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

Some growth factor-induced genes, such as the c-fos gene, are activated rapidly and transiently without intervening protein synthesis. Others, like the rat transin gene, are activated more slowly but more durably and their activation requires prior protein synthesis. It is tempting to speculate that certain rapidly-activated genes code for transcription factors which interact directly with promoter regions of genes like the transin gene to trigger their expression. Unfortunately, little is known about the majority of primary response genes to support this hypothesis. The proto-oncogene c-jun codes for the transcription factor AP-1 or a closely related protein. We show that epidermal growth factor stimulates transcription of the c-jun gene in fibroblasts as a primary response. This supports the notion that increased expression of genes encoding transcription factors is an important element of the signal transduction mechanism, assuring the long-term transcriptional response of cells to growth factors.
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PMID:Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. 313 98

Gene expression is modulated by the specific interactions of nuclear proteins with unique regulatory sequences in the genome. Proteins involved in transcriptional regulation seem to be either transcription factors or transcription modulators and their interactions are crucial in determining whether the expression of a specific gene is activated or repressed. Recently, the product of the proto-oncogene jun has been identified as the transcription factor AP-1, whereas nuclear oncoproteins fos and myc have been implicated in transcriptional transregulation of several promoters. Furthermore, the products of the fos and jun proto-oncogenes are associated in some transcription complexes. Although the nature of the association is unclear, the two proteins co-immunoprecipitate with fos antibodies in nuclear extracts. Here, we report studies that demonstrate that the fos protein directly modulates jun function by means of a heterodimer of fos and jun proteins. The fos 'leucine zipper' domain is necessary for the DNA binding of the heterodimer; a distinct domain, localized in the C-terminal region of the fos protein, is responsible for transcriptional regulation.
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PMID:Direct interaction between fos and jun nuclear oncoproteins: role of the 'leucine zipper' domain. 314 19

Induction of differentiation of F9 teratocarcinoma stem cells by retinoic acid and cAMP has been shown to involve the activation of the transcription factor AP-1 (a heterodimer of the proto-oncogene products c-Fos and c-Jun); moreover, stable expression of either Fos or Jun drives F9 cells into differentiation. Phorbol ester tumor promoters and short-wave-length ultraviolet (uv) irradiation are efficient inducers of AP-1 activity in various differentiated cells, but it has been shown that phorbol esters do not induce AP-1 activity in undifferentiated F9 cells. We examine here whether uv irradiation induces AP-1 activity in these cells and drives F9 cells into differentiation. We show that uv induces, in contrast to phorbol esters, the formation of active AP-1 by activating transcription from the c-jun gene. Ultraviolet-induced AP-1 drives transcription from AP-1-dependent promoters coding for differentiation-associated proteins (such as urokinase and keratin 18). However, in uv-treated cells, these genes are activated earlier and to a greater extent than in cells treated with retinoic acid and cAMP. More importantly, uv, in contrast to retinoic acid and cAMP, does not induce the accumulation of collagen alpha 1 (IV) and laminin B1 RNA. Our data suggest that the c-jun gene in F9 cells is accessible to immediate activation, but that uv-induced AP-1 activation does not suffice to induce the full program of F9 cell differentiation.
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PMID:Ultraviolet irradiation, although it activates the transcription factor AP-1 in F9 teratocarcinoma stem cells, does not induce the full complement of differentiation-associated genes. 752 41

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

Human papillomavirus (HPV) type 16 and 18 viral genomes are frequently detected in cervical and penile cancer biopsies. Although this strongly suggests a prominent role for HPV infection in the development of genital cancer, other genetic or environmental factors are also involved. Genital cancer is postulated to result from loss of cellular control functions, which leads to an unregulated expression of HPV oncogenic proteins. In our study, we determined the trans-activating properties of nuclear proto-oncogene proteins c-Fos, c-Jun and c-Myc on P97 enhancer/promoter activity of HPV16. Using a CAT-reporter construct containing the HPV16 enhancer/promoter element, we investigated the trans-activating effects of c-Fos, c-Jun, c-Myc, and E2 in cervical HT-3 cells. c-Fos and c-Jun overexpression resulted in a 3.3- and 3.1-fold up-regulation of CAT activity. Only 2-fold induction was determined by co-transfection with c-myc and the viral transcription factor E2. Based on these findings, we investigated the expression of HPV DNA (16 and 18) as well as nuclear proto-oncogenes (c-fos, c-jun and c-myc) in nine cervical cancers by in situ hybridisation. In six out of nine carcinomas, HPV16 and/or HPV18 DNA was detectable. All tumours showed an intense and homogeneous expression of c-fos and c-jun mRNA, while the signal for c-myc was detectable only in four specimens. These data suggest that deregulation of nuclear proto-oncogene expression may contribute to an overexpression of HPV-derived oncogenic proteins (E6 and E7), which is generally hypothesised to be an important step in the malignant transformation of HPV-associated tumours.
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PMID:Nuclear proto-oncogene products transactivate the human papillomavirus type 16 promoter. 773 93

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

The proto-oncogene c-fos encodes a nuclear protein that forms together with c-Jun or other members of the Jun family the transcription factor AP-1. The c-fos gene is inducible by UV radiation and other DNA damaging treatments which may indicate that it is required in defence against DNA damaging agents. To address this hypothesized function of c-Fos, we have compared the response of mouse fibroblasts deficient in c-Fos with the corresponding wild-type cells towards the genotoxicity of UV radiation. It is shown here that lack of c-Fos renders cells hypersensitive to the cytotoxic effect of UV light and gives rise to significant increases of UV-induced chromosomal mutations and DNA breakage. Cells lacking c-Fos were basically able to perform UV-induced repair replication, as measured by unscheduled DNA synthesis. However, with high doses of UV c-Fos deficient cells proved to be less efficient in repair synthesis than wild-type cells. Measurement of overall DNA synthesis after UV irradiation revealed that cells deficient in c-Fos are more inhibited in their recovery from the UV-induced block to replication. These data strongly suggest that c-Fos is involved in regulating the timing of DNA replication after UV irradiation by abolition of the UV-induced block to replication and thus appears to play a decisive role in the cellular defence against the genotoxic effects induced by UV radiation.
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PMID:c-Fos is involved in the cellular defence against the genotoxic effect of UV radiation. 776 97

Pancreatic beta-cell-type-specific transcription of the insulin gene is principally controlled by trans-acting factors which influence insulin control element (ICE)-mediated expression. The ICE activator is composed, in part, of the basic helix-loop-helix proteins E12, E47, and E2-5 encoded by the E2A gene. Previous experiments showed that ICE activation in beta cells was repressed in vivo by the c-jun proto-oncogene (E. Henderson and R. Stein, Mol. Cell. Biol. 14:655-662, 1994). Here we focus on the mechanism by which c-Jun inhibits ICE-mediated activation. c-Jun was shown to specifically repress the transactivation potential of the E2A proteins. Thus, we found that the activity of GAL4:E2A fusion constructs was inhibited by c-Jun. The transrepression capabilities of c-Jun were detected only in pancreatic islet cell lines that contained a functional ICE activator. Repression of GAL4:E2A was mediated by the basic leucine zipper regions of c-Jun, which are also the essential regions of this protein necessary for controlling ICE activator-stimulated expression in vivo. The specific target of c-Jun repression was the transactivation domain (located between amino acids 345 and 408 in E12 and E47) conserved in E12, E47, and E2-5. In contrast, the activation domain unique to the E12 and E47 proteins (located between amino acids 1 and 99) was unresponsive to c-Jun. Our results indicate that c-Jun inhibits insulin gene transcription in beta cells by reducing the transactivation potential of the E2A proteins present in the ICE activator complex.
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PMID:c-jun inhibits insulin control element-mediated transcription by affecting the transactivation potential of the E2A gene products. 786 33

The transactivating function of the c-Jun proto-oncogene component of the AP-1 transcription factor is acutely regulated by a wide variety of cellular signals via modulation of phosphorylation of two serines (63 and 73). The viral oncoprotein, v-Jun, while containing homologous serines, is not phosphorylated in cells. A novel family of stress-activated protein kinases (SAPKs), also termed Jun N-terminal domain kinases (JNKs), are responsible for mediating S63/73 phosphorylation in response to a variety of cellular stimuli including tumor necrosis factor-alpha, heat stress and u.v. light. The p54 alpha 1, alpha 2, p54 beta and p46 beta SAPKs are shown to bind directly to c-Jun but not to v-Jun, with an absolute requirement for c-Jun amino acids 31-47, a region deleted in v-Jun. Inactive SAPKs tightly bind c-Jun in resting cells and may be a manifestation of the 'delta' inhibitor, a previously described repressor of c-Jun function.
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PMID:Stress-activated protein kinases bind directly to the delta domain of c-Jun in resting cells: implications for repression of c-Jun function. 789 27

Single ultraviolet (u.v.) irradiation of mammalian cells in culture evokes the transcriptional activation of various proto-oncogenes, among them members of the fos/jun family which are known to play an important role in cell proliferation and differentiation. u.v. exposure of mammalian skin results in growth arrest and cell death followed by hyperproliferation of epidermal cells. To obtain information in vivo about a possible relationship between u.v.-induced proto-oncogene expression and cellular alterations, we have analysed the expression of c-fos, fosB, c-jun, junB, bcl-2 and bax in rat epidermis after single and chronic u.v. irradiation. We present data demonstrating that the transcripts of these genes are constitutively expressed in the epidermis and that expression is differentially modulated by u.v. exposure. Single u.v. irradiation causes a rapid and sustained increase in c-jun, junB and c-fos mRNA and a decline in bcl-2 transcripts, whereas expression of bax remained unchanged. c-Fos and c-Jun immunoreactivity was localized throughout the epidermal cell layers 1.5 h after single irradiation, but restricted to basal cells at 48 h suggesting an involvement in both u.v.-induced apoptosis and hyperproliferation. 48 h after chronic exposure a significantly higher induction and a totally different pattern of epidermal proto-oncogene expression was detectable which may be associated with malignancy. Superfusion of rat skin with c-fos antisense oligodeoxynucleotides inhibited the increase in c-Fos immunolabeled epidermal cells 1.5 h after single u.v. irradiation demonstrating that antisense oligodeoxynucleotides are capable of penetrating mammalian skin and modulating the u.v. response in vivo. However, suppression of the early c-Fos activation did not significantly affect the formation of sunburn cells in the u.v.-exposed epidermis. Thus, c-Fos does not seem to play a major role in u.v.-induced apoptosis or other members of the fos/jun family may compensate for a loss in c-Fos.
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PMID:Differential regulation of c-fos, fosB, c-jun, junB, bcl-2 and bax expression in rat skin following single or chronic ultraviolet irradiation and in vivo modulation by antisense oligodeoxynucleotide superfusion. 793 45


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