Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p300 and cAMP response element binding protein (CREB)-binding protein (CBP) are two highly homologous, conserved transcriptional coactivators, and histone acetyltransferases (HATs) that link chromatin remodeling with transcription. Cell transformation by viral oncogene products such as adenovirus E1A and SV40 large T antigen depends on their ability to inactivate p300 and CBP. To investigate the role of p300 in cell-cycle progression, we constructed stable rat cell lines, which conditionally overexpress p300 from a tetracycline-responsive promoter. When p300 was induced in these cells, serum-stimulated S-phase entry was significantly inhibited. The inhibition of S-phase induction was associated with down-regulation of c-Myc, but not of c-Fos or c-Jun. Simultaneous overexpression of c-Myc and p300 before serum stimulation reversed the inhibition of S-phase induction to a significant level, indicating that the inhibition of c-Myc to a large extent is responsible for the p300 inhibition of G1 exit. Similar studies with stable rat cell lines that overexpress a mutant p300, which lacks the HAT activity, showed that the intrinsic HAT activity of p300 is not required for the negative regulation of c-Myc or G1. These findings, and our previously published results (Kolli, S., Buchmann, A. M., Williams, J., Weitzman, S. & Thimmapaya, B. (2001) Proc. Natl. Acad. Sci. USA 98, 4646-4651), establish an important negative regulatory role for p300 in c-Myc expression that may be important in maintaining the cells in the G0/G1 phase of the cell cycle.
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PMID:Repression of c-Myc and inhibition of G1 exit in cells conditionally overexpressing p300 that is not dependent on its histone acetyltransferase activity. 1288 11

Although it is recognized that estrogen is one of the most important regulators of GnRH receptor (GnRHR) gene expression, the mechanism underlying the regulation at the transcriptional level is unknown. In the present study, we demonstrated that 17beta-estradiol (E2) repressed human GnRHR promoter via an activator protein 1-like motif and estrogen receptor-alpha, of which the DNA-binding domain and the ligand-binding domain were indispensable for the repression. Interestingly, the same cis-acting motif was also found to be important for both the basal activity and phorbol 12-myristate 13-acetate responsiveness of the GnRHR promoter. EMSAs indicated that multiple transcription factors including c-Jun and c-Fos bound to the activator protein 1-like site and that their DNA binding activity was not significantly affected by E2 treatment. In addition, we demonstrated that the E2 repression could be antagonized by phorbol 12-myristate 13-acetate, which stimulated c-Jun phosphorylation on serine 63, a process that is a prerequisite for recruitment of the transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP). Concomitantly, we found that overexpression of CBP could reverse the suppression in a dose-dependent manner. Taken together, our data indicate that E2-activated estrogen receptor-alpha represses human GnRHR gene transcription via an indirect mechanism involving CBP and possibly other transcriptional regulators.
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PMID:An activator protein 1-like motif mediates 17beta-estradiol repression of gonadotropin-releasing hormone receptor promoter via an estrogen receptor alpha-dependent mechanism in ovarian and breast cancer cells. 1294 46

Overexpression of keratin 16 has been observed in keratinocytes in those skin diseases characterized by hyperproliferation such as psoriasis. Therefore, keratin 16 is usually referred to as a disease-associated keratin. In the present study, we found that epidermal growth factor (EGF) increased the expression of keratin 16 mRNA and protein synthesis in a time-dependent manner in HaCaT cells. Reporter assays revealed that the EGF response region was in the range of -162 to -114 bp. Disruption of the Sp1 site (-127 to -122 bp) and the AP1 site (-148 to -142 bp) of the keratin 16 promoter by site-directed mutagenesis significantly inhibited keratin 16 promoter activity induced by EGF. Furthermore, keratin 16 gene expression induced by Ras activation was also regulated in the same manner as the EGF response. By using the DNA affinity precipitation assay in HaCaT and SL2 cells, Sp1 directly interacted with the Sp1 site of the promoter, and c-Jun and c-Fos precipitated with the Sp1 oligonucleotide was attributable to the interaction between the Sp1 and AP1 proteins. Moreover, cotransfection assays revealed that Sp1 acted synergistically with c-Jun to activate keratin 16. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter, and EGF-induced promoter activation was blocked by the viral oncoprotein E1A. Taken together, these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression.
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PMID:Induction of disease-associated keratin 16 gene expression by epidermal growth factor is regulated through cooperation of transcription factors Sp1 and c-Jun. 1295 31

Flavonoids are natural polyphenolic compounds that have anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we investigated the effects of several flavonoids on nuclear factor-kappa B (NF-kappa B) activation by using luciferase reporter gene assay. Among the flavonoids examined, luteolin showed the most potent inhibition on lipopolysaccharide (LPS)-stimulated NF-kappa B transcriptional activity in Rat-1 fibroblasts. Luteolin did not inhibit either I kappa B alpha degradation or NF-kappa B nuclear translocation, DNA binding or phosphorylation by LPS. However, luteolin prevented LPS-stimulated interaction between the p65 subunit of NF-kappa B and the transcriptional coactivator CBP. In addition, a specific PKA inhibitor that blocked the phosphorylation of CREB and c-Jun by luteolin partially reversed the inhibitory effect of luteolin on NF-kappa B.CBP complex formation and NF-kappa B transcriptional activity by LPS. These data imply that inhibition of NF-kappa B transcriptional activity by luteolin may occur through competition with transcription factors for coactivator that is available in limited amounts. Taken together, this study provides a molecular basis for the understanding of the anti-inflammatory effects of luteolin.
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PMID:Luteolin inhibits the nuclear factor-kappa B transcriptional activity in Rat-1 fibroblasts. 1296 82

The Maf transcription factors are involved in a variety of developmental and cellular differentiation processes, but their role in the differentiation of mesenchymal cells has not been described. Here, we have analyzed c-maf expression during the differentiation of adipocytes and muscle cells in cultured systems. The expression of c-maf mRNA was down-regulated during adipogenesis and up-regulated during myogenesis. In adipogenesis, the c-maf mRNA was down-regulated 58h after switching to the differentiation medium and just after PPARgamma2 mRNA was induced. A transient transfection analysis of a reporter gene containing the 5(')-flanking region of the c-maf gene showed that PPARgamma2 represses c-maf gene expression. We previously found that c-Maf, c-Jun, and Pax6 bind to and stimulate the c-maf gene. The PPARgamma2 repression of c-maf expression seems to be due, at least in part, to inhibition of the transactivation functions of c-Maf, c-Jun, and Pax6. The repression of c-maf was partly reversed by CBP, suggesting that these transcription factors compete for CBP or related transcription co-factors. In myogenesis, there was a differentiation-dependent stimulation of c-maf mRNA expression. The increased expression correlated with myoD expression. A transient transfection analysis showed that myoD stimulated a c-maf reporter gene through binding to two typical E-box elements located between 160 and 180 nucleotides upstream of the cap site. Binding of MyoD to the E-boxes was confirmed by a gel mobility shift assay and DNaseI footprinting analysis. Combined, these results suggest that the c-maf gene plays an important role during the differentiation of adipocyte and muscle cells from mesenchymal fibroblast cells.
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PMID:Regulation and differential expression of the c-maf gene in differentiating cultured cells. 1452 12

The HTLV-1 transcriptional activator Tax is required for viral replication and pathogenesis. In concert with human CREB, Tax recruits the human transcriptional coactivator and histone acetyltransferase p300/CBP to the HTLV-1 promoter. Here we investigate the structural features of the interaction between Tax and the KIX domain of p300/CBP. Circular dichroism spectroscopy, nuclear magnetic resonance chemical shift perturbation mapping, and sedimentation equilibrium analysis show that KIX binds a Tax subdomain corresponding to residues 59-98 of Tax (called Tax(59-98)). Circular dichroism spectroscopy suggests that Tax(59-98) is intrinsically disordered (natively unfolded) in isolation and adopts an ordered conformation upon binding KIX. The interaction is disrupted by a single amino acid variation of Tax(59-98) in which leucine 68 is substituted with proline. Chemical shift perturbation mapping reveals that the Tax-binding surface of KIX is distinct from that utilized by CREB, and corresponds to the site of KIX that interacts with the human transcription factors c-Jun and mixed lineage leukemia protein (MLL). Sedimentation equilibrium analysis shows that Tax and the phosphorylated KID domain of CREB can simultaneously bind KIX to form a ternary 1:1:1 complex. The results provide a molecular description of the concerted recruitment of p300/CBP via the KIX domain by Tax and phosphorylated CREB during Tax-mediated gene expression.
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PMID:KIX-mediated assembly of the CBP-CREB-HTLV-1 tax coactivator-activator complex. 1458 Jan 93

In response to lipopolysaccharide (LPS) exposure, macrophages activate the transcription of a large number of pro-inflammatory genes by way of signaling pathways downstream of the LPS receptor, Toll-Like Receptor 4. Many of these genes are expressed sequentially in time, with early synthesis events resulting in the secretion of soluble factors that drive the transcription of genes expressed later in the activation cycle. In this study we show that human blood-derived macrophages pretreated with oxidized low density lipoprotein (OxLDL) fail to transcribe and secrete interferon beta (IFNbeta) immediately following LPS stimulation. As such, the normal downstream activation of Stat1 is blocked, and numerous IFNbeta/Stat1-activated genes, including the chemokines IP10 and ITAC, are weakly expressed or not expressed at all in these cells. Inspection of the LPS-induced activation state of several transcription factors known to play a prominent role in IFNbeta transcription reveals that, although NFkappaB, c-Jun, and ATF-2 activation appears normal, the LPS-induced activation of IFNbeta regulatory factor 3 (IRF3), as measured by DNA-binding activity and association with the coactivator CBP, is inhibited in the OxLDL pre-treated cells. These IRF3 activities have been shown to be essential for the initiation of transcription of the IFNbeta gene, and the loss of these activities presumably accounts for the lack of LPS-induced IFN beta transcription seen in the OxLDL pre-treated cells.
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PMID:Oxidized low density lipoprotein blocks lipopolysaccharide-induced interferon beta synthesis in human macrophages by interfering with IRF3 activation. 1510 17

The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that integrates randomly into the T-cell genome. Two long terminal repeats (LTRs) flank the integrated provirus. The upstream and downstream LTRs carry identical promoter sequences. Studies with other retroviruses suggest that the downstream promoter is silent and that RNA polymerases initiating at the upstream promoter proceed through the 3' LTR. In this study, we used the chromatin immunoprecipitation assay to compare the binding of transcription regulatory proteins at both the upstream and downstream promoters in HTLV-1-infected cell lines and adult T-cell leukemia-lymphoma cells. Unexpectedly, we detected a nearly equal distribution of activator (Tax, CREB, ATF-1, ATF-2, c-Fos, and c-Jun) and regulatory protein (CBP, p300, TAF(II)250, and polymerase II) binding at both the upstream and downstream promoters. Consistent with this observation, we found that the downstream promoter was transcriptionally active, suggesting that the two promoters are functionally equivalent. We also detected asymmetrical binding of histone deacetylases (HDAC-1, -2, and -3) at both promoters. All three HDACs strongly repressed Tax transactivation, and this repression correlated with displacement of Tax from the HTLV-1 promoter. These effects were reciprocal, as Tax expression reversed HDAC repression and displaced HDACs from the HTLV-1 promoter. These data suggest that HTLV-1 transcriptional regulation at both the 5' and 3' LTRs is mediated, in part, through the mutually exclusive binding of Tax and HDACs at the proviral promoters.
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PMID:Transcription regulatory complexes bind the human T-cell leukemia virus 5' and 3' long terminal repeats to control gene expression. 1522 16

We report a new strategy for the parallel identification of O-GlcNAc-glycosylated proteins from cell lysates. The approach permits specific proteins of interest to be rapidly interrogated for the modification in any tissue or cell type and can be extended to peptides to facilitate the mapping of glycosylation sites. As an illustration of the approach, we identified four new O-GlcNAc-glycosylated proteins of low cellular abundance (c-Fos, c-Jun, ATF-1, and CBP) and two short regions of glycosylation in the enzyme O-GlcNAc transferase (OGT). The ability to target specific proteins across various tissue or cell types complements emerging proteomic technologies and should advance our understanding of this important posttranslational modification.
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PMID:Parallel identification of O-GlcNAc-modified proteins from cell lysates. 1532 82

The interferon-beta promoter has been studied extensively as a model system for combinatorial transcriptional regulation. In virus-infected cells the transcription factors ATF-2, c-Jun, interferon regulatory factor (IRF)-3, IRF-7 and NF-kappaB, and the coactivators p300/CBP play critical roles in the activation of this and other promoters. It remains unclear, however, why most other combinations of AP-1, IRF and Rel proteins fail to activate the interferon-beta gene. Here we have explored how different IRFs may cooperate with other factors to activate transcription. First we showed in undifferentiated embryonic carcinoma cells that ectopic expression of either IRF-3 or IRF-7, but not IRF-1, was sufficient to allow virus-dependent activation of the interferon-beta promoter. Moreover, the activity of IRF-3 and IRF-7 was strongly affected by promoter context, with IRF-7 preferentially being recruited to the natural interferon-beta promoter. We fully reconstituted activation of this promoter in insect cells. Maximal synergy required IRF-3 and IRF-7 but not IRF-1, and was strongly dependent on the presence of p300/CBP, even when these coactivators only modestly affected the activity of each factor by itself. These results suggest that specificity in activation of the interferon-beta gene depends on a unique promoter context and on the role played by coactivators as architectural factors.
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PMID:Mechanism for transcriptional synergy between interferon regulatory factor (IRF)-3 and IRF-7 in activation of the interferon-beta gene promoter. 1535 47


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