Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation of terminally differentiated plasma cells represents the critical final step in B-cell differentiation. In this study, utilizing oligonucleotide microarray analysis, we describe the highly specialized genetic profile exhibited by terminally differentiated plasma cells. A total of 1476 known genes were differentially expressed by plasma cells compared with B cells. Plasma cells displayed an up-regulation, induction, or a selective retention of a unique constellation of transcription factors, including members of the AP-1, nuclear factor-kappaB (NF-kappaB), nuclear factor of activated T cells (NFAT), and octamer binding factor families. Interestingly, plasma cells also displayed a down-regulation of several RNA polymerase I- related factors, consistent with terminal differentiation, and exhibited a down-regulation of the TATA box binding protein. Furthermore, plasma cells displayed alterations in multiple components of the Wnt and Notch signaling pathways and showed a unique pattern of apoptosis and proliferation-associated genes. Unexpectedly, plasma cells displayed an up-regulation of 2 factors normally associated with microenvironmental positioning of neuronal cells, reelin and neuropilin-1. These results supply insight into the developmental genetics of plasma cell differentiation and provide a foundation for further analysis of plasma cell biology.
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PMID:Gene expression profiling reveals a highly specialized genetic program of plasma cells. 1254 63

1,25(OH)2D regulates a number of cellular events which contribute to its ability to stimulate differentiation of the keratinocyte. 1,25(OH)2D raises the intracellular calcium (Cai) level in part by increasing the expression of the calcium receptor (CaR). This sensitizes the cell to extracellular calcium, triggering the signaling pathway coupled to the CaR, which results in a rise in Cai. 1,25(OH)2D induces the family of phospholipases C (PLC). These enzymes mediate the hydrolysis of phosphatidyl inositol bisphosphate (PIP2) to form inositol tris phosphate (IP3) and diacylglycerol (DG), which stimulate calcium release from intracellular stores and activate protein kinases C (PKC), respectively. The CaR and other G protein coupled receptors signal through PLC-beta, whereas tyrosine kinase growth factor receptors such as the EGF receptor signal through PLC-gamma. Calcium and PKC regulate the expression of genes in part by controlling the levels and activity of AP-1 transcription factors. 1,25(OH)2D also directly induces structural genes such as involucrin, a substrate for transglutaminase, which crosslinks it to other substrates to form the cornified envelope. 1,25(OH)2D regulates gene expression by activating the vitamin D receptor (VDR), a transcription factor, which, in combination with the retinoid X receptor (RXR) or retinoid A receptor (RAR), binds to its vitamin D response elements (VDRE) in the promoters of genes whose expression it regulates. The VDR also binds to one of two coactivator complexes, Mediator/DRIP (VDR interacting proteins) or p160/SRC (steroid hormone receptor complex), complexes which link the VDR to the RNA polymerase complex. We have recently discovered that the binding of VDR to these complexes is sequential. Binding to Mediator/DRIP occurs in the undifferentiated keratinocyte, but as the cell differentiates, DRIP(205) (the key protein of the DRIP complex binding to the VDR) levels fall, and p160/SRC binding takes over. We hypothesize that this sequential replacement of Mediator/DRIP by p160/SRC is critical for differentiation. Squamous cell carcinomas (SCC) fail to respond to the prodifferentiating actions of 1,25(OH)2D. These cells have normal levels of VDR and normal binding of VDR to VDREs. However, they fail to down-regulate DRIP(205) such that the p160/SRC complex fails to bind to VDR. This lack of sequential binding of these coactivator complexes to the VDR, we believe, maintains the cell in a state of continued proliferation and blocks the ability of 1,25(OH)2D to induce the expression of genes required for the differentiation process.
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PMID:Squamous cell carcinomas fail to respond to the prodifferentiating actions of 1,25(OH)2D: why? 1289 16

Human N -acetyltransferase Type I (NAT1) catalyses the acetylation of many aromatic amine and hydrazine compounds and it has been implicated in the catabolism of folic acid. The enzyme is widely expressed in the body, although there are considerable differences in the level of activity between tissues. A search of the mRNA databases revealed the presence of several NAT1 transcripts in human tissue that appear to be derived from different promoters. Because little is known about NAT1 gene regulation, the present study was undertaken to characterize one of the putative promoter sequences of the NAT1 gene located just upstream of the coding region. We show with reverse-transcriptase PCR that mRNA transcribed from this promoter (Promoter I) is present in a variety of human cell-lines, but not in quiescent peripheral blood mononuclear cells. Using deletion mutant constructs, we identified a 20 bp sequence located 245 bases upstream of the translation start site which was sufficient for basal NAT1 expression. It comprised an AP-1 (activator protein 1)-binding site, flanked on either side by a TCATT motif. Mutational analysis showed that the AP-1 site and the 3' TCATT sequence were necessary for gene expression, whereas the 5' TCATT appeared to attenuate promoter activity. Electromobility shift assays revealed two specific bands made up by complexes of c-Fos/Fra, c-Jun, YY-1 (Yin and Yang 1) and possibly Oct-1. PMA treatment enhanced expression from the NAT1 promoter via the AP-1-binding site. Furthermore, in peripheral blood mononuclear cells, PMA increased endogenous NAT1 activity and induced mRNA expression from Promoter I, suggesting that it is functional in vivo.
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PMID:Identification of a minimal promoter sequence for the human N-acetyltransferase Type I gene that binds AP-1 (activator protein 1) and YY-1 (Yin and Yang 1). 1294 72

There are several unorthodox features, which distinguish the non-redundant and unique novel matrix metalloproteinase-26 (MMP-26) (an enzyme that has recently evolved and does not exist in rodents but is present in humans) from other members of the MMP superfamily. This report describes our recent efforts to gain a better understanding of the mechanisms which restrict expression of MMP-26 to certain cell/tissue types. We examined transcriptional regulation of the human MMP-26 gene in normal and malignant cells. The AP-1 and Tcf-4 sites of the MMP-26 promoter appear most potent in regulating the expression of the MMP-26-luciferase chimera in HEK293 embryonic kidney and MCF7 breast carcinoma cells. Key regulators of the Wnt pathway (beta-catenin and lymphoid enhancer-binding factor/T-cell factor with which beta-catenin associates) enhanced the transcriptional activity of MMP-26 suggesting that the MMP-26 gene is a likely target of the Wnt pathway. Immunostaining, gene arrays and reverse-transcriptase polymerase chain reaction (RT-PCR) confirm the presence of MMP-26 in normal cells, including the apical epithelial conjunctiva cells of the human eye, as well as in malignant cells of epithelial origin. MMP-26 predominantly accumulates in its proenzyme form in the intracellular milieu of the transfected breast carcinoma MCF7 cells. This study brings us a step forward towards a better understanding of the unconventional role, regulation and functions of epithelial cell MMP-26 in physiological conditions and in neoplasms.
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PMID:Beta-catenin regulates the gene of MMP-26, a novel metalloproteinase expressed both in carcinomas and normal epithelial cells. 1500 46

Transcriptional initiation of eukaryotic genes depends on the cooperative interaction of various transcription factors. Using the yeast two-hybrid assay, we have identified the murine Rcd-1 protein as a cofactor of the c-myb proto-oncogene product. Rcd-1 is evolutionarily conserved among many species, and moreover the yeast homologue CAF40 is part of the carbon catabolite repressor protein transcriptional mediator thought to be involved in the negative regulation of genes transcribed by RNA polymerase II. Rcd-1 is located mainly in the nucleus, and it interacts with c-Myb both in vitro and in vivo. The activation of the myeloid c-myb-specific mim-1 promoter is repressed by Rcd-1. Interestingly, rcd-1 is an erythropoietin regulated gene, which also represses the action of the AP-1 transcription factor on its target genes.
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PMID:c-Myb protein interacts with Rcd-1, a component of the CCR4 transcription mediator complex. 1520 11

Binding sites for the dimeric transcription factor activator protein (AP)-1 are found in numerous immunoregulatory and inflammatory genes. The precise mechanisms by which AP-1 activates or represses immune response genes and in particular the roles of individual AP-1 subunits in inflammatory responses are largely unknown. We report here that c-Fos and Fos-related antigen-1 (Fra-1), two inducible components of AP-1, are recruited to the endogenous interleukin (IL)-8 promoter in an IL-1-dependent manner. c-Fos activates IL-8 transcription and synergizes in this effect with p65 NF-kappaB. In contrast, Fra-1 strongly inhibits inducible IL-8 transcription. Fra-1 activation involves its stabilization, ubiquitination, and interaction with histone deacetylase-1. Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA synthesis simultaneously. This disturbs the inducible recruitment of TATA box-binding protein and RNA polymerase II to the IL-8 promoter. Additional experiments reveal that, in conjunction with p65 NF-kappaB, the MEK1-ERK-dependent synthesis of c-Fos and Fra-1 serves to adjust the overall expression level of IL-8 in response to two of its physiological inducers, IL-1 and epidermal growth factor. Relative to c-Fos, the delayed recruitment of Fra-1 to the IL-8 promoter provides an example how AP-1 subunits may dampen excessive chemokine synthesis.
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PMID:MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. 1561 16

Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.
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PMID:Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2. 3190 Mar 76

Abnormal expression of TGF-beta1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-kappaB and AP-1, in activation of the TGF-beta1 gene and histone acetylation at the TGF-beta1 promoter. IL-1beta-induced TGF-beta1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of kappaB kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-kappaB and AP-1 pathways. We demonstrated that IL-1beta activated the p65 subunit of NF-kappaB and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-Jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-beta1 promoter. The specific NF-kappaB and AP-1 binding sites in the TGF-beta1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-beta1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1beta-induced TGF-beta1 mRNA expression. Our results suggest that IL-1beta-stimulated transcription of TGF-beta1 is temporally regulated by NF-kappaB and AP-1 and involves histone hyperacetylation at distinct promoter sites.
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PMID:NF-kappaB and activator protein 1 response elements and the role of histone modifications in IL-1beta-induced TGF-beta1 gene transcription. 1636 56

During Ag stimulation of T cells, the recognition of B7 molecules by the CD28 costimulatory receptor increases the level of c-Fos, a component of the AP-1 transactivator known to bind the 5' Il2 gene enhancer. In this study, we show that the costimulation of Fos transcription by CD28 is associated with increased binding of p300/CREB-binding protein (CBP) molecules at the Fos promoter, and is blocked by an adenoviral E1A molecular antagonist of p300/CBP. Furthermore, transcriptional activation by a C-terminal domain of CBP is strengthened when CD28 molecules are actively signaling. This increased amount and activity of p300/CBP molecules at the Fos gene correlated with higher histone H4 acetylation and RNA polymerase II association with the promoter. These data suggest a global mechanism whereby CD28 signaling influences the rate and intensity of new gene expression during Ag recognition via direct control over the coactivator function of p300/CBP.
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PMID:p300/Cyclic AMP-responsive element binding-binding protein mediates transcriptional coactivation by the CD28 T cell costimulatory receptor. 1678 36

The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site-specific manner as illustrated by in vitro reconstituted chromatin transcription experiments. Knockdown of Brd4 in human cells alleviates E2-mediated repression of HPV transcription. The E2-interacting domain at the extreme C terminus and the chromatin targeting activity of a bromodomain-containing region are both essential for the corepressor activity of Brd4. Interestingly, E2-Brd4 blocks the recruitment of TFIID and RNA polymerase II to the HPV E6 promoter region without inhibiting acetylation of nucleosomal histones H3 and H4, indicating an acetylation-dependent role of Brd4 in the recruitment of E2 for transcriptional silencing of HPV gene activity. Our finding that Brd4 is a component of the virus-assembled transcriptional silencing complex uncovers a novel function of Brd4 as a cellular cofactor modulating viral gene expression.
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PMID:Brd4 links chromatin targeting to HPV transcriptional silencing. 1692 Oct 27


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