here we ask whether despite the great linea... | 10.1038/nrc3431 | This study demonstrates the proximity of chromosomal loci that are involved in the formation of RET –PTC translocations, thus providing a structural basis and explanation for the formation of genetic rearrangements. |
10.1002/cncr.23869 | 18,152,904 | Abstract BACKGROUND. The phosphatidylinositol 3‐kinase (PI3K)/AKT pathway plays an important role in thyroid tumorigenesis and progression. Genetic alterations, particularly PIK3CA amplification and mutations and ras mutations, are the major cause of aberrant activation of this pathway in thyroid tumors. Epigenetic sil... | 10.1038/nrc3431 | This study proposes a model in which activation of the PI3K–AKT pathway, driven by genetic alterations, causes aberrant methylation and hence silencing of PTEN , which in turn leads to the failure in terminating PI3K–AKT signalling, thus creating a self-amplification loop that enhances and maintains the constitutive ac... |
10.1073/pnas.1004934107 | 60,370,781 | Although B-Raf V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf V600E gene set signature associated with tumor p... | 10.1038/nrc3431 | This study demonstrates an important role of TSP1 and its relationship with BRAF-V600E, thus providing an excellent example of the role of the tumour microenvironment in thyroid tumorigenesis. |
10.1073/pnas.0510849103 | 107,223,169 | Activation of the phosphatidylinositol 3-kinase (PI3K)–AKT/protein kinase B signaling pathway has been associated with multiple human cancers. Recently we showed that AKT is activated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma [thyroid hormone β receptor (TRβ) PV/PV mice... | 10.1038/nrc3431 | This study demonstrates robust activation of the PI3K–AKT pathway by a mutant thyroid hormone β-receptor that causes FTC in mice, thus providing the first animal data to support an important role of the PI3K–AKT pathway in the tumorigenesis of FTC. |
10.1210/en.2009-1017 | 120,326,390 | TSH is the major stimulator of thyrocyte proliferation, but its role in thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular thyroid carcinoma (FTC) (TRβPV/PV mice). These mice, harboring a dominantly negative mutation (PV) of the thyroid hormone-β receptor (TRβ), exhibi... | 10.1038/nrc3431 | This study demonstrated for the first time that a transgenic mouse model of thyroid tumorigenesis promoted by a mutation (in this case, mutant THR ) requires an intact TSHR pathway. |
10.1073/pnas.1015557108 | 83,005,028 | Mutations of BRAF are found in ∼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf ( LSL-Braf V600E /TPO-Cre ) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progressi... | 10.1038/nrc3431 | Similarly to reference 138, this study also demonstrated a requirement for an intact TSHR pathway, this time for BRAF-V600E-induced thyroid tumorigenesis in transgenic mice. |
10.1210/jc.2009-1888 | 60,309,807 | Abstract Context: Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes. Objectives: This study was conducted to test the therapeutic potential of targeting the aberrantly activate... | 10.1038/nrc3431 | This study demonstrated robust expression of thyroid iodide-handling genes and radioiodine uptake in thyroid cancer cells by simultaneously targeting MAPK, PI3K–AKT and histone deacetylase systems, which could be enhanced by TSH, thus providing strong clinical implications for the treatment of thyroid cancer. |
10.1210/jc.2003-032050 | 20,043,537 | Abstract Numerous biomolecular markers have been studied to improve the accuracy of fine needle aspiration biopsy (FNAB) in the diagnostic and prognostic evaluation of thyroid tumors, but none of them has yet become clinically useful. The recently discovered BRAF mutation, which occurs specifically in papillary thyroid... | 10.1038/nrc3431 | References 171 and 172 are the first studies to demonstrate the feasibility of BRAF mutation testing on thyroid FNAB samples for the diagnosis of thyroid cancer. |
10.1126/science.278.5335.135 | 82,799,344 | Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice.... | 10.1038/nrg862 | Reports the cloning of Agrp and that it acts as an antagonist of neuronal melanocortin receptors (as does agouti). Mice that overexpress agouti or Agrp were also created. They both developed obesity, but only agouti mutants had a yellow coat colour. |
10.1126/science.274.5289.948 | 62,221,701 | The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-res... | 10.1038/nrc3430 | The structure that described the hydrophobic p53-binding pocket of MDM2, on which many drug discovery efforts are now based. |
10.1126/science.1092472 | 41,615,346 | MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy... | 10.1038/nrc3430 | This paper describes the first small-molecule MDM2 antagonist that inhibits the p53–MDM2 interaction and activates p53 in a non-genotoxic manner. |
10.1073/pnas.0809506106 | 102,587,808 | Phenotypic mutations (errors occurring during protein synthesis) are orders of magnitude more frequent than genetic mutations. Consequently, the sequences of individual protein molecules transcribed and translated from the same gene can differ. To test the effects of such mutations, we established a bacterial system in... | 10.1038/nrg2662 | One of the first studies to investigate the effect of transcription errors on protein evolution in an experimental system. TEM1 β-lactamase expressed using an error-prone RNA polymerase evolved an increased level of gene expression, increased thermostability and increased mutational robustness. |
10.1261/rna.294907 | 103,876,479 | Estimates of missense error rates (misreading) during protein synthesis vary from 10 −3 to 10 −4 per codon. The experiments reporting these rates have measured several distinct errors using several methods and reporter systems. Variation in reported rates may reflect real differences in rates among the errors tested or... | 10.1038/nrg2662 | A highly accurate measurement of specific amino acid misincorporation frequencies under translation. |
10.1126/science.1124514 | 103,086,806 | Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunctio... | 10.1038/nrg2662 | This study provides insights into the nature of cellular costs due to protein misfolding. It shows how aggregation-prone proteins can induce cytotoxic effects by destabilizing marginally stable essential proteins. |
10.1002/eji.200324228 | 20,542,158 | Abstract Newer members of the B7‐CD28 superfamily include the receptor PD‐1 and its two ligands, PD‐L1 and PD‐L2. Here, we characterize the expression of PD‐1, PD‐L1, and PD‐L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non‐obese diabetic (NOD) mice and brain from mi... | 10.1038/nrc1630 | Describes the relationship and role of the programmed death receptors and immune regulation. |
10.1182/blood-2002-07-1956 | 122,356,950 | Abstract T-cell defects and premature thymic atrophy occur in cancer patients and tumor-bearing animals. We demonstrate that exposure of mice to recombinant vascular endothelial growth factor (VEGF) at concentrations similar to those observed in advanced stage cancer patients reproduces this profound thymic atrophy and... | 10.1038/nrc1630 | Characterizes the association of VEGF expression and depressed T-cell function in cancer. |
10.1200/jco.2004.12.040 | 122,503,349 | Purpose To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer. Patients and Methods Patients with measurable locally advanced o... | 10.1038/nrc1630 | The first work reporting the activity of a monoclonal antibody to EGFR and chemotherapy in patients with metastatic pancreatic cancer. |
10.4049/jimmunol.171.4.2161 | 120,872,272 | Abstract HER-2/neu is overexpressed in several cancers including 30% of breast carcinomas, and correlates with a poor outcome. HER-2/neu-transgenic (neu-N) mice that overexpress the non-transforming rat neu develop spontaneous mammary carcinomas and demonstrate immunotolerance to the neu protein similar to that observe... | 10.1038/nrc1630 | Establishes a synergistic effect when combining antigen-specific antibodies and vaccine approaches in preclinical models |
10.1126/science.1213230 | 41,363,423 | Stochastic or Asymmetric Fate Determination? During an adaptive immune response, B lymphocytes rapidly divide and differentiate into effector cell populations, including antibody-secreting plasmablasts and memory B cells. Many also change the class of antibody they secrete, through a process called isotype switching. D... | 10.1038/nri3795 | In this paper, cell tracking studies show that the outcomes of B cell differentiation are the consequence of competing internal processes in the cell. |
10.1126/science.1213495 | 20,040,005 | Stochastic or Asymmetric Fate Determination? During an adaptive immune response, B lymphocytes rapidly divide and differentiate into effector cell populations, including antibody-secreting plasmablasts and memory B cells. Many also change the class of antibody they secrete, through a process called isotype switching. D... | 10.1038/nri3795 | This study shows the asymmetric segregation of several proteins, including BCL-6, in GC B cells. The authors suggest that this asymmetry leads to the diverse fates of daughter cells. |
10.1152/physrev.00024.2006 | 41,215,220 | Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disord... | 10.1038/nrm2391 | A recent review focusing on studies of lipid effects on insulin resistance in human subjects. |
10.2337/diab.46.1.3 | 41,584,348 | Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent ... | 10.1038/nrm2391 | Demonstrates that infusion of free fatty acids acutely induces insulin resistance in human subjects. |
10.1210/en.2007-1713 | 125,150,957 | Organisms store energy for later use during times of nutrient scarcity. Excess energy is stored as triacylglycerol in lipid droplets during lipogenesis. When energy is required, the stored triacylglycerol is hydrolyzed via activation of lipolytic pathways. The coordination of lipid storage and utilization is regulated ... | 10.1038/nrm2391 | Summarizes recent developments in the field of lipid-droplet structure and function. |
10.1126/science.1175371 | 125,297,532 | Lysine Acetylation Catalog Covalent posttranslational modification is an essential cellular regulatory mechanism by which the activity of proteins can be controlled. Advances in mass spectrometry made it possible for Choudhary et al. (p. 834 , published online 16 July) to assess the prevalence of lysine acetylation thr... | 10.1038/nrd3031 | Eye-opening landmark paper illustrating the extent of acetylation of non-histone proteins. |
10.1073/pnas.0700298104 | 41,231,027 | The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repressi... | 10.1038/nrd3031 | Important study that highlighted the dynamic complexing of HATs and HDACs with FOXP3. |
10.1073/pnas.0706487104 | 41,270,371 | Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates... | 10.1038/nrd3031 | Fascinating explanation of why class IIa HDACs lack significant HDAC activity. |
10.1073/pnas.0430973100 | 41,754,510 | Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, c... | 10.1038/nrd3031 | This paper presents the first evidence of a selective pharmacological inhibitor of a single HDAC isoform, HDAC6. |
10.1073/pnas.0903919106 | 102,727,808 | Infectious tolerance describes the process of CD4 + regulatory T cells (Tregs) converting naïve T cells to become additional Tregs. We show that antigen-specific Tregs induce, within skin grafts and dendritic cells, the expression of enzymes that consume at least 5 different essential amino acids (EAAs). T cells fail t... | 10.1038/nrd3031 | Fascinating extension of the concept that T regs can act by competing for essential nutrients by moving beyond the tryptophan/IDO concept to use multiple signalling pathways. |
10.1083/jcb.200312071 | 101,639,703 | The functional properties of tendon require an extracellular matrix (ECM) rich in elongated collagen fibrils in parallel register. We sought to understand how embryonic fibroblasts elaborate this exquisite arrangement of fibrils. We show that procollagen processing and collagen fibrillogenesis are initiated in Golgi to... | 10.1038/nrm3902 | This paper shows how embryonic fibroblasts produce an ECM that is rich in elongated, parallel, collagen fibrils, through the initiation of collagen fibrillogenesis by targeting collagen fibril-containing Golgi-to-plasma membrane carriers (GPCs) to plasma membrane protrusions. |
10.1146/annurev.cellbio.20.010403.094555 | 20,629,204 | ▪ Abstract Significant advances have been made in the application of genetics to probe the functions of basement membrane laminins. These studies have shown that different laminin subunits profoundly affect tissue morphogenesis, starting around the time of embryonic implantation and extending through organogenesis and ... | 10.1038/nrm3902 | This paper discusses how different laminin proteins affect invertebrate and vertebrate tissue morphogenesis through the induction and the maintenance of cell polarity, the establishment of barriers between tissue compartments and the protection of adherent cells from anoikis. |
10.1146/annurev-cellbio-100109-104020 | 29,222,078 | In the process of matrix assembly, multivalent extracellular matrix (ECM) proteins are induced to self-associate and to interact with other ECM proteins to form fibrillar networks. Matrix assembly is usually initiated by ECM glycoproteins binding to cell surface receptors, such as fibronectin (FN) dimers binding to α5β... | 10.1038/nrm3902 | This is an excellent review highlighting the major steps, molecular interactions and cellular mechanisms involved in assembling fibronectin into a fibrillar matrix. |
10.1182/blood-2003-05-1556 | 46,288,219 | Abstract GATA-1 is the founding member of a transcription factor family that regulates growth and maturation of a diverse set of tissues. GATA-1 is expressed primarily in hematopoietic cells and is essential for proper development of erythroid cells, megakaryocytes, eosinophils, and mast cells. Although loss of GATA-1 ... | 10.1038/nrc1525 | Comprehensive review of currently available models of decreased haematopoietic GATA1 function in vivo and the effects on megakaryocytic differentiation. |
10.4049/jimmunol.162.2.948 | 139,062,681 | Abstract A spectrum of disease severity has been observed in patients with Lyme disease, with ∼60% of untreated individuals developing arthritis. The murine model of Lyme disease has provided strong evidence that the genetic composition of the host influences the severity of arthritis following infection with Borrelia ... | 10.1038/nri1267 | This study describes genetic linkage analyses for mice with heritable susceptibility to Lyme arthritis. It shows that arthritis consists of independent traits, such as swelling and leukocytic infiltrates, each with multigenic control. |
10.1002/art.10772 | 124,165,313 | Abstract Objective To assess the binding of outer surface protein A (OspA) and human lymphocyte function–associated antigen 1 (hLFA‐1) peptides to 5 major histocompatibility complex (MHC) molecules. Methods Peptide binding to the MHC molecules was determined by in vitro binding assays, and binding was correlated with t... | 10.1038/nri1267 | This study shows that the strength of binding of OspA peptides to HLA-DR molecules correlates with the frequency of these HLA-DR alleles in patients with treatment-resistant Lyme arthritis. |
10.1126/science.281.5377.703 | 79,799,213 | Treatment-resistant Lyme arthritis is associated with immune reactivity to outer surface protein A (OspA) of Borrelia burgdorferi , the agent of Lyme disease, and the major histocompatibility complex class II allele DRB1*0401 . The immunodominant epitope of OspA for T helper cells was identified. A homology search reve... | 10.1038/nri1267 | This is the original study that presents the concept of molecular mimicry in patients with treatment-resistant Lyme arthritis. |
10.4049/jimmunol.166.8.5286 | 79,939,045 | Abstract Antibiotic treatment-resistant Lyme arthritis is a chronic inflammatory joint disease that follows infection with Borrelia burgdorferi (Bb). A marked Ab and T cell response to Bb outer surface protein A (OspA) often develops during prolonged episodes of arthritis. Furthermore, cross-reaction between the bacter... | 10.1038/nri1267 | This study presents data that concern the concept of molecular mimicry in patients with treatment-resistant Lyme arthritis. |
10.1242/dev.128.21.4289 | 20,885,812 | Mutations in ribosomal protein (RP) genes in Drosophila lead to strong developmental phenotypes, expressed in the semi-dominant Minute syndrome. In plants, however, mutations in RP genes have so far only been reported to result in recessive developmental phenotypes. We present the analysis of an Arabidopsis promoter-tr... | 10.1038/nrm3359 | Shows differential expression of RPS5 paralogues in A. thaliana development. |
10.1139/o90-190 | 15,382,327 | Vegetatively growing amoebae, if shaken in a starvation (nonnutrient) buffer, acquire aggregation competence, but do not embark on a morphogenetic program. The quantitative variation of ribosomal proteins in vegetative and aggregation-competent cells was compared by labeling the different cell types with [ 35 S]methion... | 10.1038/nrm3359 | Demonstrates dramatic changes in ribosome composition as D. discoideum shifts from vegetatively growing to aggregation-competent. |
10.1038/sj.embor.7400291 | 39,373,484 | The receptor for activated C‐kinase (RACK1) is a scaffold protein that is able to interact simultaneously with several signalling molecules. It binds to protein kinases and membrane‐bound receptors in a regulated fashion. Interestingly, RACK1 is also a constituent of the eukaryotic ribosome, and a recent cryo‐electron ... | 10.1038/nrm3359 | Reviews, together with reference 59, the multiple functions of RACK1 as a protein that associates with the ribosome. |
10.1126/science.3672135 | 122,814,089 | Two structurally distinct nuclear genes code for cytoplasmic small subunit ribosomal RNA's in the parasite Plasmodium berghei . Stable transcripts from one of the ribosomal RNA genes are found almost exclusively in those stages of the life cycle that develop in the mosquito. When the parasite infects the mammalian host... | 10.1038/nrm3359 | Shows that different forms of rRNAs are expressed in different stages in the lifecycle of Plasmodium berghei. |
10.1126/science.1123835 | 61,733,174 | The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to can... | 10.1038/nrm3359 | First paper that shows the importance of rRNA pseudouridylation in viral and cellular IRES-mediated translation. |
10.1101/gad.1832209 | 58,603,682 | Most eukaryotic mRNAs are translated using a cap-dependent mechanism of translation. However, ∼10% of mammalian mRNAs initiate translation using a cap-independent mechanism that is not well understood. These mRNAs contain an internal ribosome entry site (IRES) located in the 5′ untranslated region. The cricket paralysi... | 10.1038/nrm3359 | Shows that a ribosomal protein interacts directly with an IRES element and regulates translation mediated by the IRES. |
10.1101/gad.1056303 | 38,527,843 | ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we report that mice lacking UBP43, a protease that removes ISG15 from ISGylated proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient cells... | 10.1038/nri1226 | Together with reference 56, this study shows an important role of protein ISGylation in the positive regulation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT)-signalling pathway. |
10.1126/science.278.5344.1803 | 61,042,224 | The signal transducer and activator of transcription–3 (Stat3) protein is activated by the interleukin 6 (IL-6) family of cytokines, epidermal growth factor, and leptin. A protein named PIAS3 (protein inhibitor of activated STAT) that binds to Stat3 was isolated and characterized. The association of PIAS3 with Stat3 in... | 10.1038/nri1226 | This paper reports the first identification of protein inhibitor of activated STAT (PIAS) proteins in the negative regulation of STATs. |
10.1073/pnas.171302098 | 61,172,440 | Transcriptional activation by, and therefore the physiologic impact of, activated tyrosine-phosphorylated STATs ( s ignal t ransducers and a ctivators of t ranscription) may be negatively regulated by proteins termed PIAS ( p rotein i nhibitors of a ctivated s tats), as shown by previous experiments with mammalian cell... | 10.1038/nri1226 | This paper provides genetic evidence that Drosophila PIAS might negatively regulate the Drosophila JAK–STAT pathway. |
10.1128/jb.187.23.8104-8113.2005 | 41,622,584 | ABSTRACT The twin-arginine translocation (Tat) pathway is present in a wide variety of prokaryotes and is capable of exporting partially or fully folded proteins from the cytoplasm. Although diverse classes of proteins are transported via the Tat pathway, in most organisms it facilitates the secretion of a relatively s... | 10.1038/nrmicro1440 | Shows that the Tat pathway is essential for aerobic growth of H. volcanii in complex media, confirming the hypothesis that in halophilic archaea the Tat pathway is the main protein-secretion route instead of the Sec translocase. |
10.1099/mic.0.26364-0 | 62,553,312 | Homologues of the protein constituents of the Klebsiella pneumoniae ( Klebsiella oxytoca ) type II secreton (T2S), the Pseudomonas aeruginosa type IV pilus/fimbrium biogenesis machinery (T4P) and the Methanococcus voltae flagellum biogenesis machinery (Fla) have been identified. Known constituents of these systems incl... | 10.1038/nrmicro1440 | Extensive phylogenetic comparison of the components of type IV pilus assembly/type II secretion systems and the archaeal flagellum-assembly system. Indicates common mechanisms in the assembly of the associated surface structures in prokaryotes. |
10.1111/j.1365-2958.2005.04294.x | 104,096,068 | Summary Proteinaceous, hair‐like appendages known as fimbriae or pili commonly extend from the surface of prokaryotic cells and serve important functions such as cell adhesion, biofilm formation, motility and DNA transfer. Here we show that a novel group of archaea from cold, sulphidic springs has developed cell surfac... | 10.1038/nrmicro1440 | Reports on one of the most complex prokaryotic extracytoplasmic structures described so far that fulfils a role in cellular adherence. An important question is how these hooks are assembled at the cell surface. |
10.1046/j.1365-2958.2001.02336.x | 101,193,862 | The extreme thermoacidophilic archaeon Sulfolobus solfataricus grows optimally at 80°C and pH 3 and uses a variety of sugars as sole carbon and energy source. Glucose transport in this organism is mediated by a high‐affinity binding protein‐dependent ATP‐binding cassette (ABC) transporter. Sugar‐binding studies reveale... | 10.1038/nrmicro1440 | Shows that the hyperthermoacidophile S. solfataricus contains two types of sugar-binding protein, one of which is synthesized with a type IV pilin-like signal sequence that is processed in a similar manner to pilins in bacteria, and flagella in archaea. |
10.1073/pnas.90.21.10159 | 123,521,710 | The present investigation studied the influence of the blastocyst's state of activity on the "window" of implantation in the receptive uterus in the mouse. The receptive state of the uterus is defined as the limited time when the uterine milieu is favorable to blastocyst acceptance and implantation. In the mouse, impla... | 10.1038/nrg1808 | This study, which uses a delayed-implantation mouse model, showed for the first time that the receptive state of the uterus alone is not sufficient for successful implantation, but that blastocysts must also achieve implantation competency. The differential roles of oestrogen and catecholoestrogens in establishing the ... |
10.1073/pnas.0402597101 | 20,542,107 | Delayed implantation (embryonic diapause) occurs when the embryo at the blastocyst stage achieves a state of suspended animation. During this period, blastocyst growth is very slow, with minimal or no cell division. Nearly 100 mammals in seven different orders undergo delayed implantation, but the underlying molecular ... | 10.1038/nrg1808 | This study analyses global gene expression in dormant and activated mouse blastocysts, providing evidence that gene-expression patterns are distinct at these two different physiological states of the embryo. |
10.1073/pnas.92.21.9460 | 20,324,609 | Using a reverse transcription-coupled PCR, we demonstrated that both brain and spleen type cannabinoid receptor (CB1-R and CB2-R, respectively) mRNAs are expressed in the preimplantation mouse embryo. The CB1-R mRNA expression was coincident with the activation of the embryonic genome late in the two-cell stage, wherea... | 10.1038/nrg1808 | This work provided the first evidence for the presence of the G-protein-coupled cannabinoid receptors CB1 and CB2 in preimplantation mouse embryos. The differential roles of endocannabinoids in embryo–uterine interactions during implantation are further illustrated in references 33 and 35–37. |
10.1210/me.2003-0403 | 83,088,815 | Abstract Successful implantation absolutely depends on the reciprocal interaction between the implantation-competent blastocyst and the receptive uterus. Expression and gene targeting studies have shown that leukemia inhibitory factor (LIF), a cytokine of the IL-6 family, and Hoxa-10, an abdominalB-like homeobox gene, ... | 10.1038/nrg1808 | This work was the first to provide evidence that cytokines, homeotic proteins and morphogens in the mouse uterus constitute a molecular circuitry that is crucial to implantation. |
10.1073/pnas.98.3.1047 | 83,184,869 | The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at t... | 10.1038/nrg1808 | This article provides a comprehensive account of the expression of morphogens, including HH, BMP, WNT and FGF signalling in the mouse uterus during the periimplantation period. The evidence that HH signalling in the uterine epithelial–mesenchymal interaction is important for implantation was later reported in reference... |
10.1242/dev.120.5.1071 | 104,371,785 | Heparin-binding EGF-like growth factor (HB-EGF) is a newly discovered member of the EGF family of growth factors. HB-EGF can bind to two loci on cell surfaces, heparan sulphate proteoglycans and EGF-receptor (EGF-R), and either one or both of these interactions could play a role in cell-cell interactions. In the rodent... | 10.1038/nrg1808 | The role of HB-EGF as an early initiator of molecular crosstalk between the blastocyst and uterus before attachment was first illustrated in this study. |
10.1126/science.1079546 | 106,652,247 | Trophoblast adhesion to the uterine wall is the requisite first step of implantation and, subsequently, placentation. At the maternal-fetal interface, we investigated the expression of selectin adhesion systems that enable leukocyte capture from the bloodstream. On the maternal side, human uterine epithelial cells up-r... | 10.1038/nrg1808 | This study shows that, in humans, selectin oligosaccharide ligands are expressed in the receptive uterine lining, while the Tr cell surface is decorated with L-selectin. Further evidence indicates that this ligand–receptor signalling is important for human implantation. |
10.1242/dev.129.12.2879 | 125,247,570 | Cytosolic phospholipase A2α (cPLA2α) is a major provider of arachidonic acid (AA) for the cyclooxygenase (COX) system for the biosynthesis of prostaglandins (PGs). Female mice with the null mutation for Pla2g4a (cPLA2α) produce small litters and often exhibit pregnancy failures, although the cause(s) of these defects r... | 10.1038/nrg1808 | This work shows that mouse uteri that lack cPLA2α transiently defer on-time implantation, creating an adverse ripple effect throughout the course of pregnancy and leading to poor pregnancy outcome. A similar phenotype is observed in lpA3 -null mice, as reported in reference 80. The importance of on-time implantation in... |
10.1242/dev.124.2.289 | 83,301,607 | At least one polar body, almost invariably the second, persists intact to the early blastocyst stage in nearly two-thirds of mouse conceptuses of the PO strain. The distribution in early blastocysts of these surviving polar bodies was highly non-random. Most not only lay in the mid-region of the embryonic-abembryonic a... | 10.1038/nrg1808 | This article proposes the concept of the embryonic axis and cell polarity during mouse preimplantation development. The ongoing debate on this subject is further highlighted in references 89–92,96,101,107 and 108. |
10.1146/annurev.genom.6.080604.162146 | 62,456,491 | ▪ Abstract As whole-genome sequencing efforts extend beyond more traditional model organisms to include a deep diversity of species, comparative genomic analyses will be further empowered to reveal insights into the human genome and its evolution. The discovery and annotation of functional genomic elements is a necessa... | 10.1038/nrg2185 | An excellent review outlining how various comparative sequence analysis methods combined with different sequence data sets affect the sensitivity, specificity and phylogenetic scope for detecting constrained sequences. |
10.1073/pnas.93.15.7690 | 59,632,490 | Stress protein GRP78/BiP is highly induced in progressively growing tumors and has recently been shown to exert a protective role against lysis by cytotoxic T cells and tumor necrosis factor in vitro. This raises the question whether the in vitro observed protective function of GRP78/BiP translates into the in vivo sit... | 10.1038/nrc1505 | Directly demonstrated the significance of ER-chaperone upregulation in tumour progression. |
10.1101/gad.1165804 | 100,748,868 | The tumor suppressor p53, a sensor of multiple forms of cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis. We demonstrate that endoplasmic reticulum (ER) stress inhibits p53-mediated apoptosis. The mechanism of inhibition involves the increased cytoplas... | 10.1038/nrc1505 | Showed that p53 is regulated by both the hypoxic and the ER-stress response pathways, but in opposite ways. |
10.1101/gad.12.12.1812 | 125,283,580 | Eukaryotes respond to the presence of unfolded protein in the endoplasmic reticulum (ER) by up-regulating the transcription of genes encoding ER protein chaperones, such as BiP. We have isolated a novel human cDNA encoding a homolog to Saccharomyces cerevisiae Ire1p, a proximal sensor for this signal transduction pathw... | 10.1038/nrc1505 | Identified the mammalian homologue of yeast Ire1 kinase, which is ubiquitously expressed, and provided the first proof that the signalling machinery of the UPR pathway is highly conserved. |
10.1091/mbc.10.11.3787 | 104,230,624 | The unfolded protein response (UPR) controls the levels of molecular chaperones and enzymes involved in protein folding in the endoplasmic reticulum (ER). We recently isolated ATF6 as a candidate for mammalian UPR-specific transcription factor. We report here that ATF6 constitutively expressed as a 90-kDa protein (p90A... | 10.1038/nrc1505 | Identified ATF6, a new member of the mammalian UPR pathway that is not present in yeast. It delineated the unique mechanism of activation of the ER-localized transmembrane protein during ER stress, which involves cleavage of the cytosolically disposed transcription factor domain from the ER membrane. |
10.1126/science.2024119 | 122,704,941 | In Saccharopolyspora erythraea , the genes that govern synthesis of the polyketide portion of the macrolide antibiotic erythromycin are organized in six repeated units that encode fatty acid synthase (FAS)-like activities. Each repeated unit is designated a module, and two modules are contained in a single open reading... | 10.1038/nrmicro1287 | References 3 and 4 report the first sequencing of a modular PKS gene. |
10.1126/science.8036492 | 102,270,037 | Macrocyclic polyketides have been subjects of great interest in synthetic and biosynthetic chemistry because of their structural complexity and medicinal activities. With expression of the entire 6-deoxyerythronolide B synthase (DEBS) (10,283 amino acids) in a heterologous host, substantial quantities of 6-deoxyerythro... | 10.1038/nrmicro1287 | Reports the first biosynthesis of a polyketide macrolactone in the heterologous host Streptomyces coelicolor |
10.1126/science.287.5453.640 | 41,118,136 | The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading modul... | 10.1038/nrmicro1287 | Describes the production of epothilone in the heterologous host E. coli |
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