UNIPROT:P05412 - FACTA Search

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

The differentiation of both embryonal carcinoma (EC) and embryonic stem (ES) cells can be triggered in culture by exposure to retinoic acid and results in the transcriptional induction of both the endogenous mouse keratin 18 (mK18) intermediate filament gene and an experimentally introduced human keratin 18 (K18) gene as well as a variety of other markers characteristic of extraembryonic endoderm. The induction of K18 in EC cells is limited, in part, by low levels of ETS and AP-1 transcription factor activities which bind to sites within a complex enhancer element located within the first intron of K18. RNA levels of ETS-2, c-Jun, and JunB increase upon the differentiation of ES cells and correlate with increased expression of K18. Occupancy of the ETS site, detected by in vivo footprinting methods, correlates with K18 induction in ES cells. In somatic cells, the ETS and AP-1 elements mediate induction by a variety of oncogenes associated with the ras signal transduction pathway. In EC cells, in addition to the induction by these limiting transcription factors, relief from negative regulation is mediated by three silencer elements located within the first intron of the K18 gene. These silencer elements function in F9 EC cells but not their differentiated derivatives, and their activity is correlated with proteins in F9 EC nuclei which bind to the silencers and are reduced in the nuclei of differentiated F9 cells. The induction of K18, associated with the differentiation of EC cells to extraembryonic endoderm, is due to a combination of relief from negative regulation and activation by members of the ETS and AP-1 transcription factor families.
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PMID:AP-1, ETS, and transcriptional silencers regulate retinoic acid-dependent induction of keratin 18 in embryonic cells. 752 51

Several different oncogenes and growth factors promote G1 phase progression. Cyclin D1, the regulatory subunit of several cyclin-dependent kinases, is required for, and capable of shortening, the G1 phase of the cell cycle. The present study demonstrates that transforming mutants of p21ras (Ras Val-12, Ras Leu-61) induce the cyclin D1 promoter in human trophoblasts (JEG-3), mink lung epithelial (Mv1.Lu), and in Chinese hamster ovary fibroblast cell lines. Site-directed mutagenesis of AP-1-like sequences at -954 abolished p21ras-dependent activation of cyclin D1 expression. The AP-1-like sequences were also required for activation of the cyclin D1 promoter by c-Jun. In electrophoretic mobility shift assays using nuclear extracts from cultured cells and primary tissues, several AP-1 proteins (c-Jun, JunB, JunD, and c-Fos) bound the cyclin D1 -954 region. Cyclin D1 promoter activity was stimulated by overexpression of mitogen-activated protein kinase (p41MAPK) or c-Ets-2 through the proximal 22 base pairs. Expression of plasmids encoding either dominant negative MAPK (p41MAPKi) or dominant negatives of ETS activation (Ets-LacZ), antagonized MAPK-dependent induction of cyclin D1 promoter activity. Epidermal growth factor induction of cyclin D1 transcription, through the proximal promoter region, was antagonized by either p41MAPKi or Ets-LacZ, suggesting that ETS functions downstream of epidermal growth factor and MAPK in the context of the cyclin D1 promoter. The activation of cyclin D1 transcription by p21ras provides evidence for cross-talk between the p21ras and cell cycle regulatory pathways.
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PMID:Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. 755 24

Expression of interstitial collagenase (MMP-1) has been detected in stromal fibroblasts of various malignant tumors. Here, we have studied the effect of three structurally different ETS transcription factors (ETS-1, ERGB/Fli-1, and PU.1) on MMP-1 promoter activity in NIH3T3 fibroblasts. ETS-1 increased the activity of 3.8 kb MMP-1 promoter construct up to tenfold, while ERGB/Fli-1 or PU.1 alone had no marked effect on basal promoter activity. ETS-1 also markedly potentiated enhancement of MMP-1 promoter by both c-Jun and JunB, whereas ERGB/Fli-1 augmented only the effect of c-Jun. Interestingly, PU.1 abolished induction of MMP-1 promoter by both c-Jun and JunB. Stimulation of MMP-1 promoter by 12-O-tetradecanoyl phorbol-13-acetate and okadaic acid was differentially augmented by ETS-1 and ERGB/Fli-1, and abrogated by PU.1. Co-transfection studies with MMP-1 promoter 5'-deletion constructs revealed that AP-1 site was necessary for PU.1-elicited suppression. As compared to control cell lines, PU.1-positive stable cells exhibited clearly weaker binding of c-Jun and JunD containing AP-1 complexes to MMP-1 promoter AP-1 element, as well as marked reduction in basal level and induction of c-jun mRNA by 12-O-tetradecanoyl phorbol-13-acetate and okadaic acid, suggesting a novel mechanism for PU.1-mediated inhibition of AP-1 dependent gene expression. These results show that three structurally distinct ETS transcription factors differently modulate AP-1 dependent upregulation of MMP-1 gene expression.
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PMID:Differential regulation of interstitial collagenase (MMP-1) gene expression by ETS transcription factors. 917 63

During Drosophila embryogenesis, ectodermal cells of the lateral epithelium stretch in a coordinated fashion to internalize the amnioserosa cells and close the embryo dorsally. This process, dorsal closure, requires two signaling pathways: the Drosophila Jun-amino-terminal kinase (DJNK) pathway and the Dpp pathway. We have identified mutations in DJun and show that DJNK controls dorsal closure by activating DJun and inactivating the ETS repressor Aop/Yan by phosphorylation. DJun and Aop regulate dpp expression in the most dorsal row of cells. Secreted Dpp then instructs more ventrally located cells to stretch. Our results provide a causal link between the DJNK and Dpp pathways during dorsal closure. Interestingly, in vertebrates, transforming growth factor-beta and c-Jun regulate collagenase gene expression during wound healing, a process that also involves the closing of an epithelial sheath.
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PMID:Drosophila Jun kinase regulates expression of decapentaplegic via the ETS-domain protein Aop and the AP-1 transcription factor DJun during dorsal closure. 922 20

The ETS domain transcription factor PU.1 is necessary for the development of monocytes and regulates, in particular, the expression of the monocyte-specific macrophage colony-stimulating factor (M-CSF) receptor, which is critical for monocytic cell survival, proliferation, and differentiation. The bZIP transcription factor c-Jun, which is part of the AP-1 transcription factor complex, is also important for monocytic differentiation, but the monocyte-specific M-CSF receptor promoter has no AP-1 consensus binding sites. We asked the question of whether c-Jun could promote the induction of the M-CSF receptor by collaborating with PU.1. We demonstrate that c-Jun enhances the ability of PU.1 to transactivate the M-CSF receptor promoter as well as a minimal thymidine kinase promoter containing only PU.1 DNA binding sites. c-Jun does not directly bind to the M-CSF receptor promoter but associates via its basic domain with the ETS domain of PU.1. Consistent with our observation that AP-1 binding does not contribute to c-Jun coactivation is the observation that the activation of PU.1 by c-Jun is blocked by overexpression of c-Fos. Phosphorylation of c-Jun by c-Jun NH2-terminal kinase on Ser-63 and -73 does not alter the ability of c-Jun to enhance PU.1 transactivation. Activated Ras enhances the transcriptional activity of PU.1 by up-regulating c-Jun expression without changing the phosphorylation pattern of PU.1. The activation of PU.1 by Ras is blocked by a mutant c-Jun protein lacking the basic domain. The expression of this mutant form of c-Jun also completely blocks 12-O-tetradecanoylphorbol-13-acetate-induced M-CSF receptor promoter activity during monocytic differentiation. We propose therefore that c-Jun acts as a c-Jun NH2-terminal kinase-independent coactivator of PU.1, resulting in M-CSF receptor expression and development of the monocytic lineage.
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PMID:c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. 998 37

Mechanical ventilation of patients can be a life-saving treatment, but also imposes additional stress on the lung. Mitogen-activated protein kinases (MAPK) represent a family of protein kinases that become phosphorylated and activated by many different forms of stress. Using Western blot analysis, the present study analysed the effects of high distending pressure ventilation on the activation of the MAPK extracellular signal-related kinases (ERK)-1/2, c-Jun amino-terminal kinases (JNK) and p38 kinase, and on the MAPK-activated transcription factors c-Jun, ETS-like protein (Elk)-1 and activating transcription factor (ATF)-2. In adult rats, ventilation with high pressure (45/10 peak inspiratory pressure/positive end-expiratory pressure in cmH2O) for 30 or 60 min did not affect arterial oxygenation, but resulted in enhanced phosphorylation of ERK-1/2, JNK, c-Jun, Elk-1 and ATF-2 compared to normally ventilated (13/3) rats. The activation of ERK-1/2 and JNK was located to cells resembling alveolar type II cells. In addition, high pressure ventilation enhanced phosphorylation of the inhibitor of nuclear factor (NF)-kappaB and nuclear translocation of the transcription factor NF-kappaB. In isolated perfused mouse lungs, the MAPK/ERK kinase inhibitor U0126 prevented ventilation-induced activation of ERK-1/2 and Elk-1, but had no effect on ventilation-induced cytokine release. The present authors conclude that mechanical ventilation triggers specific signalling pathways, such as the mitogen-activated protein kinase and the nuclear factor-kappaB pathways, which may contribute to pulmonary inflammation and proliferation.
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PMID:Ventilation-induced activation of the mitogen-activated protein kinase pathway. 1241 88

Overexpression of SPRR1B in bronchial epithelial cells is a marker for early metaplastic changes induced by various toxicants/carcinogens. Previously, we have shown that the transcriptional stimulation of SPRR1B expression by phorbol 12-myristate 13-acetate (PMA) is mainly mediated by a -150/-94 bp enhancer harboring two critical 12-O-tetradecanoylphorbol-13-acetate-responsive elements (TREs) and by Jun.Fra-1 dimers. Here, we show that a region between -54 and -39 bp containing an ETS-binding site (EBS) and a GC box is essential for both basal and PMA-inducible SPRR1B transcription. In vivo footprinting demonstrated binding of transcription factors to these elements. However, unlike enhancer TREs, exposure of cells to PMA did not significantly alter the footprinting pattern at these elements. Mutations that crippled both the EBS and GC box suppressed both basal and PMA-inducible SPRR1B transcription. Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3. Although ESE-1 synergistically activated c-Jun- and PMA-enhanced SPRR1B transcription, coexpression of Sp1 and ESE-1 showed no synergistic or additive effect on promoter activity, indicating an obligatory role for AP-1 proteins in such regulation. In support of this notion, deletion or mutation of two functional TREs inhibited ESE-1- and Sp1-enhanced promoter activation. Thus, the interaction between ESE-1 and Sp1, and AP-1 proteins that bind to the proximal and distal promoter regions, respectively, play a critical role in the induction of squamous differentiation marker expression in bronchial epithelial cells.
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PMID:Interplay between proximal and distal promoter elements is required for squamous differentiation marker induction in the bronchial epithelium: role for ESE-1, Sp1, and AP-1 proteins. 1268 75

Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein 1 (AP1), in toxicant-induced epithelial injury, repair, and cellular transformation. Here, we have investigated the transcriptional regulation of fra-1 by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human bronchial epithelial (HBE) cells, which are the direct targets of inhaled toxins/carcinogens. In contrast to a transient induction by H2O2, TPA persistently activated fra-1 transcription, principally at the transcriptional level. A deletion analysis of the fra-1 promoter revealed that several cis-elements located between -105/+32 and -283/-105 bp mediate minimal and basal promoter activities, respectively. A region between -379 and -283 bp, which harbors a putative TPA response element, a GC box, and an Ets-like binding site, was required for high level TPA-inducible expression. Mutations in any of these cis-elements markedly reduced both basal and TPA-inducible expression. Thus, cooperative interactions between factors binding to multiple cis-elements of the -379/-283 promoter region appear to regulate TPA-induced fra-1 transcription in HBE cells. Consistent with this finding, electrophoretic mobility shift assays indicated the formation of multiple complexes consisting of the AP1-, Sp-, and ETS-specific family of transcription factors with the -379/-283 fragment. Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. Chromatin immunoprecipitation assays revealed an enhanced recruitment of c-Jun, Jun-D, and Fra-2 to the endogenous fra-1 promoter upon TPA stimulation. These results underscore the regulatory role of c-Jun, Jun-D, and Fra-2 in TPA-inducible fra-1 expression in HBE cells in vivo.
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PMID:Multiple cis-elements mediate the transcriptional activation of human fra-1 by 12-O-tetradecanoylphorbol-13-acetate in bronchial epithelial cells. 1367 79

The mechanisms of action of Ewing's sarcoma (EWS) associated EWS-ETS oncoproteins have largely remained unresolved. Here, we analyzed how two EWS-ETS proteins, EWS-ER81 and EWS-Fli-1, in vitro activate the matrix metalloproteinase (MMP)-1 promoter that is upregulated in a subset of EWSs. EWS-ER81 and EWS-Fli-1 interact with and thereby activate the MMP-1 promoter, which is potentiated by the cofactor p300 and the proto-oncoprotein c-Jun. Further, EWS-ER81 binds to c-Jun in vitro and in vivo. The interaction between c-Jun, p300 and EWS-ER81 or EWS-Fli-1 may also be relevant to the regulation of other yet-to-be-identified genes that are responsible for EWS formation.
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PMID:Upregulation of the matrix metalloproteinase-1 gene by the Ewing's sarcoma associated EWS-ER81 and EWS-Fli-1 oncoproteins, c-Jun and p300. 1455 May 55

Homeobox genes encode transcription factors that regulate embryonic development and postnatal events. Rhox5 (previously called Pem), the founding member of a homeobox gene cluster that we recently identified on the X chromosome, is selectively expressed in granulosa cells in the ovary and other somatic-cell types in other reproductive organs. In this report, we investigate its regulation in granulosa cells in the rat ovary. We found that Rhox5 expression in the ovary is governed by the Rhox5 distal promoter and is expressed at least as early as Day 5 postpartum. Rhox5 mRNA levels are regulated during the ovarian cycle, peaking before ovulation. Deletion analysis revealed a 25-nt element essential for distal promoter transcription in primary granulosa cells. This distal promoter element contains two ETS and one SP1 transcription-factor family binding sites that mutagenesis analysis indicated were essential for high-level transcription. This element was both necessary and sufficient for transcription, because it activated transcription when placed upstream of a heterologous minimal promoter. Cold competition and electrophoretic mobility shift assay studies demonstrated that SP1, SP3, and the ETS family transcription factor GABP bound this element. Dominant-negative forms of GABP and SP3 repressed distal promoter expression in primary rat granulosa, showing that these factors are crucial for Rhox5 expression. Cotransfection of dominant-negative mutants indicated that Rhox5 expression in granulosa cells is regulated by the c-Jun N-terminal protein kinase (JNK, MAPK8) and RAS pathways, which are known to be upstream of ETS family transcription factors. The discovery that Rhox5 expression in granulosa cells is regulated by MAPK pathways and ETS and SP1 family members provides an opportunity to understand how these regulatory pathways and factors collaborate to regulate gene expression during the ovarian cycle.
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PMID:Regulation of the Rhox5 homeobox gene in primary granulosa cells: preovulatory expression and dependence on SP1/SP3 and GABP. 1609 60

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