Input: Although sensitivity to M-CSF can be modulated by regulation of receptor expression and function, M-CSF responsiveness is largely determined at a postreceptor level.

M-CSF

M-CSF


Input: To date, little is known about the intracellular pathway of M-CSF signal transduction.

M-CSF


Input: We have therefore investigated the changes in protein kinase C (PKC) activity upon exposure of monocytes to M-CSF.

protein kinase C

PKC

M-CSF

monocytes


Input: We show that M-CSF activates and translocates PKC.

M-CSF

PKC


Input: Inhibition of PKC by the isoquinoline derivative H7 abolishes induction of M-CSF by M-CSF.

PKC

M-CSF

M-CSF


Input: Furthermore, activation of PKC was pertussis-toxin-sensitive and was associated with the detection of an NF kappa B protein in nuclear extracts of M-CSF -induced blood monocytes but not in monocytes exposed to medium treatment only.

PKC

NF kappa B protein

M-CSF -induced blood monocytes

monocytes


Input: The results suggest that M-CSF induction of M-CSF involves G proteins, PKC and NF kappa B.

M-CSF

M-CSF

G proteins

PKC

NF kappa B


Input: Clone pAT 133 identifies a gene that encodes another human member of a class of growth factor-induced genes with almost identical zinc-finger domains.

Clone pAT 133

growth factor-induced genes

zinc-finger domains


Input: We report the structure and regulation of a gene represented by clone pAT 133, which is induced upon transition from a resting state (G0) through the early phase of the cell cycle (G1 ).

clone pAT 133


Input: The pAT 133 gene is immediately induced, with FOS -like kinetics, in human T cells and in fibroblasts.

pAT 133 gene

FOS

human T cells

fibroblasts


Input: Primary structure analysis showed that the encoded protein contains three tandem zinc-finger sequences of the type Cys2-Xaa12-His2.

tandem

zinc-finger sequences


Input: This zinc-finger region, which is thought to bind DNA in a sequence-specific manner, is similar (greater than 80% on the amino acid level) to two previously described transcription factors pAT 225/EGR1 and pAT 591/EGR2.

zinc-finger region

transcription factors

pAT 225/EGR1


Input: Except for the conserved zinc-finger domains, the amino acid sequences of the three proteins are distinct.

zinc-finger domains

amino acid sequences


Input: This structural similarity suggests that the pAT 133 gene encodes a transcription factor with a specific biological function.

pAT 133 gene

transcription factor


Input: Comparing the regulation of these related zinc-finger -encoding genes showed coordinate induction upon mitogenic stimulation of resting T lymphocytes and of resting fibroblasts.

zinc-finger -encoding genes

resting T lymphocytes

resting fibroblasts


Input: However, upon transition from a proliferating (G1) to a resting state of the cell cycle the three genes were differently regulated.


Input: In human histiocytic U937 cells mRNA of clone pAT 133 was constitutively expressed, whereas mRNA of pAT 225/EGR1 was induced upon induction of terminal differentiation.

human histiocytic U937 cells mRNA

mRNA

pAT 225/EGR1


Input: In contrast mRNA representing pAT 591/EGR2 was not expressed in these cells.


Input: This difference in gene regulation suggests distinct biological roles in the control of cell proliferation for the respective proteins.


Input: v-erbA overexpression is required to extinguish c-erbA function in erythroid cell differentiation and regulation of the erbA target gene CAII.

v-erbA

c-erbA

erythroid cell

erbA target gene

CAII


Input: The v-erbA oncoprotein represents a retrovirus-transduced oncogenic version of the thyroid hormone (T3/T4) receptor c-erbA (type alpha).

v-erbA oncoprotein

thyroid hormone (T3/T4) receptor

c-erbA (type alpha)


Input: It contributes to virus-induced erythroleukemia by efficiently arresting differentiation of red cell progenitors and by suppressing transcription of erythrocyte-specific genes.

red cell progenitors

erythrocyte-specific genes


Input: Here, we show that v-erbA and c-erbA bind directly to sequences within the promoter of the erythrocyte-specific carbonic anhydrase II (CAII ), a gene whose transcription is efficiently suppressed by v-erbA.

v-erbA

c-erbA

erythrocyte-specific carbonic anhydrase II

v-erbA

promoter

CAII


Input: This erbA-binding site confers thyroid hormone responsiveness to a heterologous promoter in transient expression experiments and is a target for efficient down-regulation of CAII transcription by the v-erbA oncoprotein.

erbA-binding site

heterologous promoter

CAII

v-erbA oncoprotein


Input: In stably transformed erythroblasts coexpressing the v-erbA oncoprotein and the c-erbA/T3 receptor at an approximately equimolar ratio, c-erbA activity is dominant over v-erbA.

stably transformed erythroblasts

v-erbA oncoprotein

c-erbA/T3 receptor

c-erbA

v-erbA


Input: T3 efficiently induced erythroid differentiation in these cells, thus overcoming the v-erbA -mediated differentiation arrest.

v-erbA


Input: Likewise, T3 activated CAII transcription as well as transient expression of a T3 -responsive reporter gene containing the CAII -specific erbA-binding site.

CAII

T3 -responsive reporter gene

CAII -specific erbA-binding site


Input: The c-erbA -dependent activation of this CAII reporter construct could only be suppressed by very high amounts of v-erbA.

c-erbA

v-erbA

CAII reporter construct


Input: Our results suggest that overexpression of v-erbA is required for its function as an oncoprotein.

v-erbA

oncoprotein


Input: Anti-CD2 receptor antibodies activate the HIV long terminal repeat in T lymphocytes.

Anti-CD2 receptor antibodies

HIV long terminal repeat

T lymphocytes


Input: The CD2 T lymphocyte glycoprotein surface molecule mediates both cell to cell adhesion and T cell activation, two processes that are involved in the spread of HIV infection.

CD2 T lymphocyte glycoprotein surface molecule


Input: Treatment of chronically HIV-infected PBMC with anti-CD2 mAb has been shown to induce the expression of infectious virus from these cultures.

chronically HIV-infected PBMC

anti-CD2 mAb


Input: In this study we investigated the mechanisms whereby anti-CD2 antibodies stimulate viral production.

anti-CD2 antibodies


Input: We demonstrate that treatment of transiently transfected T lymphocytes with anti-CD2 antibodies results in activation of the HIV long terminal repeat.

T lymphocytes

anti-CD2 antibodies

HIV long terminal repeat


Input: Furthermore, CAT assays using mutated HIV long terminal repeat -CAT constructs and gel shift assays demonstrate that this activation is dependent on the NF-kappa B enhancer.

CAT

HIV long terminal repeat -CAT constructs

NF-kappa B enhancer


Input: These studies suggest that interaction of CD2 with its natural ligand, LFA-3, may play a role in regulation of HIV expression.


Input: Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1.

NF-kappa B transcription factor


Input: Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes.


Input: In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line.

human T cell line


Input: The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form.

NF-kappa B

transcription factor

inactive cytoplasmic form


Input: N-acetyl-L-cysteine (NAC ), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2.

NF-kappa B


Input: NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin.

NF-kappa B

TNF-alpha

lectin

double-stranded RNA


Input: This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI.

NF-kappa B


Input: ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.

inhibitory subunit

I kappa B

NF-kappa B


Input: Inhibition of transcription factors belonging to the rel/ NF-kappa B family by a transdominant negative mutant.

transcription factors

rel/ NF-kappa B family

transdominant negative mutant


Input: The KBF1 factor, which binds to the enhancer A located in the promoter of the mouse MHC class I gene H-2Kb, is indistinguishable from the p50 DNA binding subunit of the transcription factor NF-kappa B, which regulates a series of genes involved in immune and inflammatory responses.

KBF1 factor

p50 DNA binding subunit

transcription factor

NF-kappa B

enhancer A

promoter

mouse MHC class I gene


Input: The KBF1/p50 factor binds as a homodimer but can also form heterodimers with the products of other members of the same family, like the c-rel and v-rel (proto)oncogenes.

KBF1/p50 factor

homodimer

heterodimers


Input: The dimerization domain of KBF1/p50 is contained between amino acids 201 and 367.

dimerization domain

between amino acids 201 and 367


Input: A mutant of KBF1/p50 (delta SP ), unable to bind to DNA but able to form homo- or heterodimers, has been constructed.

delta SP

heterodimers


Input: This protein reduces or abolishes in vitro the DNA binding activity of wild-type proteins of the same family (KBF1/p50, c- and v- rel ).

wild-type proteins


Input: This mutant also functions in vivo as a trans-acting dominant negative regulator: the transcriptional inducibility of the HIV long terminal repeat (which contains two potential NF-kappa B binding sites) by phorbol ester (PMA) is inhibited when it is co-transfected into CD4+ T cells with the delta SP mutant.

trans-acting dominant negative regulator

NF-kappa B

delta SP

HIV long terminal repeat

CD4+ T cells


Input: Similarly the basal as well as TNF or IL1-induced activity of the MHC class I H-2Kb promoter can be inhibited by this mutant in two different cell lines.

TNF

MHC class I H-2Kb promoter

cell lines


Input: These results constitute the first formal demonstration that these genes are regulated by members of the rel/ NF-kappa B family.

rel/ NF-kappa B family


Input: Tissue-specific expression of the platelet GPIIb gene.

platelet GPIIb gene


Input: One of the major objectives in the study of thrombogenesis is to determine the mechanisms by which a hematopoietic progenitor is activated and committed to the megakaryocytic lineage.

hematopoietic progenitor

megakaryocytic lineage


Input: Recent development of primary cultures of human megakaryocytes and the molecular cloning of genes that are specific to this lineage offer the possibility of getting some insights into the genetic mechanisms that control megakaryocytopoiesis.

primary cultures

human megakaryocytes


Input: One gene of interest is the glycoprotein IIb (GPIIb) gene; GPIIb, the alpha subunit of the platelet cytoadhesin GPIIb-IIIa, is produced in megakaryocytes at an early stage of the differentiation, whereas the other subunit of this complex, GPIIIa, is expressed in other cells.

glycoprotein IIb (GPIIb) gene

GPIIb

alpha subunit

platelet cytoadhesin GPIIb-IIIa

GPIIIa

megakaryocytes


Input: For these reasons, the 5'-flanking region of the GPIIb gene was used to identify the regions that interact with DNA-binding nuclear factors.

5'-flanking region

GPIIb gene

DNA-binding nuclear factors


Input: A fragment extending from -643 to +33 is capable of controlling the tissue-specific expression of the CAT gene in transfection experiments.

-643 to +33

CAT gene


Input: Within this region, we have identified several sequences that are implicated in DNA protein interactions as shown in DNAse I footprints and gel mobility shift assays.

DNAse I


Input: One region, centered at -54, is similar to a nuclear factor E1-binding site, and a region located at position -233 contains a CCAAT motif.

nuclear factor E1-binding site

CCAAT motif


Input: Two domains centered at positions -345 and -540, respectively, bind proteins that are present in megakaryocytic cells and nonrelated cells as well.

megakaryocytic cells

nonrelated cells


Input: Finally, two other domains, located at positions -460 and -510, interact with proteins that are only present in megakaryocytic cells.

megakaryocytic cells


Input: In addition, deletion of the region containing these two domains results in a significant decrease of the promoter activity.

promoter


Input: It is very likely that these domains bind megakaryocyte-specific nuclear proteins acting as positive transcription factors.

megakaryocyte-specific nuclear proteins

positive

transcription factors


Input: Lymphocyte glucocorticoid receptor binding during depression and after clinical recovery.

glucocorticoid receptor


Input: Lymphocyte glucocorticoid receptor binding parameters were studied in 15 severely depressed patients during depression and after clinical recovery, and in 15 healthy controls.

Lymphocyte glucocorticoid receptor


Input: There was no difference in glucocorticoid receptor number or affinity between depressed patients and recovered or control subjects.

glucocorticoid receptor


Input: Afternoon ACTH and cortisol concentrations did not differ significantly between the three groups.


Input: No relationship could be established between glucocorticoid receptor binding and antidepressant medication.

glucocorticoid receptor


Input: These data support the view of an impaired ligand-induced plasticity of glucocorticoid receptor regulation rather than the hypothesis of decreased glucocorticoid receptor numbers during depression.

glucocorticoid receptor

glucocorticoid receptor


Input: Every enhancer works with every promoter for all the combinations tested: could new regulatory pathways evolve by enhancer shuffling?

promoter


Input: The promoters and enhancers of cell type-specific genes are often conserved in evolution, and hence one might expect that a given enhancer has evolved to work best with its own promoter.

promoters

enhancers

enhancer

promoter


Input: While this expectation may be realized in some cases, we have not found evidence for it.


Input: A total of 27 combinations of different promoters and enhancers were tested by transfection into cultured cells.

promoters

enhancers

cultured cells


Input: We found that the relative efficiency of the enhancers is approximately the same, irrespective of the type of promoter used, i.e., there was no strong preference for any given enhancer/ promoter combination.

enhancers

promoter

promoter


Input: Notably, we do not see particularly strong transcription when the immunoglobulin kappa enhancer (or the immunoglobulin heavy chain enhancer) is used to activate a kappa gene promoter.

immunoglobulin kappa enhancer

enhancer

promoter

immunoglobulin heavy chain


Input: We propose that a generally permissive enhancer/ promoter interaction is of evolutionary benefit for higher eukaryotes: by enhancer shuffling, genes could be easily brought under a new type of inducibility/cell type specificity.

promoter


Input: Towards a molecular understanding of T-cell differentiation.


Input: Lymphoid differentiation is one of the best studied examples of mammalian development.


Input: Here Hans Clevers and Michael Owen describe how the cloning of the genes that encode T-cell-specific membrane proteins allows the identification of transcription factors that control the expression of these T-cell genes.

T-cell-specific membrane proteins

transcription factors

T-cell genes


Input: Such transcription factors play a key role in the development of the mature T-cell phenotype by functioning as'master regulators of T-cell differentiation'.

transcription factors


Input: A study on the circadian rhythm of glucocorticoid receptor.

glucocorticoid receptor


Input: Circadian rhythm in glucocorticoid receptor (GR) was studied in the rat liver and human peripheral leukocytes.

glucocorticoid receptor

GR

rat liver

human peripheral leukocytes


Input: For rats exposed to a natural environmental photic cycle or a 12L:12D artificial light regime, peak values of hepatic GR were detected between 23:00 and 02:00 h.

hepatic GR


Input: Except for a 4-hour advancement of the peak, a similar circadian rhythm of hepatic GR was detected in rats reared under a reversed lighting regimen (12D:12L; lights on between 18:30 and 06:30 h).

hepatic GR


Input: In human leukocytes, the peak value of GR was found to parallel that of plasma cortisol with high and low values detected at 04:00-08:00 h and 23:00-24:00 h, respectively.

human leukocytes

GR


Input: In patients suffering from Cushing's syndrome, the circadian rhythm of plasma cortisol either disappeared or was inverted while that of GR did not significantly deviate from the normal subjects.

GR


Input: For apoplexic patients with lesions localized to the base of the brain as indicated by computerized tomography, the diurnal variation of GR was abolished.

GR


Input: Conversely, diurnal rhythmicity persisted in apoplexy patients whose lesions were in the cerebral cortex.


Input: Thus, we postulated that the circadian modification of GR was independent of the diurnal fluctuations in plasma cortisol level or the circadian variations in environmental lighting and that the rhythmicity might be regulated by the' circadian pacemaker' located in the human basal brain.

GR


Input: These diurnal variations in GR might serve to coordinate the reactivity of the target cells to cortisol because the diurnal rhythms of a GR -mediated response, the fractional inhibition of chemotactic migration rate of polymorphonuclear leukocytes by cortisol, were found to be synchronous with those of GR.

GR

GR

GR

target cells

polymorphonuclear leukocytes


Input: Transcription factor requirements for U2 snRNA -encoding gene activation in B lymphoid cells.

Transcription factor

U2 snRNA

B lymphoid cells


Input: Transcription of a human U2 small nuclear RNA(snRNA)-encoding gene in HeLa cells requires a distal enhancer element, which is composed of one octamer motif (Oct) and three Sp 1-binding sites.

U2 small nuclear RNA(snRNA)-encoding gene

distal enhancer element

octamer motif

Oct

Sp 1-binding sites

HeLa cells


Input: To study the transcription factor requirement in B-cells, different U2 enhancer constructions were transfected into the lymphoid cell line, BJA-B.

transcription factor

B-cells

U2 enhancer constructions

lymphoid cell line

BJA-B


Input: The results showed that the activation of U2 snRNA transcription in B-cells also requires an enhancer comprising both the Oct and at least one Sp 1-binding site.

B-cells

Oct

Sp 1-binding site


Input: Deletion of all the Sp 1-binding sites from the enhancer reduces transcription by 80-90% in HeLa, as well as in BJA-B cells, whereas the removal of the octamer-binding site reduces transcription to levels below detection in both cell types.

Sp 1-binding sites

enhancer

octamer-binding site

BJA-B cells


Input: Enhancers containing a single Oct have, nevertheless, the capacity to partially activate U2 snRNA transcription in both HeLa cells, in which only OTF-1 is expressed, and in BJA-B cells in which OTF-2 is the predominantly expressed octamer-binding factor.

Oct

U2 snRNA

HeLa cells

BJA-B cells

octamer-binding factor


Input: The most likely interpretation of our results is that both the ubiquitous transcription factor, OTF-1, and the B-cell-specific transcription factor, OTF-2, can activate U2 snRNA transcription.

transcription factor

B-cell-specific

transcription factor

U2 snRNA


Input: The results also revealed a similar functional cooperation between the transcription factors which bind to the Oct and the adjacent Sp 1-binding site in BJA-B cells, as has been observed in HeLa cells, since a template which contains a weak binding site for OTFs expresses wild-type levels of U2 snRNA in both cell types when the weak octamer-binding site is combined with a Sp 1-binding site.

Oct

Sp 1-binding site

OTFs

octamer-binding site

Sp 1-binding site

BJA-B cells

HeLa cells

U2 snRNA


Input: One base pair change abolishes the T cell-restricted activity of a kB-like proto-enhancer element from the interleukin 2 promoter.

kB-like proto-enhancer element

interleukin 2 promoter


Input: The inducible, T cell-specific enhancers of murine and human Interleukin 2 (Il-2) genes contain the kB-like sequence GGGATTTCACC as an essential cis-acting enhancer motif.

T cell-specific enhancers

murine and human Interleukin 2 (Il-2) genes

kB-like sequence

essential cis-acting enhancer motif


Input: When cloned in multiple copies this so-called TCEd (distal T cell element) acts as an inducible proto-enhancer element in E14 T lymphoma cells, but not in HeLa cells.

TCEd

distal T cell element

proto-enhancer element

E14 T lymphoma cells

HeLa cells


Input: In extracts of induced, Il-2 secreting El4 cells three individual protein factors bind to TCEd DNA.

Il-2 secreting El4 cells

protein factors

TCEd DNA


Input: The binding of the most prominent factor, named TCF-1 (T cell factor 1 ), is correlated with the proto-enhancer activity of TCEd.

T cell factor 1

TCEd


Input: TCF-1 consists of two polypeptides of about 50 kD and 105 kD; the former seems to be related to the 50 kD polypeptide of NF-kB.

50 kD polypeptide

NF-kB


Input: Purified NF-kB is also able to bind to the TCEd, but TCF-1 binds stronger than NF-kB to TCEd DNA.

Purified NF-kB

NF-kB

TCEd

TCEd


Input: The conversion of the TCEd to a'perfect' NF-kB binding site leads to a tighter binding of NF-kB to TCEd DNA and, as a functional consequence, to the activity of the'converted' TCEd motifs in HeLa cells.

TCEd

'perfect' NF-kB binding site

TCEd DNA

'converted' TCEd motifs

NF-kB

HeLa cells


Input: Thus, the substitution of the underlined A residue to a C within the GGGATTTCACC motif abolishes its T cell-restricted activity and leads to its functioning in both El4 cells and HeLa cells.

GGGATTTCACC motif

El4 cells

HeLa cells


Input: These results indicate that lymphocyte-specific factors binding to the TCEd are involved in the control of T cell specific-transcription of the Il-2 gene.

TCEd

Il-2 gene


Input: An erythroid specific enhancer upstream to the gene encoding the cell-type specific transcription factor GATA-1.

erythroid specific enhancer

cell-type specific transcription factor


Input: The transcription factor GATA-1 is expressed in a subset of hemopoietic cells, where it mediates the cell-type specific expression of several genes.

transcription factor

hemopoietic cells


Input: We have cloned the mouse and human GATA-1 genes.

GATA-1 genes


Input: A region upstream to the first exon, and highly conserved between mouse and man, acts as an erythroid specific enhancer in transient assays, if linked to the GATA-1 or to the SV40 promoter.

erythroid specific enhancer

SV40 promoter


Input: The activity of the enhancer is almost completely dependent on the integrity of a dimeric GATA-1 binding site.

dimeric GATA-1 binding site


Input: Demonstration of a 1,25-dihydroxyvitamin D3 -responsive protein in human lymphocytes: immunologic crossreactivity and inverse regulation with the vitamin D receptor.

1,25-dihydroxyvitamin D3 -responsive protein

vitamin D receptor

human lymphocytes


Input: Using Western blot analysis with a monoclonal antibody recognizing a 17-amino acid epitope of the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]receptor, we have detected two crossreacting proteins in activated normal human lymphocytes.

monoclonal antibody

17-amino acid epitope

1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]receptor

crossreacting proteins

activated normal human lymphocytes


Input: The smaller of the two proteins (50 kDa) was indistinguishable from the classical 1,25(OH)2D3 receptor and, similar to the classical 1,25(OH)2D3 receptor, was upregulated in a dose-dependent fashion by 1,25(OH)2D3.

50 kDa

1,25(OH)2D3 receptor

1,25(OH)2D3 receptor


Input: The larger crossreacting protein exhibited an electrophoretic mobility of 80 kDa, was localized in the cell cytosol, and appeared to be specific for activated lymphocytes since it was not detected in several other human cells including monocytes.

80 kDa

activated lymphocytes

human cells

monocytes


Input: More strikingly, the 80-kDa protein was downregulated in a dose-dependent fashion by 1,25(OH)2D3; this effect was independent of the mode of lymphocyte activation and specific for the 1,25(OH)2D3 metabolite of vitamin D3.

80-kDa protein


Input: However, two potent immunosuppressive agents, glucocorticoids and cyclosporin A, also inhibited the 80-kDa protein.

80-kDa protein


Input: Regulation of glucocorticoid receptors in human mononuclear cells: effects of glucocorticoid treatment, Cushing's disease and ketoconazole.

glucocorticoid receptors

human mononuclear cells


Input: Glucocorticoid receptors (GcR) were determined by a whole cell assay in human mononulear leukocytes (hMNL) from control subjects, patients receiving glucocorticoid therapy for systemic diseases and Cushing's disease patients with or without ketoconazole therapy.

Glucocorticoid receptors

GcR

human mononulear leukocytes

hMNL


Input: Prolonged corticosteroid treatment resulted in down-regulation of GcR, while the mean level of GcR in Cushing's disease was normal.

GcR

GcR


Input: In this group, however, receptor levels and morning plasma cortisol values showed a negative correlation, indicating a subtle down-regulatory effect.


Input: Furthermore, GcR were unaltered after these patients received ketoconazole, in spite of a marked reduction in morning plasma cortisol and urinary free cortisol.

GcR


Input: We also observed that ketoconazole was a weak competitor of GcR in intact cells, although it significantly inhibited [3H] dexamethasone binding in cytosolic preparations from rat tissues.

GcR

intact cells


Input: The results suggested that GcR in hMNL are down-regulated by synthetic steroids given in vivo, but they showed very mild down-regulation in hypercortisolemic patients suffering from Cushing's disease.

GcR

hMNL


Input: Finally, we did not observed either up-regulation or antagonism of GcR by ketoconazole treatment, at the time that cortisol levels of patients with Cushing's disease were reduced.

GcR


Input: This indicates that the beneficial effects of ketoconazole in Cushing's disease are due to adrenal cortisol suppression and not to interaction with GcR of target cells, and that the process of GcR regulation in hMNL is a complex phenomenon awaiting further elucidation.

GcR

GcR

target cells

hMNL


Input: HTLV-1 Tax induces expression of various immediate early serum responsive genes.

HTLV-1 Tax

immediate early serum responsive genes


Input: Human T-cell leukemia virus type 1 (HTLV-1) is an etiological agent of adult T-cell leukemia (ATL ).


Input: We showed here by mobility-shift assay that T-cell lines transformed with the virus contained high levels of AP-1 activities.

T-cell lines


Input: Consistent with this result, these cell lines expressed increased levels of mRNAs encoding the AP-1 proteins, c-Fos, Fra-1, c-Jun, JunB, and JunD.

mRNAs

AP-1 proteins

c-Fos

c-Jun

JunB

JunD


Input: Previously, transcription of the c-fos gene has been reported to be transactivated by the viral transcription factor, Tax1.

c-fos gene

viral transcription factor


Input: By using the human T-cell line (JPX-9 ), in which expression of the Tax1 is inducible, we showed that expression of mRNAs for Fra-1, c-Jun, and JunD was also transactivated by Tax1.

human T-cell line

c-Jun

JunD

mRNAs


Input: Moreover, Tax1 activated expression of two other transcription factors having zinc finger motifs, Egr-1 and Egr-2, in the same cells.

transcription factors

zinc finger motifs


Input: The Tax1 -inducible transcription factors identified here are encoded by the members of immediate early genes under the control of growth signals.

Tax1 -inducible transcription factors

immediate early genes


Input: Thus, Tax1 was suggested to replace growth signals, at least in part, by this mechanism.


Input: Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid -resistant bronchial asthma.

Glucocorticoid receptor

monocytes


Input: The mechanism of corticosteroid resistance in bronchial asthma has been studied by determining the rank order of potency for different corticosteroids in inhibiting the generation of a 3 kD molecule from peripheral blood monocytes isolated from corticosteroid-sensitive (CS) and corticosteroid-resistant (CR) asthmatic subjects, which augments leukotriene B4 (LTB4) generation by human neutrophils (PMN) stimulated by calcium ionophore.

peripheral blood monocytes

human neutrophils

PMN


Input: In addition, binding studies with (3H) dexamethasone have been performed to determine the dissociation constant (Kd) and receptor numbers (Ro) in the monocytes of these two groups of subjects.

monocytes


Input: The concentration of corticosteroid producing 50% inhibition (IC50) was 600 nM, 70 nM, and 0.5 nM for hydrocortisone, methylprednisolone, and dexamethasone, respectively, in monocytes from CS individuals.

monocytes


Input: There was only weak inhibition of the generation of enhancing activity by the corticosteroids in the CR asthmatic individuals.


Input: The dexamethasone Kd was 2.45 +/- 0.58 nM (mean +/- SEM, n = 6) in the CS group and 1.6 +/- 0.35 nM (mean +/- SEM, n = 6) in the CR group of patients (p = 0.14).


Input: The Ro in the CS group was 3,605 +/- 984 binding sites per nucleus (mean +/- SEM, n = 6) and 4,757 +/- 692 binding sites per nucleus (mean +/- SEM, n = 6) in the CR group (p = 0.23).


Input: These findings indicate that corticosteroid resistance in bronchial asthma cannot be explained by abnormalities in corticosteroid receptor characteristics.


Input: Vitamin D receptor expression in human lymphocytes.

Vitamin D receptor

human lymphocytes


Input: Signal requirements and characterization by western blots and DNA sequencing.


Input: The signals controlling the expression of the receptor protein for 1 alpha,25-dihydroxyvitamin D3 in normal human lymphocytes and the relationship of this protein to the classical vitamin D receptor were examined.

receptor protein

classical vitamin D receptor

human lymphocytes


Input: Lymphocytes activated with the OKT3 antibody to the T-cell antigen receptor expressed fewer binding sites as compared to lymphocytes that were activated by the polyclonal activator phytohemagglutinin (PHA ).

Lymphocytes

lymphocytes

OKT3 antibody

T-cell antigen receptor

phytohemagglutinin

PHA


Input: However, combination of OKT3 and phorbol myristate acetate produced a concentration of binding sites similar to the PHA -activated cells.

PHA

-activated cells


Input: The receptor from OKT3 and OKT3 + phorbol myristate acetate -activated lymphocytes exhibited decreased binding to DNA-cellulose compared to PHA -activated lymphocytes.

-activated

lymphocytes

PHA -activated lymphocytes


Input: In lymphocytes activated either by PHA or OKT3 (but not in resting cells ), a 50-kDa species cross-reacting with a monoclonal antibody against the intestinal vitamin D receptor was detected.

lymphocytes

resting cells

PHA

50-kDa species

monoclonal antibody

intestinal vitamin D receptor


Input: Finally, RNA from activated lymphocytes was amplified by polymerase chain reaction using oligonucleotide primers flanking the 196 base pair long region encoding the DNA-binding domain of the human intestinal receptor.

RNA

activated

lymphocytes

196 base pair long region

DNA-binding domain

human intestinal receptor


Input: The amplified product showed an identical nucleotide sequence to the DNA-binding domain of the human intestinal receptor.

identical nucleotide sequence

DNA-binding domain

human intestinal receptor


Input: These findings suggest that expression of the 1,25-(OH)2D3 receptor in lymphocytes is triggered by distinct and contingent signals, and that the protein and the mRNA encoding it are identical to the classical vitamin D receptor.

1,25-(OH)2D3 receptor

classical

vitamin D receptor

lymphocytes

mRNA


Input: Comparison of constitutive and inducible transcriptional enhancement mediated by kappa B-related sequences: modulation of activity in B cells by human T-cell leukemia virus type I tax gene.

kappa B-related sequences

human T-cell leukemia virus type I tax gene

B cells


Input: The kappa B sequence (GGGACTTTCC) binds a factor, NF-kappa B, that is constitutively found in its functional, DNA binding form only in B lymphocytes.

kappa B sequence

NF-kappa B

B lymphocytes


Input: A factor with apparently indistinguishable sequence specificity can be induced in many other cell types, where it is used to regulate inducible gene expression.


Input: For example, kappa B-related sequences have been shown to be important for the transcription of a few inducible genes, such as the interleukin 2 receptor alpha-chain gene and the beta-interferon gene.

kappa B-related sequences

interleukin 2 receptor alpha-chain gene

gene

beta-interferon


Input: However, these genes are not constitutively active in B lymphocytes, suggesting that other regulatory mechanisms must play a role in determining the patterns of expression.

B lymphocytes


Input: We have investigated the constitutive and inducible transcriptional activity mediated by five kappa B-related sequence elements in two different cell types.

kappa B-related sequence elements


Input: We show that in S194 plasma cells the activity of each element correlates well with the relative affinity of B-cell-derived NF-kappa B for that element.

S194 plasma cells

B-cell-derived NF-kappa B


Input: This leads to significantly lower transcription enhancement by sites derived from the interleukin 2 receptor or T-cell receptor genes in S194 cells.

interleukin 2 receptor

T-cell receptor genes

S194 cells


Input: However, in either EL-4 (T) cells or S194 cells, both lower-affinity sites can be significantly induced by the tax gene product of human T-cell leukemia virus type I, showing that NF-kappa B activity can be modulated even in a B-cell line that constitutively expresses this factor.

EL-4 (T) cells

S194 cells

B-cell line

tax gene product

NF-kappa B


Input: Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice.

B-cell population

human interferon regulatory factor 1

gene


Input: Interferons (IFNs) are well known both as antiviral proteins and as potent regulators of cell growth and differentiation.

Interferons

IFNs

antiviral proteins


Input: In fact, IFNs inhibit growth of various normal and transformed cell types.

IFNs

normal

transformed cell types


Input: Previously, a nuclear factor, IRF-1 (interferon regulatory factor 1 ), which binds to type I IFN and some IFN -inducible gene promoters, was identified and cloned.

nuclear factor

interferon regulatory factor 1

type I IFN

IFN -inducible gene promoters


Input: Since the IRF-1 gene is both virus and IFN inducible, an intriguing issue is raised as to whether the IRF-1 gene is functioning in IFN -mediated regulation of cell growth and differentiation.

IFN

IFN

gene


Input: In this study, we generated transgenic mice carrying the human IRF-1 gene linked to the human immunoglobulin heavy-chain enhancer.

human IRF-1 gene

human immunoglobulin heavy-chain enhancer


Input: In the transgenic mice, all the lymphoid tissues examined showed a dramatic reduction in the number of B lymphocytes (B cells ).

B lymphocytes

B cells


Input: Preparation and analysis of bone marrow cells from the chimeric mice indicated that the bone marrow is the effective site for specific depletion of the B-cell population.

bone marrow cells

B-cell population


Input: In fact, transgenic bone marrow cells cocultured with a bone marrow-derived stromal cell line revealed an altered B-cell maturation pattern.

transgenic bone marrow cells

bone marrow-derived stromal cell line

B-cell


Input: Characterization of a cofactor that regulates dimerization of a mammalian homeodomain protein.

cofactor

mammalian homeodomain protein


Input: Dimerization among transcription factors has become a recurrent theme in the regulation of eukaryotic gene expression.

transcription factors


Input: Hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is a homeodomain-containing protein that functions as a dimer.

Hepatocyte nuclear factor-1 alpha

HNF-1 alpha

homeodomain-containing protein

dimer


Input: A dimerization cofactor of HNF-1 alpha (DCoH) was identified that displayed a restricted tissue distribution and did not bind to DNA, but, rather, selectively stabilized HNF-1 alpha dimers.

dimerization

cofactor

HNF-1 alpha

DCoH

HNF-1 alpha dimers


Input: The formation of a stable tetrameric DCoH-HNF-1 alpha complex, which required the dimerization domain of HNF-1 alpha, did not change the DNA binding characteristics of HNF-1 alpha, but enhanced its transcriptional activity.

tetrameric DCoH-HNF-1 alpha complex

dimerization domain

HNF-1 alpha

HNF-1 alpha


Input: However, DCoH did not confer transcriptional activation to the GAL4 DNA binding domain.

DCoH

GAL4 DNA binding domain


Input: These results indicate that DCoH regulates formation of transcriptionally active tetrameric complexes and may contribute to the developmental specificity of the complex.

DCoH

tetrameric complexes

developmental specificity

complex


Input: Glucocorticoid resistance in chronic asthma.


Input: Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro.

glucocorticoid receptor

peripheral blood T cell


Input: A total of 37 chronic, severe, nonsmoking asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid-sensitive or -resistant on the basis of changes in FEV1, FVC, and peak expiratory flow (PEF) after oral prednisolone.


Input: The resistant patients showed no significant improvements in airflow limitation.


Input: Phytohemagglutinin (PHA )-induced proliferation of peripheral blood T lymphocytes from the sensitive but not the resistant asthmatic patients was significantly (p less than 0.01) inhibited by dexamethasone (10(-7) mol/L), reflecting a shift of the dose-response curve.

Phytohemagglutinin

PHA

peripheral blood T lymphocytes


Input: When all the asthmatic patients were analyzed together, there was a significant correlation between the degree of sensitivity of T cells to dexamethasone and the clinical responsiveness to prednisolone (p less than 0.01).

T cells


Input: No differences were observed between six of the sensitive and resistant patients in the clearance of plasma prednisolone derived from orally administered prednisone.


Input: Peripheral blood mononuclear cell glucocorticoid receptors were also characterized in five sensitive and seven resistant patients.

Peripheral blood mononuclear cell

glucocorticoid receptors


Input: The numbers and binding affinities of these receptors could not account for the observed difference in the susceptibility of these cells to functional inhibition by dexamethasone in vitro.

receptors


Input: These results suggest that clinical glucocorticoid resistance in chronic asthma does not reflect abnormal glucocorticoid clearance but may be due at least partly to a relative insensitivity of T lymphocytes to glucocorticoids.

T lymphocytes


Input: This lack of sensitivity is unexplained but is not attributable to abnormalities of cellular glucocorticoid receptors.

cellular glucocorticoid receptors


Input: Inhibition of phorbol ester-induced monocytic differentiation by dexamethasone is associated with down-regulation of c-fos and c-jun (AP-1 ).

c-fos

c-jun


Input: Previous studies have shown that treatment of human myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation and expression of the c-jun and c-fos early response genes.

human myeloid leukemia cells


Input: The present work demonstrates that the glucocorticoid dexamethasone inhibits TPA -induced increases in c-jun and c-fos mRNA levels in U-937 leukemia cells.

U-937 leukemia cells


Input: These findings were associated with a block in appearance of the monocytic phenotype, including inhibition of TPA -induced increases in lamin A, lamin C, and vimentin transcripts.

monocytic phenotype


Input: Other studies have demonstrated that TPA -induced monocytic differentiation and expression of the c-jun and c-fos genes in myeloid leukemia cells are regulated by protein kinase C (PKC ).

c-jun

c-fos genes

myeloid leukemia cells

protein kinase C

PKC


Input: The finding that dexamethasone has no effect on TPA -induced activation of PKC suggests that this glucocorticoid inhibits signals downstream or parallel to this enzyme.

PKC

enzyme


Input: Nuclear run-on assays demonstrate that: (1) induction of c-jun and c-fos expression by TPA is regulated by transcriptional mechanisms, (2) TPA -induced expression of c-jun and c-fos does not require protein synthesis, and (3) TPA -induced expression of both genes is inhibited at the transcriptional level by dexamethasone.

c-jun

c-fos


Input: To further define the effects of dexamethasone at the molecular level, we prepared a series of deleted c-jun promoter fragments linked to the chloramphenicol acetyltransferase (CAT) gene.

c-jun promoter fragments

) gene

chloramphenicol acetyltransferase

CAT


Input: Increases in CAT activity during transient expression of these constructs in TPA -treated U-937 cells could be assigned to the region (-97 to -20) of the promoter that contains the AP-1 binding site.

CAT

TPA -treated U-937 cells

promoter

AP-1 binding site


Input: This induction of CAT activity was sensitive to dexamethasone.

CAT


Input: These findings suggest that dexamethasone down-regulates TPA -induced transcription of the c-jun gene during monocytic differentiation by inhibiting activation of the AP-1 site.

c-jun

AP-1 site


Input: Tumor necrosis factor-alpha mRNA accumulation in human myelomonocytic cell lines.

Tumor necrosis factor-alpha mRNA

human myelomonocytic cell lines


Input: Role of transcriptional regulation by DNA sequence motifs and mRNA stabilization.

DNA sequence motifs


Input: The cytokine TNF mediates many of the pathologic signs of cachexia, inflammation, and sepsis.

cytokine

TNF


Input: The current work describes the regulation of TNF in human myelomonocytic cell lines after PMA stimulation.

TNF

human myelomonocytic cell lines


Input: The cell lines exhibit a low level of constitutive TNF mRNA expression.

cell lines

TNF mRNA


Input: Within 2 to 4 h of PMA exposure, steady state levels of TNF mRNA are markedly elevated in all myelomonocytic cell lines studied.

TNF mRNA

myelomonocytic cell lines


Input: This rise is due to increased mRNA stability, which increased by almost twofold, and to an overall increase in transcription, which rises by more than sixfold.


Input: At the level of the genomic TNF gene, a DNase I hypersensitive site is detected within the TNF promoter between -200 to -100 bp relative to the transcription initiation site.

genomic TNF gene

DNase I hypersensitive site

TNF promoter

-200 to -100 bp

transcription initiation site


Input: Although absent in nonexpressing erythroleukemia cell lines, the DNase I site is present in uninduced myelomonocytic cell lines and is not changed after PMA induction.

nonexpressing erythroleukemia cell lines

uninduced myelomonocytic cell lines

DNase I site


Input: The PMA induction of c-fos mRNA correlated well with TNF gene induction; expression of genes encoding other proteins in the AP-1 complex (junB and junD) were also induced by PMA.

c-fos mRNA

TNF

AP-1 complex

junB

junD


Input: The nuclear extracts from resting and induced ML-1 cells contain proteins binding specifically to the AP-1, AP-2, and NF kappa B sequence located within the TNF promoter.

induced ML-1 cells

TNF promoter


Input: PMA induction increases the level of a number of specific binding complexes relative to the resting cells.

specific binding complexes

resting cells


Input: The regulatory mechanisms of the human and murine TNF genes are discussed.


Input: Enhancement of human immunodeficiency virus 1 replication in monocytes by 1,25-dihydroxycholecalciferol.

monocytes


Input: Human immunodeficiency virus (HIV) expression and replication are under tight regulatory control.


Input: We demonstrate that 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] enhances the replication of monocyte- and lymphocyte-tropic strains of HIV-1 up to 10,000-fold in monocyte cell lines, peripheral blood monocytes, and unfractionated peripheral blood mononuclear cells.

monocyte cell lines

peripheral blood monocytes

unfractionated peripheral blood mononuclear cells


Input: 1,25(OH)2D3 is therefore one of the most potent regulators of HIV-1 replication described to date.


Input: Precursors of 1,25(OH)2D3 enhance HIV-1 replication in proportion to their affinity for the 1,25(OH)2D3 intracellular receptor, suggesting that 1,25(OH)2D3 influences HIV-1 replication by mechanisms involving this receptor.

1,25(OH)2D3 intracellular receptor


Input: These studies may have important implications for the design of effective therapy of HIV-1 infection.


Input: Transforming growth factor-beta suppresses human B lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secreted form of Ig mRNA.

Transforming growth factor-beta

human B lymphocyte Ig

membrane form

secreted form

Ig mRNA


Input: Transforming growth factor-beta (TGF-beta) inhibits B cell Ig secretion and reduces B cell membrane Ig expression.

Transforming growth factor-beta

TGF-beta

Ig

Ig

B cell

B cell


Input: The addition of TGF-beta to human B lymphocyte cultures stimulated with Staphylococcus aureus Cowan strain I and IL-2 completely inhibited B cell Ig secretion (greater than 90%) and decreased B cell surface IgM, IgD, kappa L chain, and lambda L chain expression.

TGF-beta

Ig

human B lymphocyte cultures

B cell

B cell


Input: In contrast, TGF-beta had only minimal effects on two other B cell membrane proteins, HLA-DR and CD20.

TGF-beta

membrane proteins

HLA-DR

B cell


Input: Internal labeling with [35S]methionine and immunoprecipitation with anti-IgM, anti-kappa, and anti-lambda antibodies revealed a striking reduction in kappa L chain in the presence of TGF-beta.

anti-IgM

anti-kappa

anti-lambda antibodies

kappa L chain

TGF-beta


Input: A less pronounced reduction in lambda L chain and microH chain was also noted.

lambda L chain

microH chain


Input: Northern blot analysis of RNA purified from B cells treated with TGF-beta for varying time intervals revealed a significant decrease in steady state kappa and lambda L chain mRNA levels.

B cells

TGF-beta


Input: Furthermore, a significant decrease in the switch from the membrane forms of mu and gamma to their respective secreted forms was noted in the presence of TGF-beta.

membrane forms

mu

gamma

secreted forms

TGF-beta


Input: Nuclear run-on experiments demonstrated decreased transcription of kappa L chain.

kappa L chain


Input: The effects of TGF-beta on two transcriptional regulatory factors, Oct-2 and nuclear factor (NF) kappa B, known to be important in Ig gene transcription were examined.

TGF-beta

transcriptional regulatory factors

nuclear factor (NF) kappa B

Ig


Input: Oct-2 mRNA levels and both Oct-2 and NF-kappa B proteins in nuclear extracts were not altered by treatment with TGF-beta.

Oct-2 mRNA

NF-kappa B proteins

TGF-beta


Input: In contrast, levels of the transcriptional factor AP-1, which is not known to be important in B cell Ig production, were reduced by TGF-beta.

transcriptional factor AP-1

Ig

TGF-beta

B cell


Input: These findings demonstrate that TGF-beta decreases B lymphocyte Ig secretion by inhibiting the synthesis of Ig mRNA and inhibiting the switch from the membrane form to the secreted forms of mu and gamma mRNA.

TGF-beta

Ig

Ig mRNA

membrane form

secreted forms


Input: The mechanism by which TGF-beta inhibits Ig chain synthesis is unclear although it does not involve inhibition of the binding of NF-kappa B or Oct-2 to their respective target sequences.

TGF-beta

NF-kappa B


Input: Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer.

cis-regulatory element

human T-cell receptor delta gene enhancer


Input: A family of transcriptional activators has recently been identified in chickens; these transcriptional activators recognize a common consensus motif (WGATAR) through a conserved C4 zinc finger DNA-binding domain.

transcriptional activators

transcriptional activators

C4 zinc finger DNA-binding domain

consensus motif

WGATAR


Input: One of the members of this multigene family, cGATA-3, is most abundantly expressed in the T-lymphocyte cell lineage.

T-lymphocyte cell lineage


Input: Analysis of human and murine GATA-3 factors shows a striking degree of amino acid sequence identity and similar patterns of tissue specificity of expression in these three organisms.

amino acid sequence


Input: The murine and human factors are abundantly expressed in a variety of human and murine T-cell lines and can activate transcription through a tissue-specific GATA-binding site identified within the human T-cell receptor delta gene enhancer.

human and

murine T-cell lines

tissue-specific GATA-binding site

human T-cell receptor delta gene enhancer


Input: We infer that the murine and human GATA-3 proteins play a central and highly conserved role in vertebrate T-cell-specific transcriptional regulation.


Input: Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection.

NF-kappa B

HIV-1 protease


Input: Transcription of the human immunodeficiency virus type-1 (HIV-1) genome is regulated in part by cellular factors and is stimulated by activation of latently infected T cells.

human immunodeficiency virus type-1 (HIV-1) genome

cellular factors

latently infected T cells


Input: T-cell activation also correlates with the induction of the factor NF-kappa B which binds to two adjacent sites in the HIV-1 long terminal repeat.

NF-kappa B

HIV-1 long terminal repeat


Input: This factor consists of two DNA-binding subunits of relative molecular mass 50,000 (50K) associated with two 65K subunits.

DNA-binding subunits

65K subunits


Input: It is located in the nucleus in mature B cells, but is present in other cell types as an inactive cytoplasmic complex.

mature B cells

inactive cytoplasmic complex


Input: External stimuli, including those that activate T cells, result in nuclear translocation of active NF-kappa B.

T cells

NF-kappa B


Input: The cloning of the complementary DNA for the 50K subunit helped to identify an exclusively cytoplasmic 105K precursor (p105) (V.B., P.K. and A.I., manuscript submitted).

complementary DNA

50K subunit

cytoplasmic 105K precursor


Input: The expression of active NF-kappa B might therefore also be regulated by the extent of processing of p105.

NF-kappa B


Input: Because HIV-1 requires active NF-kappa B for efficient transcription, we tested the effect of HIV-1 infection on the processing of the human 105K precursor.

NF-kappa B

human 105K precursor


Input: We show here that the HIV-1 protease can process p105 and increases levels of active nuclear NF-kappa B complex.

nuclear NF-kappa B complex


Input: 1,25-Dihydroxyvitamin D3 receptor RNA: expression in hematopoietic cells.

1,25-Dihydroxyvitamin D3 receptor

RNA

hematopoietic cells


Input: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] induces differentiation and inhibits proliferation of myeloid leukemic cells from various lines and patients; these effects are probably mediated through the 1,25(OH)2D3 receptor.

myeloid leukemic cells

1,25(OH)2D3 receptor


Input: Little is known of expression of 1,25(OH)2D3 receptor RNA in hematopoietic cells.

1,25(OH)2D3 receptor RNA

hematopoietic cells


Input: We examined the expression and modulation of expression of 1,25(OH)2D3 receptor RNA in various proliferating and nonproliferating hematopoietic cells.

1,25(OH)2D3 receptor

RNA


Input: Constitutive expression of 1,25(OH)2D3 receptor RNA was detected in various kinds of hematopoietic cells, including macrophages and activated T lymphocytes, as well as in cell lines KG-1 (myeloblasts ), HL-60 (promyelocytes ), ML-3 (myelomonoblasts ), U937, THP-1 (monoblasts ), K562 (erythroblasts ), and S-LB1 (HTLV-1-transfected T lymphocytes ).

1,25(OH)2D3 receptor RNA

hematopoietic cells

T lymphocytes

T lymphocytes

myeloblasts

promyelocytes

myelomonoblasts

monoblasts

erythroblasts


Input: Receptor transcripts were 4.6 kilobases (kb), and no variant sizes were observed.

Receptor transcripts

4.6 kilobases


Input: All cell lines examined in this group also expressed 1,25(OH)2D3 receptors.

1,25(OH)2D3 receptors


Input: Most B lymphocyte lines expressed negligible levels of 1,25(OH)2D3 receptor RNA and protein; however; analysis of a lymphoid/myeloid somatic hybrid suggested that suppression of expression of 1,25(OH)2D3 receptor RNA in B lymphocytes may be a dominant characteristic.

B lymphocyte lines

lymphoid/myeloid somatic hybrid

1,25(OH)2D3 receptor

1,25(OH)2D3 receptor

RNA

RNA

B lymphocytes


Input: HL-60 cells were cultured with 10(-7) mol/L 1,25(OH)2D3 for 24 to 72 hours, and levels of expression of 1,25(OH)2D3 receptor and its RNA were examined.

HL-60 cells

1,25(OH)2D3 receptor

RNA


Input: Levels of RNA coding for the receptor were not modulated by exposure to high levels of ligand.

RNA

receptor


Input: Levels of occupied 1,25(OH)2D3 receptor protein increased in these HL-60 cells; but the total number of 1,25(OH)2D3 receptors decreased about 50% at 24 hours and returned toward normal at 72 hours.

1,25(OH)2D3 receptor protein

1,25(OH)2D3 receptors

HL-60 cells


Input: Steady-state levels of 1,25(OH)2D3 receptor RNA were not affected by terminal differentiation of HL-60 toward either granulocytes or macrophages.

1,25(OH)2D3 receptor

RNA

granulocytes

macrophages


Input: Nondividing macrophages from normal individuals also expressed 1,25(OH)2D3 receptor RNA.

macrophages

1,25(OH)2D3 receptor

RNA


Input: In contrast, nondividing peripheral blood lymphocytes from normal individuals did not express 1,25(OH)2D3 receptor RNA; with stimulation of proliferation of these cells, accumulation of 1,25(OH)2D3 receptor RNA increased markedly.

nondividing peripheral blood lymphocytes

1,25(OH)2D3 receptor RNA

RNA

1,25(OH)2D3 receptor


Input: Half-life (t1/2) of 1,25(OH)2D3 receptor RNA in T lymphocytes was short (1 hour) as determined by measuring decay of the message after addition of actinomycin D.

1,25(OH)2D3 receptor

RNA

T lymphocytes


Input: Consistent with this short t1/2, accumulation of 1,25(OH)2D3 receptor RNA increased in cells as their protein synthesis was inhibited.

1,25(OH)2D3 receptor

RNA


Input: Further studies are required to understand the physiologic role of 1,25(OH)2D3 receptors in myeloid cells and proliferating T lymphocytes.

1,25(OH)2D3 receptors

myeloid cells

proliferating

T lymphocytes


Input: Expression of c-jun, jun B and jun D proto-oncogenes in human peripheral-blood granulocytes.

c-jun,

jun B and

jun D proto-oncogenes

human peripheral-blood granulocytes


Input: We have found that purified human peripheral-blood granulocytes express constitutively significant levels of proto-oncogenes c-jun, jun B and jun D mRNA.

purified human peripheral-blood granulocytes

proto-oncogenes


Input: Upon functional activation of granulocytes by 4 beta-phorbol 12-myristate 13-acetate (PMA ), the levels of c-jun, jun B and jun D transcripts were increased.

granulocytes


Input: The three jun genes showed a similar time course in their induction by PMA, maximal mRNA levels being reached after 60 min of induction.

jun genes


Input: These results suggest that expression of c-jun, jun B and jun D genes might be involved in terminal granulocyte differentiation or in regulating granulocyte functionality.

c-jun

jun B

jun D genes

terminal granulocyte

granulocyte


Input: The 29-kDa proteins phosphorylated in thrombin-activated human platelets are forms of the estrogen receptor -related 27-kDa heat shock protein.

29-kDa proteins

estrogen receptor -related 27-kDa heat shock protein

thrombin-activated human platelets


Input: Thrombin plays a critical role in platelet activation, hemostasis, and thrombosis.

Thrombin


Input: Cellular activation by thrombin leads to the phosphorylation of multiple proteins, most of which are unidentified.

multiple proteins


Input: We have characterized several 29-kDa proteins that are rapidly phosphorylated following exposure of intact human platelets to thrombin.

29-kDa proteins

thrombin

intact human platelets


Input: A murine monoclonal antibody raised to an unidentified estrogen receptor-related 29-kDa protein selectively recognized these proteins as well as a more basic, unphosphorylated 27-kDa protein.

murine monoclonal antibody

unidentified estrogen receptor-related 29-kDa protein

unphosphorylated 27-kDa protein


Input: Cellular activation by thrombin led to a marked shift in the proportion of protein from the 27-kDa unphosphorylated form to the 29-kDa phosphoprotein species.

thrombin

27-kDa unphosphorylated form

29-kDa phosphoprotein species


Input: Using this antibody, we isolated and sequenced a human cDNA clone encoding a protein that was identical to the mammalian 27-kDa heat shock protein (HSP27 ), a protein of uncertain function that is known to be phosphorylated to several forms and to be transcriptionally induced by estrogen.

cDNA clone

mammalian 27-kDa heat shock protein


Input: The 29-kDa proteins were confirmed to be phosphorylated forms of HSP27 by immunoprecipitation studies.

29-kDa proteins


Input: Thus, the " estrogen receptor-related protein" is HSP27, and the three major 29-kDa proteins phosphorylated in thrombin -activated platelets are forms of HSP27.

29-kDa proteins

thrombin

-activated platelets


Input: These data suggest a role for HSP27 in the signal transduction events of platelet activation.

platelet


Input: Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta ), that binds to the immunoglobulin kappa 3' enhancer and the immunoglobulin heavy-chain mu E1 site.

delta

immunoglobulin kappa 3' enhancer

immunoglobulin heavy-chain mu E1 site


Input: We have determined that the developmental control of immunoglobulin kappa 3' enhancer (kappa E3') activity is the result of the combined influence of positive- and negative-acting elements.

immunoglobulin kappa 3' enhancer

kappa E3'

positive- and negative-acting elements


Input: We show that a central core in the kappa E3' enhancer is active at the pre-B-cell stage but is repressed by flanking negative-acting elements.

kappa E3' enhancer

flanking negative-acting elements


Input: The negative-acting sequences repress enhancer activity in a position- and orientation-independent manner at the pre-B-cell stage.

negative-acting sequences


Input: We have isolated a human cDNA clone encoding a zinc finger protein (NF-E1) that binds to the negative-acting segment of the kappa E3' enhancer.

human cDNA clone

negative-acting segment

kappa E3' enhancer

zinc finger protein


Input: This protein also binds to the immunoglobulin heavy-chain enhancer mu E1 site.

immunoglobulin heavy-chain enhancer mu E1 site


Input: NF-E1 is encoded by the same gene as the YY-1 protein, which binds to the adeno-associated virus P5 promoter.

YY-1 protein

adeno-associated virus P5 promoter


Input: NF-E1 is also the human homologue of the mouse delta protein, which binds to ribosomal protein gene promoters.

human homologue

mouse delta protein

ribosomal protein gene promoters


Input: The predicted amino acid sequence of this protein contains features characteristic of transcriptional activators as well as transcriptional repressors.

amino acid sequence

transcriptional activators

transcriptional repressors


Input: Cotransfection studies with this cDNA indicate that it can repress basal promoter activity.

cDNA

basal promoter


Input: The apparent dual function of this protein is discussed.


Input: A human putative lymphocyte G0/G1 switch gene containing a CpG-rich island encodes a small basic protein with the potential to be phosphorylated.

human putative lymphocyte G0/G1 switch gene

CpG-rich island

small basic protein


Input: Genes actively involved in the G0/G1 switch (G0S genes) may be differentially expressed during the lectin -induced switch of lymphocytes from the G0 to the G1 phases of the cell cycle.

G0/G1 switch

G0S genes

lectin

lymphocytes


Input: This paper presents studies of G0S2, a member of a set of putative G0S genes, for which cDNAs were cloned and selected on the basis of differential cDNA hybridization.

cDNAs

G0S genes


Input: G0S2 mRNA increases transiently within 1-2 hr of the addition of lectin or cycloheximide to cultured blood mononuclear cells.

G0S2 mRNA

lectin

cultured blood mononuclear cells


Input: Comparison of a nearly full-length cDNA sequence with the corresponding genomic sequence reveals one small intron and an open reading frame in the second exon.

nearly full-length cDNA sequence

genomic sequence

open reading frame

exon


Input: The derived 103-amino-acid basic protein has two potential alpha-helical domains separated by a hydrophobic region with the potential to generate turns and assume a beta-sheet conformation.

103-amino-acid basic protein

alpha-helical domains

hydrophobic region


Input: Consistent with involvement in the G0/G1 switch, the protein contains potential sites for phosphorylation by protein kinase C and casein kinase II.

G0/G1 switch

protein kinase C

casein kinase II


Input: The gene contains a CpG-rich island suggesting expression in the germ line.

CpG-rich island


Input: An upstream segment contains tandem dinucleotide repeats (CT)19/(CA)16.

upstream segment

tandem dinucleotide repeats


Input: There is a suitably located TATA box, but potential sites for CCAAT-box binding factors are far upstream, embedded in a 42-nucleotide repeat element.

TATA box

CCAAT-box

42-nucleotide repeat element

binding factors


Input: Potential sites for transcription factors AP1, AP2, and AP3 are consistent with rapid transcriptional activation in response to inducing agents.

transcription factors


Input: USF-related transcription factor, HIV-TF1, stimulates transcription of human immunodeficiency virus-1.

USF-related transcription factor


Input: The transcription factor HIV-TF1, which binds to a region about 60 bp upstream from the enhancer of the human immunodeficiency virus-1 (HIV-1 ), was purified from human B cells.

transcription factor

60 bp upstream

human B cells


Input: HIV-TF1 had a molecular weight of 39,000.


Input: Binding of HIV-TF1 to the HIV long terminal repeat (LTR) activated transcription from the HIV promoter in vitro.

HIV long terminal repeat

LTR

HIV promoter


Input: The HIV-TF1 -binding site in HIV LTR was similar to the site recognized by upstream stimulatory factor (USF) in the adenovirus major late promoter.

HIV-TF1 -binding site

HIV LTR

adenovirus major late promoter

upstream stimulatory factor

USF


Input: DNA-binding properties of HIV-TF1 suggested that HIV-TF1 might be identical or related to USF.

USF


Input: Interestingly, treatment of purified HIV-TF1 by phosphatase greatly reduced its DNA-binding activity, suggesting that phosphorylation of HIV-TF1 was essential for DNA binding.

phosphatase


Input: The disruption of HIV-TF1 -binding site induced a 60% decrease in the level of transcription from the HIV promoter in vivo.

HIV-TF1 -binding site

HIV promoter


Input: These results suggest that HIV-TF1 is involved in transcriptional regulation of HIV-1.


Input: Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency.

dihydropyrimidine dehydrogenase


Input: A potentially more common pharmacogenetic syndrome.


Input: This study describes the inheritance of a defect in pyrimidine catabolism and its association with drug-induced toxicity in a patient receiving 5-fluorouracil (FUra) as adjuvant chemotherapy for breast carcinoma.


Input: The study population included the affected patient (proband ), nine of her blood relatives, and seven healthy volunteers.


Input: The activity of dihydropyrimidine dehydrogenase (DPD ), the initial enzyme of pyrimidine (and FUra) catabolism, in peripheral blood mononuclear cells was measured in each subject by a specific radiometric assay using FUra as the substrate.

dihydropyrimidine dehydrogenase

DPD

enzyme

peripheral blood mononuclear cells


Input: The proband had no detectable DPD activity.

DPD


Input: When enzyme levels in the proband and relatives were compared with that in controls, an autosomal recessive pattern of inheritance was demonstrated.


Input: This is the third patient with severe FUra toxicity secondary to an alteration in pyrimidine catabolism and the second from our clinic population suggesting that the frequency of this genetic defect may be greater than previously thought.


Input: Monitoring DPD activity may be important in the management of patients experiencing severe toxicity secondary to FUra chemotherapy.

DPD


Input: Transactivation of the human immunodeficiency virus promoter by human herpesvirus 6 (HHV-6) strains GS and Z-29 in primary human T lymphocytes and identification of transactivating HHV-6 (GS) gene fragments.

human immunodeficiency virus promoter

transactivating HHV-6 (GS) gene fragments

primary human T

lymphocytes


Input: Human herpesvirus 6 (HHV-6) can activate the human immunodeficiency virus (HIV) promoter and accelerate cytopathic effects in HIV-infected human T cells.

human immunodeficiency virus (HIV) promoter

HIV-infected human T cells


Input: This study examines the regions of the HIV promoter required for HHV-6 transactivation in a heterogeneous population of primary human T lymphocytes with or without antigenic stimulation.

HIV promoter

primary human T lymphocytes


Input: Two different strains of HHV-6, GS and Z29, transactivated the HIV promoter.

HIV promoter


Input: The GS strain transactivated the promoter in both stimulated and resting T cells, while the Z29 strain increased HIV promoter activity only in stimulated T cells.

promoter

HIV promoter

T cells

stimulated T cells


Input: Three DNA clones containing HHV-6(GS) genomic fragments transactivated the HIV promoter in cotransfected T cells.

HHV-6(GS) genomic fragments

HIV promoter

cotransfected T cells


Input: A 21.4-kb DNA clone, pZVB70, showed the highest transactivating ability, while two other DNA fragments, pZVB10 (6.2 kb) and pZVH14 (8.7 kb), showed lower activity.

21.4-kb DNA clone

DNA fragments


Input: One of these clones, pZVH14, activated the HIV promoter construct containing a mutation in the NF kappa B site.

HIV promoter construct

NF kappa B site


Input: However, this mutated NF kappa B promoter was not transactivated during HHV-6(GS) infection or after cotransfection with pZVB70 or pZVB10.

mutated NF kappa B promoter


Input: These data indicate that the NF kappa B sites of the HIV promoter are essential for its transactivation during HHV-6(GS) infection.

NF kappa B sites

HIV promoter


Input: By increasing HIV promoter activity in primary T lymphocytes, HHV-6 may consequently increase HIV replication, leading to an increase in the cytopathic effect on coinfected human T cells.

HIV promoter

primary T lymphocytes

coinfected human T cells


Input: Inhibition of HIV-1 replication and NF-kappa B activity by cysteine and cysteine derivatives.

NF-kappa B


Input: HIV-1 proviral DNA contains two binding sites for the transcription factor NF-kappa B.

HIV-1 proviral DNA

binding sites

transcription factor

NF-kappa B


Input: HIV-1 -infected individuals have, on average, abnormally high levels of tumour necrosis factor alpha (TNF alpha) and abnormally low plasma cysteine levels.

tumour necrosis factor alpha

TNF alpha


Input: We therefore investigated the effects of cysteine and related thiols on HIV-1 replication and NF-kappa B expression.

NF-kappa B


Input: The experiments in this report show that cysteine or N-acetylcysteine (NAC) raise the intracellular glutathione (GSH) level and inhibit HIV-1 replication in persistently infected Molt-4 and U937 cells.

U937 cells


Input: However, inhibition of HIV-1 replication appears not to be directly correlated with GSH levels.


Input: Cysteine and NAC also inhibit NF-kappa B activity as determined by electrophoretic mobility shift assays and chloramphenicol acetyl-transferase (CAT) gene expression under control of NF-kappa B binding sites in uninfected cells.

NF-kappa B

chloramphenicol acetyl-transferase

CAT

NF-kappa B

binding sites

uninfected cells


Input: This suggests that the cysteine deficiency in HIV-1 -infected individuals may cause an over-expression of NF-kappa B -dependent genes and enhance HIV-1 replication.

NF-kappa B

-dependent genes


Input: NAC may be considered for the treatment of HIV-1 -infected individuals.


Input: A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer.

thymus-specific member

HMG protein family

human T cell receptor C alpha enhancer


Input: The human T cell-specific transcription factor TCF-1 alpha plays a key role in the tissue-specific activation of the T cell receptor (TCR) C alpha enhancer and binds to pyrimidine -rich elements (5'-PyCTTTG-3') present in a variety of other T cell-specific control regions.

human T cell-specific transcription factor

TCF-1 alpha

T cell receptor

TCR

pyrimidine -rich elements

T cell-specific control regions


Input: Using amino acid sequence information derived from the DNA affinity-purified protein, we have now isolated cDNA clones encoding TCF-1 alpha.

amino acid sequence

DNA affinity-purified protein

TCF-1 alpha

cDNA clones


Input: The TCF-1 alpha cDNA contains a single 68-amino-acid domain that is homologous to a region conserved among high-mobility group (HMG) and nonhistone chromosomal proteins.

TCF-1 alpha cDNA

68-amino-acid domain

high-mobility group

HMG

nonhistone chromosomal proteins


Input: Expression of full-length and mutant cDNA clones in bacteria reveal that the single HMG motif, which is predicted to contain two extended alpha-helical segments, is sufficient to direct the sequence-specific binding of TCF-1 alpha to DNA.

full-length

mutant cDNA clones

DNA

single HMG motif

alpha-helical segments

TCF-1 alpha


Input: Northern blot experiments demonstrate further that TCF-1 alpha mRNA is highly tissue specific, found primarily in the thymus or T cell lines.

TCF-1 alpha mRNA


Input: The immature CEM T cell line expresses relatively low levels of TCF-1 alpha mRNA, which are increased upon activation of these cells by phorbol esters.

immature CEM T cell line

TCF-1 alpha

mRNA


Input: Interestingly, the cloned TCF-1 alpha protein is a potent transcriptional activator of the human TCR alpha enhancer in nonlymphoid cell lines, whereas the activity of the endogenous protein in T cell lines is strongly dependent on an additional T cell-specific protein that interacts with the core enhancer.

TCF-1 alpha protein

transcriptional activator

endogenous protein

human TCR alpha enhancer

core enhancer

nonlymphoid cell lines

T cell lines

T cell-specific protein


Input: TCF-1 alpha is currently unique among the newly emerging family of DNA-binding regulatory proteins that share the HMG motif in that it is a highly tissue-specific RNA polymerase II transcription factor.

TCF-1 alpha

DNA-binding regulatory proteins

HMG motif

highly tissue-specific RNA polymerase II

transcription factor


Input: A novel HIV-1 isolate containing alterations affecting the NF-kappa B element.

NF-kappa B

element


Input: Three molecular clones of HIV-1, derived from a single isolate (AL1 ), exhibited distinct replicative and cytopathic properties during propagation in a human T cell line.

human T cell line


Input: The phenotypic differences observed were attributable, in large part, to changes affecting the viral LTR.

viral LTR


Input: Nucleotide sequence and PCR analyses demonstrated the presence of novel duplications or deletions involving the NF-kappa B motif.

Nucleotide sequence

NF-kappa B motif


Input: These changes in the enhancer element were identified in the original AL1 virus stock.

enhancer element


Input: Subcloning of the variant NF-kappa B segments into LTR-driven CAT expression vectors confirmed a correlation between promoter activity and replicative/cytopathic capacity.

variant

segments

LTR-driven CAT expression vectors

NF-kappa B


Input: Multiple Oct2 isoforms are generated by alternative splicing.

Oct2 isoforms


Input: The interaction of the Oct2 transcription factor with the cognate octamer motif ATGCAAAT is a critical determinant of the lymphoid-specific expression of immunoglobulin genes.

Oct2 transcription factor

cognate octamer motif

immunoglobulin genes


Input: Ectopic expression of cloned Oct2 cDNA was shown to be sufficient to reconstitute at least some aspects of this regulation in non-lymphoid cells.

cloned Oct2 cDNA

non-lymphoid cells


Input: We describe the isolation and characterization of multiple cDNAs encoding mouse Oct2 from a mature B-cell line and we show that a variety of isoforms of this transcription factor is generated from a single gene by an alternative splicing mechanism.

multiple cDNAs

mouse Oct2

transcription factor

mature B-cell line


Input: All the isoforms retain the previously characterized POU-domain and are therefore able to bind to the octamer motif.

isoforms

octamer motif


Input: Different amounts of the various isoforms are present within the same B-cell regardless of the developmental stage of B-cell differentiation and at least some of the isoforms are conserved between mouse and humans.

isoforms

isoforms

B-cell

B-cell


Input: In cotransfection experiments we show that all the isoforms are able to activate an octamer containing promoter element in fibroblasts revealing an unexpected functional redundancy.

isoforms

octamer

promoter element


Input: Finally, we show that one of the isoforms encodes the previously described lymphoid-specific Oct2B protein which has been suggested to be involved in the function of the octamer motif in the context of the immunoglobulin heavy-chain (IgH) enhancer.

isoforms

lymphoid-specific Oct2B protein

IgH

octamer motif

immunoglobulin heavy-chain (

) enhancer


Input: [Regulation of intracellular cholesterol synthesis in hypercholesterolemia by glucocorticoids]


Input: The rate of endogenous cholesterol synthesis in blood lymphocytes and skin fibroblasts from patients with type IIa hyperlipidemia was found to be increased in comparison with healthy donors.

blood lymphocytes

skin fibroblasts


Input: The cells of hyperlipidemic patients had lowered levels of glucocorticoid receptors concomitantly with a partial loss of their sensitivity to glucocorticoids.

glucocorticoid receptors


Input: In fibroblasts from patients with hereditary hypercholesteremia of homozygous type the number of glucocorticoid receptors did not exceed 10% of their content in normal cells.

fibroblasts

normal cells

glucocorticoid receptors


Input: The decrease of the number of glucocorticoid receptors in patients with type IIa hyperlipidemia seems to be a compensatory response of cells culminating in activation of endogenous cholesterol synthesis.

glucocorticoid receptors


Input: Negative regulation of human immunodeficiency virus type 1 expression in monocytes: role of the 65-kDa plus 50-kDa NF-kappa B dimer.

NF-kappa B dimer


Input: Although monocytic cells can provide a reservoir for viral production in vivo, their regulation of human immunodeficiency virus type 1 (HIV-1) transcription can be either latent, restricted, or productive.


Input: These differences in gene expression have not been molecularly defined.


Input: In THP-1 cells with restricted HIV expression, there is an absence of DNA-protein binding complex formation with the HIV-1 promoter-enhancer associated with markedly less viral RNA production.

THP-1 cells

DNA-protein binding complex

HIV-1 promoter-enhancer

viral RNA


Input: This absence of binding was localized to the NF-kappa B region of the HIV-1 enhancer; the 65-kDa plus 50-kDa NF-kappa B heterodimer was preferentially lost.

NF-kappa B

65-kDa plus 50-kDa

NF-kappa B heterodimer

region

HIV-1 enhancer


Input: Adding purified NF-kappa B protein to nuclear extracts from cells with restricted expression overcomes this lack of binding.

NF-kappa B protein


Input: In addition, treatment of these nuclear extracts with sodium deoxycholate restored their ability to form the heterodimer, suggesting the presence of an inhibitor of NF-kappa B activity.

heterodimer

NF-kappa B


Input: Furthermore, treatment of nuclear extracts from these cells that had restricted expression with lipopolysaccharide increased viral production and NF-kappa B activity.

NF-kappa B


Input: Antiserum specific for NF-kappa B binding proteins, but not c-rel-specific antiserum, disrupted heterodimer complex formation.

NF-kappa B binding proteins

heterodimer complex


Input: Thus, both NF-kappa B -binding complexes are needed for optimal viral transcription.

NF-kappa B -binding complexes


Input: Binding of the 65-kDa plus 50-kDa heterodimer to the HIV-1 enhancer can be negatively regulated in monocytes, providing one mechanism restricting HIV-1 gene expression.

50-kDa heterodimer

HIV-1 enhancer

HIV-1 gene

monocytes


Input: Glucocorticoid receptors in normal leukocytes: effects of age, gender, season, and plasma cortisol concentrations.

Glucocorticoid receptors

normal leukocytes


Input: We measured glucocorticoid receptors (GR) in mononuclear leukocytes (MNL) isolated from peripheral blood of 145 apparently healthy volunteers (86 men and 59 women ).

glucocorticoid receptors

GR

mononuclear leukocytes

MNL


Input: An age-related decrease in the number of GR was suggested between subjects younger than 20 years and elderly subjects; there was no apparent seasonal variation in GR.

GR

GR


Input: Gender difference in the number of GR was not significant, although women showed slightly fewer GR.

GR

GR


Input: Eight patients with dermatomyositis/polymyositis were examined to determine whether the number of GR in MNL could be down-regulated by their cognate ligands.

GR

MNL


Input: The number of GR in MNL from these patients was significantly decreased one month after the initiation of prednisolone therapy.

GR

MNL


Input: However, in normal subjects, the GR in MNL did not demonstrate circadian variation, in contrast to concentrations of plasma cortisol.

GR

MNL


Input: Synergism between two distinct elements of the HTLV-I enhancer during activation by the trans-activator of HTLV-I.

HTLV-I enhancer

trans-activator


Input: We have conducted functional studies of the enhancer elements of human T-cell leukemia virus type I (HTLV-I) using the human T-cell lines Jurkat and MOLT 4, which are negative for HTLV-I, and MT-2 and TL-Mor, which carry the proviral genome of HTLV-I.

enhancer elements

human T-cell lines

Jurkat

MOLT 4


Input: Two distinct elements have been implicated in function of the HTLV-I enhancer.

HTLV-I enhancer


Input: One is the 21-base-pair (bp) core element that is responsible for trans-activation by the HTLV-I trans-activator p40tax and that has the ability to bind to cyclic-AMP responsive element binding factor (CREB )-like factor (s).

21-base-pair (bp) core element

trans-activator

cyclic-AMP responsive element binding factor (CREB )-like factor


Input: The other is a region interposed between the 21-bp elements.

21-bp elements


Input: In this study we demonstrate that a subfragment (C26) in the region between the 21-bp elements is involved in trans-activation by p40tax, possibly through binding to an NF-kappa B -like nuclear factor or factors.

21-bp elements

NF-kappa B -like nuclear factor


Input: Formation of the protein-DNA complex with the C26 subfragment was positively affected by p40tax.

protein-DNA complex

C26 subfragment


Input: The C26 element conferred partial responsiveness to p40tax when linked to one copy of the 21-bp element that, by itself, showed little activation in response to p40tax.

C26 element

21-bp element


Input: However, the C26 element alone, even when repeated, could not be activated by p40tax, unlike other NF-kappa B -binding elements.

C26 element

NF-kappa B -binding elements


Input: In contrast, the C26 element itself was profoundly activated upon stimulation with 12-O-tetradecanoylphorbol-13-acetate.

C26 element


Input: These findings therefore suggest that the HTLV-I enhancer contains multiple functional elements, including binding sites for at least CREB- and NF-kappa B- like factors, which synergistically cooperate in activation of the HTLV-I enhancer in response to p40tax.

HTLV-I enhancer

multiple functional elements

HTLV-I enhancer


Input: Our results also demonstrate that TPA-dependent activation of the HTLV-I enhancer may be mediated through the C26 element.

HTLV-I enhancer

C26 element


Input: Human tumor necrosis factor alpha gene regulation in phorbol ester stimulated T and B cell lines.

tumor necrosis factor alpha


Input: The minimal region of the human tumor necrosis factor alpha (TNF-alpha) gene promoter necessary for its transcriptional induction by phorbol esters (PMA) in human T and B lymphocyte cell lines has been localized between -52 and +89 nucleotides (nt) relative to the gene's transcriptional start site.

human tumor necrosis factor alpha (

) gene promoter

-52 and +89 nucleotides

transcriptional start site

TNF-alpha

human T and

B lymphocyte cell lines


Input: Comparison of these sequences to those required to mediate virus or lipopolysaccharide (LPS) induction of the gene reveal significant differences, and thus, the sequence requirements for PMA induction are distinct from those that mediate induction by virus or LPS.


Input: Although three sites in the TNF-alpha promoter (kappa 1, kappa 2, and kappa 3) specifically bind the transcription factor NF-kappa B in lymphoid nuclear extracts, TNF-alpha mRNA induction by PMA does not correlate with NF-kappa B binding activities displayed by different T and B cell lines.

TNF-alpha promoter

transcription factor

NF-kappa B

NF-kappa B

TNF-alpha mRNA


Input: Moreover, kappa 1-kappa 3 can each be deleted from the TNF-alpha promoter with little effect on the gene's inducibility by PMA.

kappa 1-kappa 3

promoter

TNF-alpha


Input: Therefore, TNF-alpha mRNA induction by PMA, like its induction by virus and LPS, is not primarily mediated by NF-kappa B, but rather is mediated through other sequences and protein factors.

TNF-alpha mRNA

NF-kappa B

protein factors


Input: Surprisingly, multimers of kappa 1-kappa 3 can confer PMA inducibility on a heterologous promoter in a B (Raji), but not a T (HUT78) cell line.

heterologous promoter

Raji


Input: However they are not functional on a truncated TNF-alpha promoter, indicating that promoter context and cell type specificity influence the PMA inducible function of these NF-kappa B binding sites.

TNF-alpha

NF-kappa B

promoter

binding sites


Input: Differentiation-associated expression of the Epstein-Barr virus BZLF1 transactivator protein in oral hairy leukoplakia.

Epstein-Barr virus BZLF1 transactivator protein


Input: The BZLF1 protein of Epstein-Barr virus (EBV) is a key immediate-early protein which has been shown to disrupt virus latency in EBV -infected B cells.

BZLF1 protein

immediate-early protein

EBV -infected B cells


Input: We have generated a monoclonal antibody, BZ1, to BZLF1 which reacts in immunohistology, immunoblotting, and immunoprecipitation and which recognizes both the active, dimeric form and the inactive, monomeric form of the protein.

monoclonal antibody

active, dimeric form

inactive, monomeric form


Input: Biopsies of oral hairy leukoplakia, an AIDS-associated lesion characterized by high-level EBV replication, were examined by immunohistochemistry using the BZ1 monoclonal antibody.

monoclonal antibody


Input: A differentiation-associated pattern of BZLF1 expression was observed, BZ1 reacting with nuclei of the upper spinous layer of the lesion.


Input: This finding suggests that the BZLF1 promoter may be regulated by the degree of squamous differentiation.

promoter


Input: A comparison of in situ hybridization to EBV DNA and viral capsid antigen staining with BZ1 reactivity suggested that BZLF1 expression precedes rampant virus replication.

EBV DNA

viral capsid antigen


Input: The inability to detect EBV in the lower epithelial layers of oral hairy leukoplakia raises questions concerning the nature of EBV latency and persistence in stratified squamous epithelium.


Input: [Changes in levels of leucocytic estrogen receptor in patients with menopausal type II diabetes and its significance]

leucocytic

estrogen receptor


Input: The number of estrogen receptors (ER) in human peripheral leucocytes in 12 women with menopausal type II diabetes was measured with radio-ligand binding method.

estrogen receptors

ER

human peripheral leucocytes


Input: The results were compared with those of 12 menopausal women without diabetes and 12 normal women of childbearing age.


Input: It was found that the number of ER in the patients was significantly decreased.

ER


Input: Our data indicate that decrease of ER level in leukocytes may be related to the pathogenesis of type II diabetes in menopausal period.

ER

leukocytes


Input: Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder.

glucocorticoid receptor


Input: OBJECTIVE: The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD ).

glucocorticoid receptor


Input: METHOD: They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects.

lymphocyte cytosolic

glucocorticoid receptors


Input: RESULTS: Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels.

glucocorticoid receptor


Input: The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects.

glucocorticoid receptors


Input: No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated.

glucocorticoid receptor


Input: The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety.

morning

glucocorticoid receptors


Input: CONCLUSIONS: These results provide further evidence for a dysregulation of the HPA axis in PTSD.


Input: The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD.

lymphocyte

glucocorticoid receptors


Input: Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder.


Input: The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.


Input: Induction of NF-kappa B during monocyte differentiation is associated with activation of HIV -gene expression.

NF-kappa B


Input: Cells of the monocyte-macrophage lineage are important targets of HIV infection.

monocyte-macrophage lineage


Input: We report here that the phenotypic differentiation of monocyte cell lines induced by phorbol esters or tumour necrosis factor alpha (TNF alpha) is associated with expression of nuclear factor kappa B (NF-kappa B ).

monocyte cell lines

tumour necrosis factor alpha

TNF alpha

nuclear factor kappa B

NF-kappa B


Input: In parallel with such differentiation, HIV transcription, monitored using an HIV long terminal repeat reporter gene construct, is activated in such cells under the influence of enhanced NF-kappa B expression.

HIV long terminal repeat reporter gene construct

NF-kappa B


Input: Also, in a promonocyte cell line chronically infected with HIV, NF-kappa B expression and HIV transcription were enhanced on stimulation with phorbol ester or TNF alpha.

promonocyte cell line

NF-kappa B

TNF alpha


Input: Thus, stimulation of monocyte cell lines by phorbol esters or TNF alpha induces cell differentiation and activates HIV transcription.

monocyte cell lines

TNF alpha


Input: Such a process may have fundamental implications in AIDS pathogenesis in vivo and may be important in disease progression induced by opportunistic infections directly or indirectly involving macrophages.

macrophages


Input: Demonstration of estrogen and progesterone receptors as well as Ki-67 and p-145 antigens in single tumor cells from blood and pleural effusions using a slide assay.

single tumor cells


Input: We describe a slide assay that allows the demonstration of antigens localized in the nucleus from isolated white blood cells as well as from single tumor cells derived from malignant effusions.

antigens

isolated white blood cells

single tumor cells


Input: With the antibodies Ki-67 and anti-p-145 an increased rate of nuclear and nucleolar staining resulted in cells from highly malignant lymphomas.


Input: An almost identical reaction was obtained when tumor cells from malignant effusions were tested.

tumor cells


Input: Cells isolated from the blood of patients with leukemic spread of lymphomas of low malignancy yielded a weak staining comparable to that of normal mesothelial cells from non-tumorous cavity fluids.

normal mesothelial cells


Input: The detection of estrogen and progesterone receptors (ER and PR) localized in the cell nucleus can be achieved by the same assay.

estrogen

progesterone receptors

ER

PR


Input: The reaction is enhanced by incubation of the tumor cells for 30 min at 37 degrees C prior to fixation.

tumor cells


Input: Pleural effusions from 20 patients with breast cancer were tested.


Input: ER was positive in 13 and PR was positive in 12 of the 20 samples.

ER

PR


Input: In 5 cases there was a divergent reaction with ER and PR antibody.

ER

PR


Input: The hormone receptors of the primary tumor were known in 15 (ER) and 14 (PR) patients, respectively.

hormone receptors

ER

PR


Input: In each cohort there was only one case with a negative reaction of the primary tumor and a positive reaction with the isolated tumor cells from the pleural effusions.

tumor cells


Input: These results indicate that the demonstration of hormone receptor proteins in cells from malignant effusions is possible and that there is a correlation with the status of the primary site of cancer.

hormone receptor proteins


Input: Constitutive activation of NF-kB in human thymocytes.

NF-kB

human thymocytes


Input: NF-kB is a eukaryotic transcription regulatory factor.

NF-kB

eukaryotic transcription regulatory factor


Input: In T cells and T cell lines, NF-kB is bound to a cytoplasmic proteic inhibitor, the IkB.

T cells

T cell lines

NF-kB

cytoplasmic proteic inhibitor

IkB


Input: Treatment of T cells with mitogens (phorbol esters) or cytokines (TNF alpha) induces NF-kB nuclear translocation and the subsequent expression of NF-kB dependent T cell genes.

T cells

cytokines

TNF alpha

NF-kB

NF-kB

dependent T cell genes


Input: Here we examined the activation of NF-kB in human T cell thymic progenitors.

NF-kB

human T cell thymic progenitors


Input: We report differences in (Ca2+)i requirement for NF-kB activation in thymocytes as compared to mature T cells.

NF-kB

thymocytes

T cells


Input: Furthermore, our results indicated that thymocytes have a constitutively active form of NF-kB, suggesting that they are activated in vivo.

thymocytes

constitutively active form

NF-kB


Input: TCF-1, a T cell-specific transcription factor of the HMG box family, interacts with sequence motifs in the TCR beta and TCR delta enhancers.

T cell-specific transcription factor

HMG box family

sequence motifs


Input: We have recently identified and cloned TCF-1, a T cell-specific transcription factor with specificity for the AACAAAG motif in the CD3 epsilon enhancer and for the TTCAAAG motif in the TCR alpha enhancer.

T cell-specific transcription factor

CD3 epsilon enhancer

TTCAAAG motif

TCR alpha enhancer


Input: TCF-1 belongs to the family of transcription-regulating proteins which share a region of homology termed the HMG-box.

transcription-regulating proteins

HMG-box


Input: Here, we show by gel retardation analysis that TCF-1 specifically recognizes the T beta 5 element of the TCR beta enhancer and the T delta 7 element of the TCR delta enhancer.

T beta 5 element

TCR beta enhancer

T delta 7 element

TCR delta enhancer


Input: Comparison of the sequences of all elements recognized by TCF-1 defines a consensus motif A/T A/T C A A/G A G.

elements

consensus motif

A/T A/T C A A/G A G


Input: These observations imply that TCF-1 is involved in the control of several T cell-specific genes and might thus play an important role in the establishment and maintenance of the mature T cell phenotype.

T cell-specific genes

mature T cell phenotype


Input: [Regulatory effect of insulin on glucocorticoid receptor in human peripheral leukocytes]

insulin

glucocorticoid receptor

human peripheral leukocytes


Input: The regulatory effect of insulin on the specific binding power of glucocorticoid receptor (GR) of human leukocytes was assessed by the unoccupied receptor sites capable of combining with [3H] labelled dexamethasone measured at 3 and 24 h after incubation with various concentrations of insulin added to the medium.

insulin

glucocorticoid receptor

GR

unoccupied receptor sites

insulin

human leukocytes


Input: After 3 h incubation the specific binding power with [3H] Dex was decreased by 23.3 +/- 10.0, 32.2 +/- 13.2 and 54.3 +/- 9.2% (P greater than 0.05, P greater than 0.05 and P less than 0.01 as compared with the control value of 100 in the absence of insulin) respectively in the presence of 20 mU/L (physiological testing concentration), 200 mU/L (physiological upper limit) and 2,000 mU/L (pharmacological concentration) insulin in the incubation medium.

insulin

insulin


Input: After 24 h incubation the decrease of these values increased respectively to 43.5 +/- 19.0, 56.1 +/- 20.7 and 80.2 +/- 15.5 (P less than 0.05, P less than 0.01 and P less than 0.01 compared with control).


Input: Thus the inhibitory effect of insulin on the GR binding power is both dose- and time-dependent, which strongly suggests that GR is tonically controlled by insulin concentration change under physiological conditions.

insulin

GR

GR

insulin


Input: The effect of toremifene therapy on serum immunoglobulin levels in breast cancer.

serum immunoglobulin


Input: Estrogens and anti-estrogens enhance the number of immunoglobulin (Ig)-secreting cells in pokeweed mitogen (PWM )-stimulated lymphocyte cultures.

immunoglobulin (Ig)-secreting cells

pokeweed mitogen

PWM

)-stimulated lymphocyte cultures


Input: Lymphocytes from patients who have received anti-estrogen therapy show similar enhancement of Ig-secreting cells after PWM stimulation.

Lymphocytes

Ig-secreting cells

PWM


Input: In this study the effect of anti-estrogen (toremifene) therapy on serum immunoglobulin (IgA, IgM, IgG) levels in breast cancer patients was investigated.

serum immunoglobulin

IgA

IgM

IgG


Input: Serum Ig levels were followed up to two years after or during the therapy.


Input: An unexpected finding was that the Ig levels decreased during the follow-up period.


Input: This decrease was seen in patients who responded to the therapy as well as in those who did not.


Input: Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA.

Human erythroid 5-aminolevulinate synthase

promoter

iron-responsive element

mRNA


Input: 5-Aminolevulinate synthase (ALAS) catalyzes the first step of the heme biosynthetic pathway.

5-Aminolevulinate synthase

ALAS

heme


Input: cDNA clones for the human erythroid ALAS isozyme were isolated from a fetal liver library.

cDNA clones

fetal liver library

human erythroid ALAS isozyme


Input: It can be deduced that the erythroid ALAS precursor protein has a molecular weight of 64.6 kd, and is similar in size to the previously isolated human housekeeping ALAS precursor of molecular weight 70.6 kd.

erythroid ALAS precursor protein

human housekeeping ALAS precursor


Input: The mature mitochondrial forms of the erythroid and housekeeping ALAS isozymes are predicted to have molecular weights of 59.5 kd and 64.6 kd, respectively.

housekeeping ALAS isozymes


Input: The two isozymes show little amino acid identity in their N-terminal signal sequences but have considerable sequence identity in the C-terminal two-thirds of their proteins.

isozymes

N-terminal signal sequences

C-terminal two-thirds


Input: An analysis of the immediate promoter of the human erythroid ALAS gene revealed several putative erythroid-specific cis-acting elements including both a GATA-1 and an NF-E2 binding site.

immediate promoter

human erythroid ALAS gene

erythroid-specific cis-acting elements

NF-E2 binding site


Input: An iron-responsive element (IRE) motif has been identified in the 5'-untranslated region of the human erythroid ALAS mRNA, but is not present in the housekeeping ALAS mRNA.

iron-responsive element

(IRE) motif

human erythroid ALAS mRNA

housekeeping ALAS mRNA


Input: Gel retardation experiments established that this IRE motif formed a protein - RNA complex with cytosolic extracts from human K562 cells and this binding was strongly competed with IRE transcripts from ferritin or transferrin receptor mRNAs.

IRE motif

IRE transcripts

protein - RNA complex

human K562 cells


Input: A transcript of the ALAS IRE, mutated in the conserved loop of the IRE, did not readily form this protein - RNA complex.

ALAS IRE

IRE

protein - RNA complex