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)

Dimerization plays a pivotal role in modulating the activity of the c-Jun proto-oncogene product. Heterodimerization with activating transcription factor-2 (ATF-2) alters the DNA-binding specificity of c-Jun, allowing its targeting to several cAMP responsive element (CRE)-related sequences, which control a subset of AP-1-responsive genes. Here we show that a c-Jun/ATF-2 heterodimer binds to the AP-1 site (uPA 5'-TRE) essential for the activity of the human urokinase enhancer, conferring on this element several distinctive regulatory properties. The c-Jun/ATF-2 heterodimer was identified by binding competition assays, u.v. cross linking, and monospecific antibodies. In vitro binding studies revealed that the uPA 5'-TRE sequence is recognized by the cyclic AMP-unresponsive ATF-2 factor, but not by the cyclic AMP-inducible CREB. In addition, in vivo studies suggest that ATF-2 can mediate, at the same time, the activation of the c-Jun/ATF-2 site and the repression of the canonical collagenase AP-1 site. We report that heterodimerization with c-Fos does not increase the binding of c-Jun to the uPA 5'-TRE, in contrast to the increased binding at a consensus AP-1 site. Our data further suggest that c-Fos can act as a repressor of the c-Jun/ATF-2 binding site, revealing an important functional difference, with respect to canonical AP-1 elements.
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PMID:Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. 762 51

Interferon-gamma (IFN-gamma) is an immunoregulatory cytokine expressed in large granular lymphocytes and T cells. However, the molecular mechanisms underlying IFN-gamma gene transcription have not been fully defined. Here, we analyze the mechanisms responsible for the inhibition of IFN-gamma promoter activity by the glucocorticoid hormone dexamethasone. Cotransfection assays performed in Jurkat T cells demonstrated that the activity of the initial 108 base pairs of the IFN-gamma promoter was down-regulated in the presence of dexamethasone. Furthermore, utilizing electrophoretic mobility shift analysis, we identified activator protein 1 AP-1-cAMP response element binding protein-activating transcription factor (CREB-ATF) binding elements situated in positions of the IFN-gamma promoter previously identified as essential for promoter activity. Moreover, dominant negative mutants of the c-Jun proto-oncogene were able to mimic the same down-regulatory effect exerted by dexamethasone, and mutations that abolished the binding of the AP-1 CREB-ATF factors were able to block the glucocorticoid effect. These results suggest a model involving the inhibition of IFN-gamma AP-1 CREB-ATF DNA binding complexes as one of the mechanisms involved in the negative regulatory action of glucocorticoids on IFN-gamma gene expression and support the relevance of AP-1 CREB-ATF binding factors during the transcriptional activation of the IFN-gamma promoter in T cells.
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PMID:Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun. 775 1

In adult rats, the expression of transcription factor proteins c-Jun and CREB and their colocalization with tyrosine hydroxylase (TH) were investigated in neurons of the substantia nigra compacta (SNC) axotomized by stereotaxic unilateral transection of the medial forebrain bundle (MFB). Axotomized SNC neurons were identified by injection of the retrograde tracer horseradish-peroxidase-coupled-gold (HRP-gold) into the ipsilateral striatum 5 days prior to MFB transection. Nuclear c-Jun immunoreactivity (IR) appeared 36 h after MFB transection in SNC neurons, was maximal after 5 days, and declined after 10 days. c-Jun-IR was visible in HRP-gold-labeled SNC neurons, demonstrating that c-Jun is in fact expressed in axotomized neurons. The constitutively expressed CREB (calcium/cAMP response element-binding protein, syn. CREB-1) was present in apparently all neuronal and glial cells in the brains of untreated rats including those SNC neurons that coexpressed TH. Three days following MFB transection, the nuclear CREB-IR disappeared in the axotomized SNC neurons labeled by TH-IR and was almost completely absent after 20 days in this neuronal population. The TH-IR rapidly declined 5 days after MFB transection, and 10 and 100 days post-axotomy the number of TH-labeled neurons was reduced by 52 and 80%, respectively. During this period, the majority of surviving TH positive neurons coexpressed c-Jun but were immunonegative for CREB. Between 3 and 60 days following MFB transection, the number of CREB-labeled glial cell nuclei increased in the ipsilateral substantia nigra by about 80%. Concomitantly, expression of GFAP, a marker protein for astrocytes, was also enhanced whereas nuclear c-Jun-, JunD-, and c-Fos-IR did not change in glial cells. These findings demonstrate that c-Jun can be expressed in axotomized neurons during the absence of CREB and suggest a role of c-Jun in the transcriptional control of the TH gene.
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PMID:Induction of c-Jun and suppression of CREB transcription factor proteins in axotomized neurons of substantia nigra and covariation with tyrosine hydroxylase. 782 Mar 66

The murine macrophage inflammatory protein 1 beta mRNA (MIP-1 beta) is rapidly and transiently induced in macrophages by lipopolysaccharide (LPS), serum or cycloheximide. Functional studies of the MIP-1 beta proximal promoter indicate that it is cell-specific, and serum- and LPS-responsive in macrophages. A 76-bp proximal promoter sequence (-51 to -127 bp) confers cell-specific and LPS-inducible activity when placed upstream from a heterologous promoter in both orientations. One essential cis-regulatory element within the enhancer-like sequence is an activating transcription factor/cAMP response element (CRE)-binding protein (ATF/CREB)-binding site, although the promoter is not cAMP responsive. Electrophoretic mobility shift assays and mutational analyses suggest that the promoter site is bound by nuclear protein complexes containing cAMP-independent members of the ATF/CREB family of proteins and c-Jun, and are functionally distinct from the AP1-related TPA-response element (TRE) binding activity.
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PMID:An ATF/CREB-binding site is essential for cell-specific and inducible transcription of the murine MIP-1 beta cytokine gene. 783 96

A number of signalling pathways stimulate transcription of target genes through nuclear factors whose activities are primarily regulated by phosphorylation. Cyclic AMP regulates the expression of numerous genes, for example, through the protein kinase-A (PKA)-mediated phosphorylation of transcription factor CREB at Ser 133. Although phosphorylation may stimulate transcriptional activators by modulating their nuclear transport or DNA-binding affinity, CREB belongs to a class of proteins whose phosphorylation appears specifically to enhance their trans-activation potential. Recent work describing a phospho-CREB binding protein (CBP) which interacts specifically with the CREB trans-activation domain prompted us to examine whether CBP is necessary for cAMP regulated transcription. We report here that microinjection of an anti-CBP antiserum into fibroblasts can inhibit transcription from a cAMP responsive promoter. Surprisingly, CBP also cooperates with upstream activators such as c-Jun, which are involved in mitogen responsive transcription. We propose that CBP is recruited to the promoter through interaction with certain phosphorylated factors, and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptor to the transcriptional apparatus.
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PMID:Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. 802 57

The transactivator protein of human T-lymphotropic virus type I (HTLV-I), Tax, forms multiprotein complexes with the ubiquitous transcription factor CREB and the CREB/ATF-1 heterodimer. The interaction between Tax and CREB is highly specific and results in increased binding of the Tax/CREB complexes to the HTLV-I 21-bp repeats. Despite the extensive sequence similarities between CREB and ATF-1, Tax interacts with ATF-1 only marginally. Compared with CREB, Tax/CREB exhibits greatly increased DNA recognition specificity and preferentially assembles on a consensus binding site, GGGGG(T/A)TGACG(T/C)(A/C)TA(T/C)C-CCCC, homologous to the HTLV-I 21-bp repeats. Here we report that Tax affects CREB binding to the Tax-inducible DNA elements by interacting with the basic-leucine zipper (bZip) domain of CREB. We show by domain switching that the basic region in CREB bZip can confer on c-Jun and ATF-1 leucine zippers the ability to interact with Tax in vitro. Mutational analyses further demonstrate that the amino acid residues of CREB critical for Tax/CREB interaction are Ala-Ala-Arg at positions 282-284 (AAR284), immediately upstream of the highly conserved DNA-binding domain (R/K)XX(R/K) N(R/K)XAAXX(S/C)RX(R/K)(K/R) characteristic of all bZip proteins. Specific amino acid substitutions in AAR284 of CREB weakened or abolished Tax/CREB interaction, whereas reciprocal changes in ATF-1 allowed it to interact with Tax. These results support a model in which the specific interaction between Tax and the AAR284 residues near the DNA-binding domain of CREB results in a multiprotein complex with altered DNA recognition property. This protein complex assembles selectively on the viral Tax-responsive 21-bp repeats to augment transcription.
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PMID:Expansion of CREB's DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. 820 41

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

The intracellular nonlysosomal calcium-dependent cysteine protease, m-calpain, is shown to specifically cleave the bHLHzip transcription factor USF leaving the binding and dimerisation domains intact. The resultant protein is capable of efficient DNA binding but is no longer able to activate transcription. A surprisingly high proportion of other transcription factors tested, AP1 (c-Fos/c-Jun), Pit-1, Oct-1, CP1a and b, c-Myc, ATF/CREB, AP2 and AP3 but not Sp1, were similarly cleaved by m-calpain to produce specific partial digestion products. These properties make m-calpain a particularly useful protease for proteolytic studies of transcription factors and also raise the possibility that m-calpain may be involved in vivo in regulation of turnover or transcriptional activity of a number of transcription factors.
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PMID:Specific cleavage of transcription factors by the thiol protease, m-calpain. 825 62

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 hepatitis B virus (HBV) transactivator protein HBx is enigmatic in that it stimulates a striking variety of promoters which do not share a common cis-regulatory element. As it does not bind to DNA, it has been speculated that HBx acts indirectly through cellular pathways. Under certain conditions HBx can have an oncogenic potential, which may be relevant for HBV-associated liver carcinogenesis, but until now the mechanism for transactivation and cell transformation by HBx was unclear. We report here that HBx uses a complex signal transduction pathway for transactivation. An increase in the endogenous protein kinase C (PKC) activator sn-1,2-diacylglycerol and the subsequent activation of PKC give rise to activation of the transcription factor AP-1 (Jun-Fos). As a result, HBx transactivates through binding sites for AP-1 and other PKC-dependent transcription factors (AP-2, NF-kappa B), thereby explaining the as-yet incomprehensible variety of HBx-inducible genes. As the PKC signal cascade also mediates cell transformation by tumour-promoting agents, the mechanism presented here might account for the oncogenic potential of HBx.
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PMID:Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. 844 61


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