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)

Transcription of tissue inhibitor of metalloproteinases-1 (TIMP-1), a secreted protein that regulates the activities of the metalloproteinases, collagenase and stromelysin, is activated by serum growth factors. Transient transfection experiments have revealed several regions of cis-acting regulatory sequences involved in the response of the murine TIMP-1 gene to serum. One area is in the vicinity of the promoter, consisting of a non-consensus binding site (5'-TGAGTAA-3' at -59/-53) for transcription factor AP1 and an adjacent 24 bp region of dyad symmetry that contains a PEA3-binding site. A second is an upstream region (-1020 to -780) that acts as an enhancer when linked to a heterologous promoter, and contains a consensus AP1 binding site (at -803/ -797). Gel retardation assays revealed differences between nuclear factors in mouse C3H10T1/2 cells that bound to the TIMP(-59/ -53)AP1 site and a consensus collagenase TRE (TPA-response element). The TIMP(-59/ -53)AP1 site is a promiscuous motif that binds c-Fos/c-Jun AP1 translated in vitro and is an effective competitor for binding of nuclear AP1 factors to the consensus TRE, but in addition it binds factors that do not associate with the consensus TRE. The TIMP(-59/ -53)AP1 motif and the dyad symmetry region stimulated expression from a thymidine kinase promoter in an additive fashion, and competition experiments showed that excess copies of these factor binding sites reduced expression from a reporter plasmid driven by the TIMP-1 promoter. Our data show that binding sites for AP1 and PEA3 transcription factors are involved in the regulation of TIMP-1 transcription, which suggests that the coordinated induction of TIMP-1, collagenase and stromelysin may be achieved through the actions of a shared set of nuclear transcription factors. However, the properties of the TIMP-1(-59/ -53)AP1 motif likely reflect an additional type of transcriptional regulation restricted to TIMP-1.
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PMID:Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription. 142 Mar 63

In HeLa cells transcription of the c-jun gene is activated strongly and rapidly by ultraviolet (UV) irradiation and, to a somewhat lesser extent, by treatment with phorbol ester tumor promoters. In the same cells UV and phorbol esters only marginally enhance the abundance of RNA transcribed from the jun D gene and from the gene coding for the serum response factor (which in turn acts on the UV and phorbol ester response element of the c-fos gene). In contrast to c-jun, jun B transcription is induced more efficiently by phorbol ester than by UV irradiation, suggesting that the members of the jun family are differently regulated. The promoter of c-jun carries two enhancer elements resembling AP-1 binding sites: the jun1 UV response element (URE-71 TGACATCA -64) and the jun2 URE (-190 TTACCTCA-183). These elements act independently in the UV induced expression of c-jun. In the context of the complete c-jun promoter they seem not to be required for c-jun induction by phorbol esters. When fused to the Herpes simplex thymidine kinase promoter, however, the isolated elements mediate induction by both UV and phorbol esters. UV and phorbol ester treatment of cells increases the binding of transcription factors to both elements. Both elements bind factors different in modification or/and constitution from AP-1, the heterodimeric transcription factor composed of c-Fos and c-Jun that controls the activity of the UV and phorbol ester response element (-72 TGAGTCA-66) of the human collagenase gene.
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PMID:Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response. 156 Dec 39

We present evidence that CRE-BP1 binding to the cyclic AMP (cAMP) response element (CRE) is a transcriptional activator. Transcriptional activation was assayed by cotransfection into CV-1 cells of a CRE-BP1 expression plasmid together with a reporter plasmid in which the thymidine kinase promoter and four tandem repeats of CRE were linked to the chloramphenicol acetyltransferase (CAT) gene. Cotransfection with the CRE-BP1 expression plasmid caused an 8-fold stimulation of CAT activity, while cotransfection with the plasmids to express CRE-BP1 and c-Jun induced a 32-fold stimulation of CAT activity, suggesting that a heterodimer of CRE-BP1 with c-Jun is a stronger trans-activator than a homodimer of CRE-BP1. By using a series of deletion and point mutants of CRE-BP1 in this cotransfection assay, two functional domains of CRE-BP1 were identified: the putative metal finger structure in the amino-terminal region and the leucine zipper motif linked to a cluster of basic amino acids in the carboxyl-terminal region. The former was a transcriptional activation domain in the absence of c-Jun. The latter was a DNA-binding domain, and was essential in both the presence and absence of c-Jun.
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PMID:Identification of the functional domains of the transcriptional regulator CRE-BP1. 183 93

An intragenic enhancer in the pol gene of human immunodeficiency virus type 1 has previously been identified (Verdin et al., Proc. Natl. Acad. Sci. USA 87:4874-4878, 1990). This element is composed of two subdomains both exhibiting phorbol ester-inducible enhancing activity on the viral thymidine kinase promoter in HeLa cells. Examination of the nucleotide sequence of one of these domains (nucleotides 4079 to 4342, HXB2 isolate) revealed the presence of three short DNA regions highly homologous to the recognition site for cellular transcription factor AP-1. Two short oligonucleotides containing these AP-1 sites each functioned as a phorbol ester-inducible enhancer when cloned upstream of the thymidine kinase promoter and transfected into HeLa cells. Gel mobility shift assays and competition experiments using the same two oligonucleotides demonstrated that they bound affinity-purified AP-1 or AP-1 present in uninduced and 12-O-tetradecanoylphorbol-13-acetate-induced HeLa nuclear extracts. Footprinting experiments confirmed that all three predicted sites bound purified AP-1. These results suggest that the AP-1 factor could play a role in the transcriptional regulation of human immunodeficiency virus type 1 gene expression.
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PMID:The intragenic enhancer of human immunodeficiency virus type 1 contains functional AP-1 binding sites. 194 59

Tumor promoter 12-O-tetradecanoylphorbol-13-acetate stimulates an increase in erythroid differentiation activity in human fibrosarcoma HT1080 cells. Here, we demonstrate that this process involves a rapid accumulation of five species of activin beta A/erythroid differentiation factor mRNA, followed by protein kinase C activation, and that variation in size of the activin transcripts is due to multiple 3' ends, presumably reflecting an alternative polyadenylation. In transiently transfected HT1080 cells, a 97-bp DNA fragment containing an AP-1 consensus sequence (TGAGTCA) located in the 3'-flanking region of the activin gene was capable of activating the heterologous herpes simplex virus thymidine kinase (tk) and SV40 early promoters, and a cotransfected c-Jun enhanced these fusion promoter activities. The deletion of TGAG sequences from the AP-1 element in the 97-bp DNA sequence context abolished its c-Jun-mediated activation from the tk promoter even in HT1080 cells overexpressing stably transfected c-Jun. Cotransfected adenovirus E1A products repressed the tk promoter activity enhanced by the activin AP-1 element itself or in concert with transiently transfected c-Jun, indicating that the putative AP-1 sequence acts as an activator element, depending upon c-Jun activity. These results suggest that the 3'-flanking DNA sequences of the human activin beta A subunit gene play an important role in its expression.
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PMID:Possible roles of the 3'-flanking sequences of the human activin beta A subunit gene in its expression. 848 45

We have previously described a tumor necrosis factor alpha (TNF-alpha) response element, located between residues -188 and -140 of the human decorin promoter, that mediates the inhibitory effect of TNF-alpha on decorin gene expression (Mauviel, A., Santra, M., Chen, Y.-Q., Uitto, J., and Iozzo, R. V. (1995) J. Biol. Chem. 270, 11692-11700). In this report, we demonstrate that interleukin 1 (IL-1), a pleiotropic cytokine that shares a wide variety of biological properties with TNF-alpha, uses the same cis element to up-regulate decorin gene expression. Specifically, IL-1 enhances the expression of the human decorin gene, and this effect is mediated by activation of the corresponding promoter, as shown in transient cell transfection experiments using decorin promoter-chloramphenicol acetyl transferase reporter gene constructs. Additional transfection experiments with various 5'-deletion promoter-chloramphenicol acetyltransferase constructs demonstrate that both the inhibitory effect of TNF-alpha and the stimulatory effect of IL-1 are mediated by a 48-base pair segment of the promoter, between residues -188 and -140. This region, which contains a canonical AP-1 binding site, TGAGTCA, allows an antagonistic effect of these two cytokines on the decorin promoter activity. When cloned upstream of the thymidine kinase promoter, this promoter fragment requires the AP-1 sequence to be responsive to IL-1. Supershift assays with various AP-1 antibodies identified c-Jun, Jun-B, and Fra-1 as components of the complex binding to the decorin promoter. Overexpression of c-jun, an oncogene encoding the c-Jun/AP-1 transcription factor, reduces the basal activity of both decorin and -188/-140 thymidine kinase promoter constructs. In contrast, blockage of c-jun expression with an antisense c-jun construct potentiates the stimulatory effect of IL-1 and reverses the response to TNF-alpha. These data indicate that the region between residues -188 and -140 of the human decorin promoter functions as a bimodal regulatory element and allows transcriptional repression by c-Jun/AP-1 complexes.
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PMID:Identification of a bimodal regulatory element encompassing a canonical AP-1 binding site in the proximal promoter region of the human decorin gene. 879 56

Expression of the ovine P-450 side-chain cleavage enzyme gene (CYP11A1) is stimulated by epidermal growth factor (EGF) through a pathway that involves c-Jun in JEG-3 placental cells. Growth factor signaling involves ras-dependent and ras-independent signaling pathways, which in turn regulate gene transcription through related but distinct mitogen-activated protein kinase pathways (MAPKs) including the extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs). We investigated the intracellular signaling pathways governing EGF induction of the CYP11A1 promoter. EGF stimulation of the CYP11A1 promoter (4-fold) was reduced 60% by a dominant negative mutant of ras (N17), and 30-40% by antisense ras. EGF induced both ERK and SAPK activity in JEG-3 cells. EGF-induced CYP11A1 promoter activity was reduced 60% by the MEK1 inhibitor PD098059 and 50% by a dominant negative mutant of the ERK-specific regulator MEK1. In contrast, dominant negative mutants of the SAPK-specific activator, SEK1, induced a further increase in EGF-induced CYP11A1 promoter activity. Constitutively active mutants of ras (V12 or L61) increased CYP11A1 promoter activity 6- to 8-fold. Deletion of the EGF response element (EGF-RE) between -92 and -77 bp reduced ras induction by 60%; however, a residual 3-fold induction remained through the proximal -77 bp. Mutation of the EGF-RE AP-1-like sequence in the context of the native promoter reduced CYP11A1 promoter activation by ras 60%. The EGF-RE sequence was sufficient for 6-fold activation by ras in the context of an heterologous thymidine kinase promoter. Candidate transcription factor targets (c-Jun, c-Ets-2) for the ras-signaling cascade were examined for their effects on CYP11A1 promoter activity. Overexpression of c-Jun induced the CYP11A1 promoter through the EGF-RE; however, c-Ets-2 activation of the CYP11A1 promoter (12-fold) required the proximal ras-responsive promoter sequences that are distinct from the EGF/MEK/c-Jun-responsive element. Induction of the CYP11A1 promoter by EGF involves a ras/MEK1/AP-1-dependent pathway that is distinct from induction by ras/c-Ets-2.
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PMID:Stimulation of the P-450 side chain cleavage enzyme (CYP11A1) promoter through ras- and Ets-2-signaling pathways. 888 43

Twenty-four base pairs of the human antioxidant response element (hARE) are required for high basal transcription of the NAD(P)H:quinone oxidoreductase1 (NQO1) gene and its induction in response to xenobiotics and antioxidants. hARE is a unique cis-element that contains one perfect and one imperfect AP1 element arranged as inverse repeats separated by 3 bp, followed by a "GC" box. We report here that Jun, Fos, Fra, and Nrf nuclear transcription factors bind to the hARE. Overexpression of cDNA derived combinations of the nuclear proteins Jun and Fos or Jun and Fra1 repressed hARE-mediated chloramphenicol acetyltransferase (CAT) gene expression in transfected human hepatoblastoma (Hep-G2) cells. Further experiments suggested that this repression was due to overexpression of c-Fos and Fra1, but not due to Jun proteins. The Jun (c-Jun, Jun-B, and Jun-D) proteins in all the possible combinations were more or less ineffective in repression or upregulation of hARE-mediated gene expression. Interestingly, overexpression of Nrf1 and Nrf2 individually in Hep-G2 and monkey kidney (COS1) cells significantly increased CAT gene expression from reporter plasmid hARE-thymidine kinase-CAT in transfected cells that were inducible by beta-naphthoflavone and teri-butyl hydroquinone. These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. The hARE-mediated basal expression, however, is repressed by overexpression of c-Fos and Fra1.
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PMID:Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. 896 64

The 92 kDa type IV collagenase (MMP-9), which degrades type IV collagen, has been implicated in tissue remodeling. The purpose of the current study was to determine the role of Jun amino-terminal kinase (JNK)- and extracellular signal-regulated kinase- (ERK)-dependent signaling cascades in the regulation of MMP-9 expression. Towards this end, we first determined the transcriptional requirements for MMP-9 promoter activity in a cell line (UM-SCC-1) which is an avid secretor of this collagenase. Transfection of these cells with a CAT reporter driven by progressive 5' deleted fragments of the MMP-9 promoter indicated the requirement of a region spanning -144 to -73 for optimal promoter activity. DNase I footprinting revealed a protected region of the promoter spanning nucleotides -91 to -68 and containing a consensus AP-1 motif at -79. Mutation of this AP-1 motif practically abolished the activity of the MMP-9 promoter-driven CAT reporter. Mobility shift assays indicated c-Fos and Jun-D bound to this motif and transfection of the cells with a mutated c-Jun, which quenches the function of endogenous Jun and Fos proteins, decreased MMP-9 promoter activity by 80%. UM-SCC-1 cells contained a constitutively activated JNK and the expression of a kinase-deficient JNK1 reduced the activity of a CAT reporter driven either by the MMP-9 promoter or by three tandem AP-1 repeats upstream of a thymidine kinase minimal promoter. Conditioned medium collected from UM-SCC-1 cells transfected with the dominant negative JNK1 expression vector diminished 92 kDa gelatinolysis. Similarly, interfering with MEKK, which lies upstream of JNK1, using a dominant negative expression vector reduced MMP-9 promoter activity over the same concentration range which repressed the AP-1-thymidine kinase CAT reporter construct. UM-SCC-1 cells also contained a constitutively activated ERK1. MMP-9 expression, as determined by CAT assays and by zymography, was reduced by the co-expression of a kinase-deficient ERK1. Interfering with MEK1, which is an upstream activator of ERK1, either with PD 098059, which prevents the activation of MEK1, or with a dominant negative expression construct, reduced 92 kDa gelatinolysis and MMP-9 promoter activity respectively. c-Raf-1 is an upstream activator of MEK1 and a kinase-deficient c-Raf-1 expression construct decreased the activity of a promoter driven by either the MMP-9 promoter or three tandem AP-1 repeats. Conversely, treatment of UM-SCC-1 cells with PMA, which activates c-Raf-1, increased 92 kDa gelatinolysis. These data suggest that MMP-9 expression in UM-SCC-1 cells, is regulated by JNK- and ERK-dependent signaling pathways.
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PMID:Regulation of 92 kDa type IV collagenase expression by the jun aminoterminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. 913 92

Retinyl methyl ether (RME) is known to prevent the development of mammary cancer. However, the mechanism by which RME exerts its anticancer effect is presently unclear. The diverse biological functions of retinoids, the vitamin A derivatives, are mainly mediated by their nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs are ligand-dependent transcriptional factors that either activate gene transcription through their binding to retinoic acid response elements or repress transactivation of genes containing the activator protein 1 (AP-1) binding site. Previous studies demonstrated that RME can modulate transcriptional activity of retinoid receptors on retinoic acid response elements, suggesting that regulation of retinoid receptor activity may mediate the anticancer effect of RME. In this study, we present evidence that RME can down-regulate AP-1 activity induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, insulin, growth factors, and the nuclear proto-oncogenes c-Jun and c-Fos. Transient transfection assays demonstrate that inhibition of AP-1 activity occurs on the human collagenase promoter containing an AP-1 binding site or the thymidine kinase promoter linked with an AP-1 binding site. In HeLa cells, the inhibition is observed when RAR-alpha and/or RXR-alpha but not RAR-beta or RAR-gamma expression vectors are cotransfected, whereas the endogenous retinoid receptors in breast cancer cells T-47D and ZR-75-1 were sufficient to confer the inhibition by RME. Furthermore, using gel retardation assay, we show that 12-O-tetradecanoylphorbol-13-acetate- and epidermal growth factor-induced AP-1 binding activity in breast cancer cells is inhibited by RME. These results suggest that one of the mechanisms by which RME prevents cancer development may be due to the repression of AP-1-responsive genes.
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PMID:Retinyl methyl ether down-regulates activator protein 1 transcriptional activation in breast cancer cells. 927 11


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