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)

Although human papillomavirus type 16 (HPV16) E6 protein has a transcription-modulatory activity for a wide variety of viral promoters, a cellular target for this activity of E6 has not yet been identified. In this study, using differential hybridization, we identified a mouse fibronectin (FN) gene as a putative cellular target whose expression is up-regulated by E6. Chloramphenicol acetyltransferase (CAT) assays with mouse and rat FN promoter-CAT fusion constructs indicated that HPV16 E6 transactivates the FN promoters in a p53-independent manner. Deletion and site-specific mutation analyses revealed that transactivation by HPV16 E6 depends upon a cyclic AMP response element (CRE) located at -160 relative to the start site of transcription. Gel retardation assays demonstrated that nuclear extracts from the HPV16 E6-expressing cells, compared to those from parental 10T1/2 cells, have increased binding activity to the CRE. Antibodies against c-Jun and ATF-2 disrupted this binding activity. These data indicate that HPV16 E6 transcriptionally modulates FN gene expression via the CRE by inducing the binding of the protein complexes, probably including c-Jun and ATF-2, to the CRE.
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PMID:Human papillomavirus type 16 E6 protein transcriptionally modulates fibronectin gene expression by induction of protein complexes binding to the cyclic AMP response element. 915 19

FSH is an important regulator of mammalian gametogenesis and the female reproductive cycle. Although little is known about the transcriptional regulation of the beta-subunit (the rate-limiting subunit of FSH synthesis), sequence analysis of the ovine FSHbeta promoter has revealed a number of potential activating protein-1 (AP-1; Jun/Fos)-binding sites. To determine whether the gene encoding the beta-subunit of ovine FSH (oFSHbeta) is responsive to AP-1 transcriptional complexes, chimeric constructs containing deleted portions of the oFSHbeta promoter fused to a luciferase reporter were transiently transfected along with c-Jun and c-Fos expression constructs into JAR cells. Analysis of these deletion constructs revealed that the proximal promoter of oFSHbeta is highly stimulated by c-Jun and c-Fos proteins (typically 20-fold with a reporter construct containing oFSHbeta sequences from -215 to +759 bp). This stimulation was lost when a similar construct containing sequences from -84 to +759 bp was tested. Transcriptional start site analysis using reverse transcription-PCR verified that the transcriptional initiation of the -215-bp deletion construct, with or without cotransfected c-Jun/c-Fos, was the same as that observed in vivo. Computer analysis of oFSHbeta sequences from -215 to +1 bp identified four putative AP-1-like elements, located at -155, -120, -83, and -10 bp. Gel retardation experiments using oligonucleotides corresponding to the four putative AP-1-like sites revealed that only -120 and -83 sites in oFSHbeta bound AP-1 proteins in vitro. Site-directed mutagenesis of the -120 and -83 sites showed that each element was required for stimulation by c-Jun and c-Fos proteins as well as 12-O-tetradecanoyl phorbol-13-acetate in transient transfection assays. Finally, immunocytochemical dual labeling was used to show that more than 75% of all FSHbeta-containing cells in ovine pituitary sections from cycling ewes contained nuclear c-Jun, JunB, JunD, and Fos proteins. These data, taken together, show that oFSHbeta transcription can be stimulated by c-Jun and c-Fos proteins via two functionally linked AP-1-like sites in the oFSHbeta proximal promoter and that these sites are likely to be important regulators of FSH production in vivo.
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PMID:Two proximal activating protein-1-binding sites are sufficient to stimulate transcription of the ovine follicle-stimulating hormone-beta gene. 916 57

The promoter of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) has two AP-1 cis-response elements, respectively located at positions -62 and -94 relative to the transcription start site (Wymer et al., 1989. J. Virol. 63, 2773-2784). Chloramphenicol acetyl transferase (CAT) analysis with hybrid constructions of the CAT structural gene and the ICP10 promoter or its mutants and gel retardation studies were used to examine the role of the AP-1 cis-response elements in expression from the ICP10 promoter. Basal expression from the wild-type promoter was significantly (75-90%) reduced by mutation of the upstream or downstream AP-1 element. Mutation in the upstream AP-1 element also caused a 60% reduction in c-Jun-mediated activation. Activation was decreased 40% by mutation in the downstream AP-1 element and it was abrogated by mutation of both elements. Similar results were obtained for ACT-deleted mutants and mutants in which CT was mutated to AG. The trans-activation by Vmw110 was also reduced by mutation of the AP-1 elements (10- and 2-fold for the upstream and downstream element, respectively) and it was abrogated by mutation of both AP-1 elements. Mutation of nucleotides adjacent to the AP-1 cis-response elements had no effect on trans-activation. Gel retardation assays with a DNA probe representing the wild-type ICP10 promoter and nuclear extracts from HSV-1-infected cells identified one complex that was not seen with mock-infected cells or with cells infected with a Vmw110-deleted mutant. The complex was not seen when HSV-1-infected cells were reacted with an AP-1-mutant DNA probe, and its formation was competed by an AP-1 but not a mutant AP-1 oligonucleotide. The migration of this complex was retarded by c-Fos antibody, suggesting that both AP-1 and Vmw110 are involved in its formation. A mutant deleted in all sequences upstream of the TATA box was also activated by Vmw110, but this activation was only 2-fold lower than that seen for the wild type and significantly higher (10-fold) than that seen for the double AP-1 mutants. The data suggest that AP-1 elements play a crucial role in ICP10 gene expression/activation.
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PMID:AP-1 cis-response elements are involved in basal expression and Vmw110 transactivation of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). 916 92

We have investigated whether lithium has effects on transcription factor binding to consensus DNA sequences of AP-1 and cyclic AMP-responsive element (CRE) in cultured rat neurons and in vivo. Treatment of rat cerebellar granule cells (CGC) with lithium chloride induced a concentration-dependent increase in AP-1 and CRE binding activities with maximal effects at therapeutically relevant concentrations of 0.5 and 1.0 mM. Time-course studies show that lithium's effects on AP-1 and CRE binding were biphasic within the first 24 h of treatment in immature CGC in culture and persistent in mature CGC, lasting as long as 7 days. These actions were concurrent with an increase in the mRNA levels of c-fos and c-jun, as well as the protein levels of c-Fos, c-Jun, and phosphorylated CRE binding protein (p-CREB). Gel supershift assays using transcription factor-specific antibodies revealed that p-CREB, Jun D, and a Fos family protein(s) are components of the AP-1 binding complex in untreated and lithium-treated CGC. Chronic dietary treatment of rats with lithium carbonate for 4 weeks also significantly increased AP-1 and CRE binding activity in the frontal cortex, hippocampus, amygdala, and cerebellum. Similar to the results obtained in CGC, p-CREB, Jun D, and Fos family proteins are present in the AP-1 binding sites in the frontal cortex and hippocampus of untreated and lithium-treated rats. Lithium-induced activation of transcription factor binding to AP-1 and CRE sites in vivo and in vitro provides a new avenue to study the mechanisms of action of lithium in the treatment of manic depressive illness.
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PMID:Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain. 937 64

Induction of cytochrome (CYP) P4501A2 by such polycyclic aromatic hydrocarbons as 3-methylcholanthrene (3MC) can lead to the bioactivation of carcinogenic aromatic amines and heterocyclic amines. A 3MC response element was recently identified approximately 2.2 kb upstream of the transcription start site of the human CYP1A2 gene. Sequence analysis of this enhancer identified, in addition to a binding site for the aryl hydrocarbon receptor, two other sequences, referred to as 5'AP1 and 3'AP1, each with complete homology to the phorbol 12-O-tetradecanoate 13-acetate (TPA) response element consensus sequence. Nuclear extracts from TPA-treated HepG2 cells protected both the 5'AP1 and 3'AP1 sequences against digestion with DNase I. Gel mobility shift and supershift assays revealed that TPA treatment of HepG2 results in increased binding activity of the AP-1 proteins, c-Jun, JunD, and c-Fos, to both sites. We transiently expressed, in HepG2, either a fragment containing both the 5'AP1 and 3'AP1 sites (-2.3pT81Luc) or only the 3'AP1 site (-2.2pT81Luc) cloned into a plasmid containing the luciferase gene under transcriptional control of the thymidine kinase promoter. TPA treatment of cells transfected with -2.3pT81Luc resulted in an approximately threefold induction of luciferase activity over untreated control cells, while the -2.2pT81Luc construction containing only the 3'AP1 site displayed an approximately sixfold induction. These studies suggest that the human CYP1A2 gene may be regulated by tumor promoters in addition to polycyclic aromatic hydrocarbons.
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PMID:Induction of the human CYP1A2 enhancer by phorbol ester. 946 18

Both c-Fos and prodynorphin mRNA and peptide increase unilaterally in nociceptive-specific neurons in the lumbar rat spinal cord during chronic hindpaw inflammation. To study the mechanisms underlying prodynorphin gene expression, we examined transcription factors and their interactions at the CRE/AP-1-like site, DYNCRE3, found in the prodynorphin gene promoter. CREB repressed while c-Fos and c-Jun activated transcription through the DYNCRE3 site in transient co-transfections in PC12 cells. Following inflammation of the rat hindpaw, immunostaining demonstrated a bilateral increase in phosphorylated CREB (P-CREB)-positive neurons in the spinal cord. Gel supershift studies showed that spinal cord extracts contained CREB, P-CREB, and phosphorylated c-Jun (P-c-Jun) proteins that bound to the DYNCRE3 site. We propose a model in which inflammation-induced phosphorylation of CREB relieves CREB repression at the DYNCRE3 site, P-CREB binds to the c-Fos promoter, and Fos/Fra, P-CREB, and P-c-Jun interact at the DYNCRE3 site to activate prodynorphin gene transcription.
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PMID:Transcription factor regulation of prodynorphin gene expression following rat hindpaw inflammation. 947 89

Involucrin is one of the precursor proteins of the cornified cell envelope that is formed beneath the cell membrane during terminal differentiation of keratinocytes. 12-O-tetradecanoylphorbol-13-acetate (TPA), which is a potent protein kinase C (PKC) activator, induces terminal differentiation of keratinocytes. We previously demonstrated that involucrin promoter activity is stimulated by TPA in cultured fetal rat skin keratinocytes. PKC is a large family of proteins and keratinocytes containing five PKC isozymes: alpha, delta, epsilon, eta, and zeta. In order to determine the role of the PKC isozyme(s) on involucrin gene expression, we constructed the chloramphenicol acetyl transferase (CAT)-involucrin promoter expression vector by connecting the 5'-upstream region of the human involucrin gene containing the untranslated first exon to the CAT reporter gene. The CAT-involucrin promoter expression vector was transfected with various PKC isozyme expression vectors into SV40-transformed human keratinocytes (SVHK cells). Transfection of the CAT-involucrin promoter expression vector with PKC-alpha or PKC-eta expression vectors resulted in a significant increase in the TPA-dependent involucrin promoter activity. The PKC inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride, inhibited the promoter activity stimulated by TPA. Transfection of PKC-delta, -epsilon, and -zeta had no effect on the involucrin-promoter activity. Although the promoter activity was stimulated by transfection of PKC-gamma, TPA did not enhance the promoter activity in the PKC-gamma-transfected SVHK cells. Previously we showed three AP-1 binding sites (AP1-1, -2, and -3) on the involucrin promoter region. Both the basal and the TPA-stimulated involucrin promoter activities were suppressed by deleting the AP1-1 site (-119 to -113) that is the most proximal to the transcription start site. The deletion of AP1-2 (-297 to -303) or AP1-3 (-447 to -453) did not affect the involucrin promoter activity. Gel retardation analyses disclosed that TPA stimulated the specific DNA binding of the nuclear protein(s) of control, PKC-alpha, or PKC-eta-transfected SVHK cells, but not of PKC-gamma-transfected cells. Addition of anti-c-Jun and anti-c-Fos antibodies decreased the specific protein-DNA complex band with a concomitant appearance of supershifted bands. These results indicate that PKC, specifically PKC-alpha and PKC-eta, mediates the TPA-dependent activation of involucrin gene expression of SVHK cells. PKC-gamma, which is not present in keratinocytes, also induces involucrin gene expression in a TPA-independent manner, when introduced into SVHK cells.
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PMID:The alpha and eta isoforms of protein kinase C stimulate transcription of human involucrin gene. 950 39

In eukaryotes, protein de novo synthesis is mainly under the control of transcription factors at the level of gene transcription in cell nuclei. Gel retardation electrophoresis was employed for determination of DNA-binding activity of the transcription factor activator protein-1 (AP1), which is a dimer between c-Fos and c-Jun protein families. Binding of a radiolabeled double-stranded oligonucleotide probe for AP1 was rapidly potentiated in the CA1 and CA3 subfields and the dentate gyrus of the hippocampus of gerbils with forebrain ischemia for 5 min. Similarly marked potentiation was seen in the thalamus and the striatum, but not in the frontal cortex, following the recirculation of blood supply. The potentiation was transient in the vulnerable CA1 subfield, but was rather persistent in the thalamus and the striatum in addition to the resistant CA3 subfield and dentate gyrus. However, administration of the neuroprotective drug bifemelane (10 to 20 mg/kg, i.p.) resulted in prolongation of the potentiation of AP1 binding in the CA1 subfield up to 6 hr after ischemia, without significantly affecting that in other central structures. Limited proteolysis revealed that bifemelane induced expression of the AP1 consisting of constructive proteins different from those expressed in control animals in the CA1 subfield. These results suggest that bifemelane may protect neuronal cells against ischemic injuries through molecular mechanisms associated with prolongation of the potentiation of AP1 binding in the vulnerable CA1 subfield after ischemia.
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PMID:Prolongation by bifemelane of potentiation of AP1 DNA binding in hippocampal CA1 subfield of gerbils with transient forebrain ischemia. 951 1

The involvement of serine/threonine protein phosphatases in signaling pathways that control the expression of the cyclooxygenase-2 (COX-2) gene in human chondrocytes was examined. Okadaic acid (OKA), an inhibitor of protein phosphatases 1 (PP-1) and 2A (PP-2A), induced a delayed, time-dependent increase in the rate of COX-2 gene transcription (runoff assay) resulting in increased steady-state mRNA levels and enzyme synthesis. The latter response was dose dependent over a narrow range of 1-30 nmol/L with declining expression and synthesis of COX-2 at higher concentrations due to cell toxicity. The delayed increase in COX-2 mRNA expression was accompanied by the induction of the proto-oncogenes c-jun, junB, junD, and c-fos (but not FosB or Fra-1). Increased phosphorylation of CREB-1/ATF-1 transcription factors was observed beginning at 4 h and reached a zenith at 8 h. Gel-shift analysis confirmed the up-regulation of AP-1 and CRE nuclear binding proteins, though there was little or no OKA-induced nuclear protein binding to SP-1, AP-2, NF-kappaB or NF-IL-6 regulatory elements. OKA-induced nuclear protein binding to 32P-CRE oligonucleotides was abrogated by a pharmacological inhibitor of protein kinase A (PKA), KT-5720; the latter compound also inhibited OKA-induced COX-2 enzyme synthesis. Calphostin C (CalC), an inhibitor of PKC isoenzymes, had little effect in this regard. Inhibition of 12P-CRE binding was also observed in the presence of an antibody to CREB-binding protein (265-kDa CBP), an integrator and coactivator of cAMP-responsive genes. The binding to 32P-CRE was unaffected in the presence of excess radioinert AP-1 and COX-2 NF-IL-6 oligonucleotides, although a COX-2 CRE-oligo competed very efficiently. 32P-AP-1 consensus sequence binding was unaffected by incubation of chondrocytes with KT-5720 or CalC, but was dramatically diminished by excess radioinert AP-1 and CRE-COX-2 oligos. Supershift analysis in the presence of antibodies to c-Jun, c-Fos, JunD, and JunB suggested that AP-1 complexes were composed of c-Fos, JunB, and possibly c-Jun. OKA has no effect on total cellular PKC activity but caused a delayed time-dependent increase in total PKA activity and synthesis. OKA suppressed the activity of the MAP kinases, ERK1/2 in a time-dependent fashion, suggesting that the Raf-1/MEKK1/MEK1/ERK1,2 cascade was compromised by OKA treatment. By contrast, OKA caused a dramatic increase in SAPK/JNK expression and activity, indicative of an activation of MEKK1/JNKK/SAPK/JNK pathway. OKA stimulated a dose-dependent activation of CAT activity using transfected promoter-CAT constructs harboring the regulatory elements AP-1 (c-jun promoter) and CRE (CRE-tkCAT). We conclude that in primary phenotypically stable human chondrocytes, COX-2 gene expression may be controlled by critical phosphatases that interact with phosphorylation dependent (e.g., MAP kinases:AP-1, PKA:CREB/ATF) signaling pathways. AP-1 and CREB/ATF families of transcription factors may be important substrates for PP-1/PP-2A in human chondrocytes.
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PMID:Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. 962 Jan 67

Cystatin A, a cysteine proteinase inhibitor, is one of the precursor proteins of cornified cell envelope of keratinocytes and is expressed during the late stage of keratinocyte differentiation. We have isolated and characterized the human cystatin A gene. The cystatin A gene consists of three exons and two introns. The first, the second, and the third exons consist of coding sequences that are 66, 102, and 126 base pairs in length, respectively. The first and the second introns consist of 14 and 3.6 kilobase pairs, respectively. The transcription initiation site was located 55 base pairs upstream from the first translation site. The fragment, +77 to -2595 in the 5'-flanking region of the human cystatin A gene, was subcloned into a chloramphenicol acetyltransferase (CAT) reporter vector. The expression vector, p2672CAT, produced a significant CAT activity in transiently transfected SV40-transformed human keratinocytes (SVHK cells), that were further stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent protein kinase C activator. Sequence analysis of the gene detected three TPA responsive elements (TRE-1, TRE-2, and TRE-3) and one AP-2 site on the 5' upstream promoter region. Deletion analyses of the p2672CAT vector demonstrated that TRE-2, which was located between -272 and -278, was critical for the regulation by TPA. Gel shift analyses revealed that c-Jun, JunD, and c-Fos bound to the TRE-2 region and that the p2672CAT activity level was elevated by co-transfection with c-Jun and c-Fos or with JunD and c-Fos expression vectors. Furthermore, co-transfection of SVHK cells with the protein kinase C-alpha expression vector and the p2672CAT expression vector also resulted in an increased CAT activity. These results indicate that the 5'-flanking region of the human cystatin A gene confers promoter activity and contains a TRE (TRE-2) that mediates, at least in part, the enhanced expression of this gene by TPA.
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PMID:Structure and transcriptional regulation of the human cystatin A gene. The 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element-2 site (-272 to -278) on cystatin A gene is critical for TPA-dependent regulation. 965 21


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