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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TPA-inducible transcription factor AP-1, consisting of homo- or hetero-dimers of members of the Jun- and Fos-families, regulates transcription of a wide variety of genes containing the TPA response element (TRE). In P19 embryonal carcinoma (EC) cells, Jun D is the only component of AP-1 expressed, while in these cells until now none of the members of the jun- and fos-families have been found to be inducable by external stimuli. Here we demonstrate that Jun B is the only member of the Jun- and Fos-families that is induced by Epidermal Growth Factor (EGF) in transfected murine P19 EC cells, expressing functional human EGF receptors (hEGF-Rs). Induction of jun B can be mimicked in wild type P19 EC cells by the synergistic action of the phorbol ester TPA and the calcium ionophore A23187, through activation of signal transduction pathways, that are activated simultaneously by EGF. The EGF induced jun B expression in the hEGF-R expressing P19 EC cells is mediated by an inverted repeat (IR) sequence in the jun B promoter, previously shown to be responsive to both PKC and PKA signal transduction. Transactivation of the IR sequence by EGF can be blocked completely by prior expression of antisense Jun D, but not by antisense c-Jun. These studies therefore implicate Jun D in the regulation of immediate early gene expression by external stimuli.
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PMID:EGF-induced jun B-expression in transfected P19 embryonal carcinoma cells expressing EGF-receptors is dependent on Jun D. 173 90

We applied Southwestern and Western blotting and gel retardation techniques to investigate the changes that occur in the cyclic adenosine monophosphate (cAMP)-responsive element (CRE) binding (CREB) proteins in rapidly growing, chemically induced 5123tc and 5123D Morris hepatomas. Using the CRE sequences from the c-fos, E2A, and somatostatin gene promoters, we identified in the nuclear proteins from normal unstimulated or proliferating rat liver cells six different protein factors of Mr 34,000, 36,000, 40,000, 47,000, 56,000, and 72,000 capable of binding to the element. The Mr 47,000 protein had the highest specificity for the core CRE, suggesting its importance in cAMP-mediated gene expression. We could not find the Mr 47,000 CREB protein in the 5123tc and 5123D hepatomas. Our efforts to detect this protein in the tumors by (a) using the CRE sequence from different gene promoters, (b) altering the protocol for extracting nuclear proteins, or (c) attempting to restore its DNA-binding property by phosphorylation [with endogenous protein kinase(s), a catalytic subunit of cAMP-dependent protein kinase, and protein kinase C/dephosphorylation (with alkaline phosphatase)] were unsuccessful. The loss of tje Mr 47,000 CREB protein from solid tumors of the Morris hepatoma is likely to be related to the neoplastic properties of the tumor cell rather than to cell growth because the level of this protein remained unchanged during a 6-day period of liver regeneration. The nuclear extract from the Morris hepatoma that did not have the Mr 47,000 CRE-binding factor contained proteins immunologically related to the CREB, c-Jun, and c-Fos proteins. We conclude that the Mr 47,000 factor represents a distinct member of the CRE-binding protein family and that its absence from the hepatomas may lead to aberrant expression of cAMP-inducible genes.
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PMID:Changes in cyclic adenosine monophosphate-responsive element binding proteins in rat hepatomas. 182 83

Recent evidence suggests that vasoconstrictive substances, including angiotensin II (Ang II), may function as a vascular smooth muscle growth promoting substance and may contribute to vascular hypertrophy in hypertension. Atrial natriuretic polypeptide (ANP) is known to be a physiological antagonist to Ang II in blood pressure and fluid homeostasis. Moreover, we have demonstrated that ANP can attenuate Ang II's action on vascular hypertrophy. In this study, we investigated the potential molecular mechanisms for the interaction of ANP and Ang II on vascular cell growth. Ang II dose-dependently induced RNA synthesis in post confluent cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) inhibited the hypertrophic effect of Ang II at the concentration of 10(-10) - 10(-8) M) but exerted no effect on the action of higher doses (10(-7) - 10(-6) M) of Ang II. Ang II (10(9) - 10(-8) M) and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 10(-8) M) rapidly induced c-fos as well as c-Jun and Jun-B mRNA expression in RASM cells. ANP (10(-7) M) itself had no apparent effect on the expression of these protooncogenes. Furthermore, ANP did not inhibit the induction of these protooncogenes by Ang II or PMA. Paradoxically, ANP (10(-7) M) significantly enhanced c-fos mRNA expression induced by Ang II and PMA. However, the chloramphenicol acetyl transferase (CAT) assay using a CAT expression vector containing the AP-1 binding element showed that ANP had no effect on the basal and PMA-stimulated AP-1 activity in transfected RASM cells. We conclude, therefore, that the inhibitory effect of ANP on the growth of vascular smooth muscle cells in vitro does not occur through the regulation of these protooncogene expressions.
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PMID:Interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth. 182 53

In resting human epithelial and fibroblastic cells, c-Jun is phosphorylated on serine and threonine at five sites, three of which are phosphorylated in vitro by glycogen synthase kinase 3 (GSK-3). These three sites are nested within a single tryptic peptide located just upstream of the basic region of the c-Jun DNA-binding domain (residues 227-252). Activation of protein kinase C results in rapid, site-specific dephosphorylation of c-Jun at one or more of these three sites and is coincident with increased AP-1-binding activity. Phosphorylation of recombinant human c-Jun proteins in vitro by GSK-3 decreases their DNA-binding activity. Mutation of serine 243 to phenylalanine blocks phosphorylation of all three sites in vivo and increases the inherent trans-activation ability of c-Jun at least 10-fold. We propose that c-Jun is present in resting cells in a latent, phosphorylated form that can be activated by site-specific dephosphorylation in response to protein kinase C activation.
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PMID:Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. 184 81

Transcription of the human vasoactive intestinal peptide (VIP) gene is regulated by both cyclic AMP and phorbol esters. A 17-nucleotide enhancer element within the human VIP gene mediates transcriptional activation by both phorbol esters and forskolin. Mutations of this element decrease responses to both agents, suggesting that the trans-acting proteins that mediate both modes of transcriptional regulation have similar DNA-binding characteristics. The response of the VIP enhancer element to forskolin, but not to 12-O-tetradecanoylphorbol-13-acetate, was attenuated by treatment with a recombinant inhibitor of the cAMP-dependent protein kinase, suggesting that the cAMP-dependent protein kinase and protein kinase C second messenger pathways that converge on this single enhancer element are distinct. The transcriptional activator cAMP-responsive element-binding (CREB) proteins and the c-fos.c-Jun complex interact with the VIP enhancer. The dual second messenger responses of the VIP gene may result from the interaction of this second messenger enhancer with different transcriptional activator proteins.
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PMID:Cyclic AMP- and phorbol ester-induced transcriptional activation are mediated by the same enhancer element in the human vasoactive intestinal peptide gene. 184 91

Transcription factor AP-1 is inducible by phorbol esters and thus could be considered to be one final target of the protein kinase C signal transduction pathway. AP-1 consists of the products of the fos and jun oncogenes, which associate as dimers to bind TPA-responsive promoter elements (TRE) efficiently. We show that AP-1 activity is modulated by an inhibitory protein (IP-1), present both in the nucleus and cytoplasm of several cell types. IP-1 specifically blocks DNA binding of AP-1 from nuclear extracts and of in vitro synthesized Fos/Jun proteins. It is a labile protein of 30-40 kd, which exerts its activity only in the nonphosphorylated form. Block of IP-1 function is obtained by PKA-mediated phosphorylation, possibly suggesting a cross talk mechanism at transcriptional level. Competition experiments with synthetic peptides suggest that IP-1 could interact with Fos and/or Jun leucine zippers. We speculate that IP-1 might act as a transcriptional antioncogene.
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PMID:IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. 190 Apr 58

The product of the jun proto-oncogene has been identified as one form of the transcription factor AP-1. The p55fos protein associates with jun/AP-1 by means of a heterodimer which requires intact 'leucine zipper' domains of both proteins. The fos/jun heterodimer binds to and activates transcription from TPA-responsive promoter elements (TGACTCA), which represent one final target of the protein kinase C pathway. The other main signal transduction pathway, initiated by the activation of the adenylate cyclase, involves the transcription factor CREB. The promoter element recognized by CREB, a cyclic AMP responsive element (CRE), consist of a palyndromic sequence similar to a TRE (TGACGTCA). We show that jun efficiently trans-activates CRE sequences and that fos and jun efficiently bind and cooperate in activating CRE promoter elements. The similarity between TRE and CRE sequences may involve an interplay in transcriptional regulation and 'cross-talk' between components of the two major signal transduction pathways.
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PMID:Cross-talk in signal transduction: TPA-inducible factor jun/AP-1 activates cAMP-responsive enhancer elements. 210 94

The nuclear oncoproteins fos and jun are associated as a heterodimer which binds to TPA (PMA or TPA: phorbol 12-myristate 13-acetate)- responsive promoter elements (TRE), the recognition site for the transcription factor AP-1. The fos/jun heterodimer has a higher affinity to the TRE and stimulates transcription of responsive genes more than the jun homodimer. The association of these two oncoproteins may play a central role in signal transduction and regulation of cell proliferation and differentiation. We further defined the regulation of fos and jun by studying their inducibility by second messengers in cells of hematopoietic origin. In THP-1 monocytic leukemia cells fos and jun mRNA levels are regulated in a coupled manner by second messengers activated after membrane phospholipid turnover. Addition of phospholipase C to cells, as well as stimulation of protein kinase C and release of intracellular Ca2+, caused a rapid induction of fos and jun mRNA levels, but the induction of jun mRNA showed a more persistant and less transient pattern than fos. In contrast to the phosphoinositol system, stimulation of the adenylate cyclase pathway in THP-1 cells induced only fos transcription whereas jun mRNA levels remained unchanged. A similar uncoupling of fos and jun inducibility was found after phorbol ester addition to the human erythroleukemia cell line HEL and the human promyelocytic cell line HL-60. The uncoupling of fos and jun levels might predispose cells to the formation of combinatorial transcription complexes of a different composition and activity than the fos/jun heterodimer. Indeed, nuclear extracts from THP-1 cells before or after activation of the phosphinositol or adenylate cyclase second messenger pathways revealed a correlation in fos and jun expression and specific binding of the heterocomplex to a TRE sequence.
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PMID:Coupled and uncoupled induction of fos and jun transcription by different second messengers in cells of hematopoietic origin. 215 73

Interleukin 3 (IL-3 or multi-colony-stimulating factor) plays an important role in the hematopoietic response to inflammatory stimuli through its action on both immature and mature blood cells. Like other lymphokines, IL-3 is produced in response to activation of the T-cell receptor and protein kinase C pathways. By using nuclear run-on assays of quiescent and stimulated T-cell lines, we demonstrate that IL-3 gene expression is controlled, at least in part, at the level of transcription. Functional reporter gene analysis was used to delineate two regions of the IL-3 5' flanking sequence responsible for transcriptional stimulation. DNA binding proteins that potentially mediate these responses were then recognized by mobility-shift and DNase footprinting assays. One region responsible for transcriptional enhancement was localized to the sequence GATGAATAAT, the cognate site of a transcription factor, here termed NF-IL3-A. A second region of functional activity and protein binding was localized to a single transcription factor AP-1 site. In addition three functionally inhibitory regions were identified. These results, along with the further characterization of NF-IL3-A, will contribute to the understanding of IL-3 gene regulation in stimulated T cells.
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PMID:Transcriptional regulation of interleukin 3 gene expression in T lymphocytes. 226 17

We have analyzed the modulation of amyloid beta-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human-recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.
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PMID:Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. 250 93


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