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)

The transcription factor AP-1 is an important human mediator of the cellular response to serum, growth factors, and phorbol esters such as 12-O-tetradecanoyl-phorbol-13 acetate (TPA). The AP-1 complex consists of distinct protein heterodimers encoded by the proto-oncogene c-fos and c-jun mRNA whose gene expression can be induced by TPA, cyclic AMP and growth factors. Recent findings suggest an involvement of reactive oxygen species in the pathway of TPA and protein kinase C leading to expression of c-fos and c-jun mRNA. To investigate the role of reactive oxygen species we studied the effects of alpha-lipoic acid and dihydrolipoic acid (natural thiol antioxidants) on the expression of c-fos mRNA in human Jurkat T cells. When cells were preincubated with dihydrolipoic acid (0.2 mM) the expression of c-fos mRNA was suppressed at 30 min after stimulation of TPA (0.5 microM) whereas in the case of preincubation of alpha-lipoic acid (0.2 microM), the expression was enhanced at 30 min. These studies support the idea that superoxide anion radical plays a role in the expression of c-fos mRNA.
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PMID:Effects of alpha-lipoic acid and dihydrolipoic acid on expression of proto-oncogene c-fos. 817 94

The human thyrotropin beta (hTSH beta) gene is inducible by various agents including thyrotropin-releasing hormone, phorbol esters, or the adenylyl cyclase activator forskolin. In this study, we have characterized the functional properties of the TGGGTCA motif at -1/+6 of the hTSH beta gene that is similar to the consensus phorbol ester response element (TRE) or the consensus cyclic AMP response element (CRE). We suggest that both protein kinases C and A as well as TRH share a common mediator which recognizes the TGGGTCA element in activating the hTSH beta promoter. Following stimulation by phorbol esters, forskolin, or TRH, the TGGGTCA-specific factor acts together with the pituitary-specific transcription factor Pit-1 (or GHF-1) bound to upstream sequences at -128 to -61 to mediate the induction of the hTSH beta promoter. The induction requires that both factors bind to their own binding sites, but Pit-1 neither increases the binding of the TGGGTCA-specific factor to its target sequences nor associates with this factor to form a heterodimer. The TGGGTCA-specific factor is present in three cell lines tested and is composed of protein(s) immunologically related to c-Jun and c-Fos but not to the CRE-binding protein, CREB. By using the hTSH beta reporter plasmids in which the TGGGTCA element is converted to consensus TRE or CRE motifs, we found that, within the context of the hTSH beta promoter, the TGGGTCA element is a more potent TRE or CRE than the consensus TRE or CRE sequences. Based upon the results of this study, we propose a model in which the TGGGTCA-specific AP-1-like factor functionally cooperates with the tissue-specific factor Pit-1 to activate the hTSH beta gene.
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PMID:An AP-1-like factor and the pituitary-specific factor Pit-1 are both necessary to mediate hormonal induction of human thyrotropin beta gene expression. 822 61

We have identified in mammalian cells a novel cyclic AMP response element (CRE)-binding protein of molecular mass 47 kDa. This protein was not recognized by either the CREB-327/341 or c-Jun antisera, and its tissue distribution did not overlap with those of the CREB and Jun families. For example, hepatoma and placental tissue did not contain the 47-kDa DNA-binding protein, but did contain the CREB isoforms. On the other hand, S49 lymphoma cells contained a high level of the 47-kDa DNA-binding protein but did not contain a 47-kDa Jun-related protein which was found in normal liver and hepatoma. This new 47-kDa factor bound to the CRE in the dephosphorylated form, and phosphorylation of the protein by the catalytic subunit of protein kinase A completely abolished its DNA-binding activity. The isoforms of the CREB-327/341 family, on the other hand, bound to DNA in the phosphorylated form, and alkaline phosphatase treatment reduced significantly their interaction with CRE sequence. This reverse effect of phosphorylation/dephosphorylation on the DNA-binding property of this new 47-kDa protein in particular distinguishes it from other known CREB factors and suggests that the protein might play a unique role in the regulation of cAMP-mediated transcription.
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PMID:Identification of a new cAMP response element-binding factor by southwestern blotting. 836 1

The involvement of serine/threonine protein phosphatases in signaling pathways which modulate the activity of the transcription factor AP-1 was examined. Purified protein phosphatase types 1 (PP1) and 2A (PP2A) were microinjected into cell lines containing stably transfected lacZ marker genes under the control of an enhancer recognized by AP-1. Microinjection of PP2A potentiated serum-stimulated beta-galactosidase expression from the AP-1-regulated promoter. Similarly, transient expression of the PP2A catalytic subunit with c-Jun resulted in a synergistic transactivation of an AP-1-regulated reporter gene. PP2A, but not PP1, potentiated serum-induced c-Jun expression, which has been previously shown to be autoregulated by AP-1 itself. Consistent with these results, PP2A dephosphorylated c-Jun on negative regulatory sites in vitro, suggesting one possible direct mechanism for the effects of PP2A on AP-1 activity. Microinjection of PP2A had no effect on cyclic AMP (cAMP)-induced expression of a reporter gene containing a cAMP-regulated promoter, while PP1 injection abolished cAMP-induced gene expression. Taken together, these results suggest a specific role for PP2A in signal transduction pathways that regulate AP-1 activity and c-Jun expression.
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PMID:Protein phosphatase 2A potentiates activity of promoters containing AP-1-binding elements. 838 5

Among multiple CRE (cyclic AMP response element)-binding proteins, CRE-BP1 (also designated ATF-2) has two unique characteristics: it mediates the adenovirus E1A-induced trans-activation and forms a heterodimer with c-Jun. Two structures, a putative metal finger and a leucine zipper, in CRE-BP1 are responsible for these capacities. As a new member of a CRE-BP1 family that has similar metal finger and leucine zipper structures, we have isolated cDNA clones of CRE-BPa by cross-hybridization with CRE-BP1 cDNA. CRE-BPa protein consists of 508 amino acids and has a molecular weight of 56,840. CRE-BPa protein is highly homologous with CRE-BP1 in four regions: two of them are the regions containing the putative metal finger or the DNA-binding domain consisting of the basic amino acid cluster and the leucine zipper. Like CRE-BP1, CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer. However, using the c-Myb-CRE-BPa fusion protein, it was show that CRE-BPa could not mediate the E1A-induced trans-activation. Expression of CRE-BPa mRNA was found in a limited number of cell lines, and multiple sizes of CRE-BPa mRNA species were detected in some cell lines and tissues. CRE-BPa will be useful to clarify the mechanism of CRE-mediated transcriptional activation by E1A or c-Jun.
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PMID:Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1. 844 Jul 10

We have recently shown that infection of Epstein-Barr virus (EBV) genome-positive B cells by human herpesvirus 6 (HHV-6) results in the expression of the immediate-early EBV Zebra gene, followed by virus replication (L. Flamand, I. Stefanescu, D. V. Ablashi, and J. Menezes, J. Virol. 67:6768-6777, 1993). Here we show that HHV-6 upregulates Zebra gene transcription through a cyclic AMP-responsive element (CRE) located within the Zebra promoter (Zp). Using human B- or T-cell lines transfected with ZpCat reporter gene constructs, we demonstrate that a region designated the ZII domain of Zp is the target of HHV-6 transactivation. Mutation of the consensus AP-1/CRE site within ZII abolished the inducibility of Zp by HHV-6, whereas positioning of the ZII domain upstream of the beta-globin minimal promoter conferred responsiveness following HHV-6 infection. Binding of these factors to ZII was prevented by oligonucleotides containing CRE but not by AP-1 consensus sequences. Antibodies against CRE-binding (CREB) protein but not against c-Fos or c-Jun were able to supershift the DNA-protein complex, identifying the nature of the transcription factor which binds to ZII as a member of the CREB family of proteins. Finally, transfection of CREB protein and protein kinase A expression vectors were found to activate Zp in Jurkat cells, suggesting that phosphorylated form of CREB protein can play a determining role in the EBV reactivation process.
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PMID:Cyclic AMP-responsive element-dependent activation of Epstein-Barr virus zebra promoter by human herpesvirus 6. 862 1

We report that sphingosine and short-chain ceramides activate adenylate cyclase and stimulate intracellular cyclic AMP formation in airway-smooth-muscle (ASM) cells. In each case, there is a conditional requirement for GTP-Gs alpha. Sphingosine utilizes a protein kinase C-dependent pathway to elicit activation of adenylate cyclase, whereas for short-chain ceramides the mechanism remains unidentified. In contrast, sphingosine phosphate inhibits Gs-stimulated cyclic AMP formation via a Gi-dependent mechanism. Therefore, the potential interconversion of sphingosine and sphingosine phosphate is a switch that can elicit reciprocal changes in cyclic AMP levels. This may have a significant impact upon the regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal specific kinase (JNK) by sphingolipids and may help to explain how growth factors that utilize these second messengers evoke pleiotropic responses such as proliferation and cell survival. In this context, short-chain ceramides are poor stimulators of ERKs in ASM cells, and sphingosine is inactive, whereas both sphingolipids are powerful activators of the JNK module. Activated JNK catalyses N-terminal phosphorylation of c-Jun, a kinase cascade that programmes growth arrest. Therefore, in blocking ceramide-stimulated ERK-2 activity, cyclic AMP may allow the ceramide-dependent activation of JNK to programme cells to opt out of the cell cycle. In contrast, sphingosine phosphate activates ERK-2, potentiates growth-factor-stimulated DNA synthesis and fails to activate JNK, indicating that its sequential formation from ceramide and sphingosine may commit cells to DNA synthesis. ERK-2 can be activated by both cyclic AMP-sensitive c-Raf-1 kinase-dependent and cyclic AMP-insensitive c-Raf-1 kinase-independent pathways in ASM cells. In this context, sphingosine phosphate activates ERK-2 exclusively via c-Raf-1 kinase. Sphingosine phosphate-stimulated ERK-2 activity is also abolished by pertussis toxin, indicating that c-Raf-1 kinase is activated via a Gi-dependent mechanism.
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PMID:The differential regulation of cyclic AMP by sphingomyelin-derived lipids and the modulation of sphingolipid-stimulated extracellular signal regulated kinase-2 in airway smooth muscle. 864 77

Thrombin is a potent modulator of vascular tone and vascular smooth muscle cell (VSMC) mitogenesis. Early studies from other laboratories demonstrated that cyclic AMP (cAMP) antagonizes the mitogenic effects of platelet-derived growth factor and epidermal growth factor by inhibiting the extracellular signal-regulated protein kinases (ERKs; p42, p44) group of mitogen-activated protein kinases (MAPKs) in several cell types. This report examines the role of ERKs and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases in thrombin-induced DNA synthesis in VSMCs using agents such as forskolin and dibutyrylcyclic AMP that increase intracellular cAMP levels. Both agents significantly inhibited thrombin-stimulated DNA synthesis in VSMCs. These agents, however, had no effect on thrombin induction of ERKs activation and c-Fos expression, suggesting divergence of the latter two events from the growth-signaling events of thrombin that are sensitive to inhibition by cAMP. Thrombin activated JNK1 and induced c-Jun expression in VSMCs in a time-dependent manner. In contrast to ERKs and c-Fos, thrombin-induced JNK1 activation and c-Jun expression were sensitive to inhibition by forskolin, suggesting an association of these events with thrombin-stimulated growth in these cells. Thrombin also increased AP-1 activity, and this response was significantly blunted by forskolin. Together, these results demonstrate a correlation between JNK1 activation and c-Jun expression by thrombin and their association with the mitogenic signaling events of thrombin in VSMCs.
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PMID:Cyclic AMP inhibition of thrombin-induced growth in vascular smooth muscle cells correlates with decreased JNK1 activity and c-Jun expression. 870 35

Marek's disease virus is a highly oncogenic herpesvirus that can cause T lymphomas and peripheral nerve demyelination in chickens. meq, a candidate oncogene of Marek's disease virus, encodes a basic leucine zipper (bZIP) transcription factor which contains a large proline-rich domain in its C terminus. On the basis of its bZIP structural homology, meq is perhaps the only member of the jun-fos gene family completely viral in origin. We previously showed that Meq's C-terminal domain has potent transactivation activity and that its bZIP domain can dimerize with itself and with c-Jun also. In an effort to identify viral and cellular targets of Meq, we have determined the optimal binding sites for Meq-Jun heterodimers and Meq-Meq homodimers. By a PCR-based approach using cyclic amplification of selected targets, Meq-Jun heterodimers were found to optimally bind tetradecanoylphorbol acetate response element (TRE) and cyclic AMP response element (CRE) consensus sequences. This result was consistent with the results of our previous functional analysis implicating Meq-Jun heterodimers in the transactivation of the Meq promoter through a TRE- or CRE-like sequence. Interestingly, Meq-Meq homodimers were found to bind two distinct motif elements. The first [GAGTGATG AC(G)TCATC] has a consensus which includes a TRE or CRE core flanked by additional nucleotides critical for tight binding. Methylation interference and mutational analyses confirmed the importance of the flanking residues. The sequences of a subset of TRE and CRE sites selected by Meq-Meq are closely related to the binding motif of Maf, another bZIP oncoprotein. The second putative Meq binding site (RACACACAY) bears a completely different consensus not shared by other bZIP proteins. Binding to this consensus sequence also requires secondary structure characteristics associated with DNA bending. CACA motifs are known to promote DNA curvature and function in a number of special biological processes. Our results lend further weight to the increasing importance of DNA bending in transcriptional regulation and provide a baseline for the identification of Meq-responsive targets.
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PMID:Novel DNA binding specificities of a putative herpesvirus bZIP oncoprotein. 879 63

We compared the ability of cellular and viral Jun (c-Jun and v-Jun) to transactivate target genes. c-Jun and v-Jun bind specifically to 12-O-tetradecanoylphorbol-13-acetate responsive elements [TREs, also called activator protein 1 (AP-1) motifs]. However, whereas c-Jun activates TRE-controlled promoters, v-Jun represses them. Cotransfection of the two Jun proteins reduces c-Jun-dependent transactivation. The expression of the endogenous c-jun gene, regulated through a promoter-proximal AP-1-binding site, is repressed in v-Jun-transformed chicken embryo fibroblasts. It is suggested that an M(r) 18,000 v-Jun peptide prominent in v-Jun-transformed cells acts as a transdominant-negative regulator of AP-1 activity and of c-jun expression. In contrast to the results with TRE sites, both v-Jun and c-Jun activate transcription through the human T-cell leukemia virus type I 21-bp repeat which contains a sequence homologous to the cyclic AMP responsive element. However, full-length Jun proteins bind to this site only with low affinity, and binding of the truncated v-Jun was barely detectable. These observations show that the oncogenic viral form of Jun differs from the cellular version in promoter preference and on certain promoters acts as an antagonist to c-Jun.
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PMID:Differential and antagonistic effects of v-Jun and c-Jun. 879 97


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