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)

Among the murine Jun family of transcription factors, c-Jun and JunD are closely-related proteins with similar dimerization, DNA binding and transactivating properties. However, when expressed from a self-replicating retroviral RCAS vector, c-jun, but not junD, transforms chick embryo fibroblasts. We attempted to map the regions of c-jun which are important for transformation by constructing hybrids between c-jun and junD. Using common restriction sites, we prepared six different chimeric molecules. All of these c-jun:junD hybrids code for transactivators of AP1-containing promoters. An N-terminal segment of 79 amino acids of c-Jun converts JunD into a strong transforming protein, while other segments of c-Jun contribute to a lesser extent. Contrary to what has been reported with rat embryo fibroblasts, a c-Jun derivative with serines substituted by alanines in positions 63 and 73 still transforms CEFs efficiently.
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PMID:In vitro transforming capacities of mouse c-jun:junD chimeric genes. 833 52

Hypoxic and ischemic stresses cause a series of well documented changes in myocardial cells and tissues, including increased anaerobic glycolysis, loss of contractility, changes in lipid and fatty acid metabolism, and eventual irreversible membrane damage and cell death. In this article we describe changes in the expression and regulation of the proto-oncogenes fos and jun in cardiac myocytes exposed to severe hypoxia. The mRNAs encoding c-Fos, c-Jun, Jun-D, and Jun-B were induced within 1 h of exposure to hypoxia, increased 5-10-fold between 1 and 4 h and then declined. These inductions coincided with loss in myocyte contractility but occurred before there was irreversible cell damage or significant ATP loss. Immunostaining with anti-Fos and anti-Jun antibodies revealed the accumulation of these proteins in hypoxic cell nuclei. Pre-treatment of cells with protein kinase inhibitors significantly repressed the response at the mRNA level. We propose that hypoxic stress in these cells activates signal transduction pathways, possibly involving protein kinases, that result in the inductions of fos and jun gene families. Therefore AP1 may regulate myocardial adaptive responses to hypoxia in advance of energy depletion, cell damage, or reoxygenation.
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PMID:Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. 834 64

The 5' region of the acetylcholinesterase gene from the electric ray Torpedo californica has been cloned and its cap site identified. The 5' untranslated region is divided into two exons where a small exon extending between bp -22 to -60 is alternatively spliced. Cap sites are defined at two positions, bp -138 and -143. Twenty-one base pairs 5' of the -143 cap site a repeating TATA sequence is found. Further upstream in the gene consensus sequences for Sp1, AP1, and AP2 factors are evident. The promoter region of the acetylcholinesterase gene enhances transcription of a luciferase reporter gene transfected into C2 myoblasts. However, increased transcription was not evident after C2 myoblasts were induced to form myotubes. Cotransfection of this construct with c-Jun (AP1) and AP2 expression vectors shows marked increases of transcription rates in HepG2 and C2 cells. Protein kinase A elicited regulation of expression is also evident in quail fibroblasts. In gel retardation experiments both recombinant c-Jun (AP1) and AP2 proteins bind to the appropriate Torpedo sequences. Cellular extracts from the Torpedo electric organ exhibit AP2 binding activity. Thus, although all facets of specific regulation expected upon differentiation of mammalian muscle cells were not evident, the 5'-flanking region from the Torpedo AChE gene contains consensus sequences and functional promoter elements typical of mammalian nerve and muscle systems.
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PMID:Promoter elements and transcriptional regulation of the acetylcholinesterase gene. 842 73

Treatment of U937 human leukemic cells with the phorbol ester PMA, activates both mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK), stimulates c-Jun phosphorylation and transcriptional activity, and induces a macrophage-like differentiation of U937 cells. The involvement of the MAPK pathway in mediating both the early phosphorylation and transcriptional activation events and the chronic differentiation of U937 cells was examined utilizing constitutively active MAPK kinase (MEK1) mutants. Transient expression of an activated MEK1 construct in U937 cells was found to stimulate MAPK and SAPK activity, as well as enhancing AP1-, SRE- and c-Jun-mediated transcriptional activity. Transient transfection of MAPK phosphatase-1 (MKP-1), a protein phosphatase which preferentially dephosphorylates and inactivates MAPK, inhibited the functional effects of both PMA and the constitutively active MEK1 mutants. To determine whether specific activation of the MEK/MAPK pathway was sufficient to induce hematopoietic differentiation, U937 cell lines were established that conditionally expressed the activated MEK1 mutant under the control of the human IIa metallothionein promoter. The induction of constitutively active MEK1 protein expression resulted in an increase in MEK1 activity, c-Jun and AP-1 transcriptional activity and an inhibition of U937 cell growth. However, this growth inhibition was not accompanied by U937 cell differentiation. These results suggest that a cross-talk mechanism exists between the MAPK and SAPK signal transduction pathways in U937 cells and that PMA-mediated SAPK activation may involve the MAPK pathway. Furthermore, selective activation of the MEK/MAPK pathway utilizing a constitutively active MEK1 mutant, while growth inhibitory, was not sufficient to induce the macrophage-like differentiation of U937 cells.
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PMID:Constitutively active MAP kinase kinase (MEK1) stimulates SAP kinase and c-Jun transcriptional activity in U937 human leukemic cells. 857 Jan 88

The E7 gene product of human papillomavirus type 16 (HPV16) binds to the retinoblastoma gene product (pRb) and dissociates pRb-E2F complexes. However, the observation that the ability of E7 to bind pRb is not required for the HPV16-induced immortalization of primary keratinocytes prompted a search for other cellular factors bound by E7. Using a glutathione-S-transferase (GST) fusion protein system, we show that E7 complexes with AP1 transcription factors including c-Jun, JunB, JunD and c-Fos. The ability of E7 to complex with c-Jun in vivo is demonstrated by co-immunoprecipitation and the yeast two-hybrid system. An analysis of E7 point mutants in the GST system indicates that the E7 zinc-finger motif, but not the pRb binding domain, is involved in these interactions. Using c-Jun deletion mutants, E7 binding maps between amino acids 224 and 286 of c-Jun. E7 trans-activates c-Jun-induced transcription from a Jun responsive promoter, and this activity correlates with the ability of E7 mutants to bind Jun proteins. Finally, a transcriptionally inactive c-Jun deletion, which can bind E7, interferes with the E7-induced transformation of rat embryo fibroblasts in cooperation with an activated ras, indicating that the Jun-E7 interaction is physiologically relevant and that Jun factors may be targeted in the E7 transformation pathway.
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PMID:The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors. 861 42

The p150,95 integrin (CD11c/CD18) mediates leukocyte/endothelium interactions during inflammatory reactions and certain CTL-target interactions, and is also a receptor for fibrinogen, LPS, and the complement component iC3b. CD11c/CD18 is expressed primarily on cells of the myeloid lineage and activated B lymphocytes, and is an important diagnostic marker for hairy cell leukemia. To identify the transcription factors and cis-acting elements involved in the regulated expression of CD11c/CD18 during myeloid cell differentiation and B lymphocyte activation, we have performed structural and functional analysis on the CD11c gene promoter. Electrophoretic mobility shift assays identified an AP-1 binding site (AP1-60) within the proximal promoter region and evidenced differences in the pattern of the Fos family members bound to the AP1-60 element in undifferentiated and differentiated myeloid cells, as well as between B lineage-derived cells. The involvement of the AP1-60 element in DNA-protein interactions was confirmed by means of in vivo footprinting experiments, and its functionality was demonstrated by trans activation of the CD11c promoter by c-Jun. Site-directed mutagenesis of AP1-60 greatly reduced the basal CD11c promoter activity in myeloid and B cells. Furthermore, mutations at AP1-60 inhibited the induction of the CD11c promoter activity during the PMA-triggered U937 cell differentiation, pointing out a key role for the AP-1 transcription factor complex in both the basal and the developmentally regulated expression of the p150,95 leukocyte integrin. The involvement of AP-1 in the transcription of the CD11c gene raises the possibility of altering leukocyte integrin expression by pharmacologic means and will greatly contribute to the characterization of the intracellular signals controlling the expression of leukocyte adhesion molecules.
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PMID:AP-1 regulates the basal and developmentally induced transcription of the CD11c leukocyte integrin gene. 862 14

Among the Jun family of transcription factors, only c-Jun displays full transforming potential in cooperation with activated c-Ha-Ras in primary rat embryo fibroblasts. c-Jun in combination with Ras can both induce foci of transformed cells from rat embryo fibroblast monolayers and promote the establishment of these foci as tumoral cell lines. JunB can also cooperate with Ras to induce foci but is unable to promote immortalization. We report here that JunD, in cooperation with Ras, induces foci with an efficiency similar to that of JunB. Artificial Jun/eb1 derivatives from each of the three Jun proteins were also analyzed. These constructs carry a heterologous homodimerization domain from the viral EB1 transcription factor and are thought to form only homodimers in the cell. We show here that these Jun/eb1 chimeras are potent transactivators of AP1 sites and that they can cooperate with c-Ha-Ras to induce foci. However, among all the Ras-Jun and Ras-Jun/eb1 combinations tested, only foci from Ras-c-Jun can be efficiently expanded and maintained as long-term growing cultures. Therefore, we suggest that a heterodimer containing c-Jun might be required for in vitro establishment of these primary mammalian cells.
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PMID:Stepwise transformation of rat embryo fibroblasts: c-Jun, JunB, or JunD can cooperate with Ras for focus formation, but a c-Jun-containing heterodimer is required for immortalization. 862 54

The AP1 protein c-Jun has previously been shown to stimulate polyomavirus (Py) DNA replication in vivo. In order to define the mechanism, we added purified c-Jun protein to the origin-dependent and large T antigen (LT)-dependent in vitro DNA unwinding assay. c-Jun protein was found to stimulate by approximately 5-fold the unwinding of a 290 bp linear DNA fragment containing both the Py origin and the AP1 recognition sequence to which c-Jun binds. Efficient levels of stimulation were specifically observed at limiting concentrations of LT for unwinding. Under similar conditions, Py DNA replication was stimulated to a comparable extent by AP1 in a purified in vitro replication assay. Mobility shift and DNase I footprinting assays showed that c-Jun stimulates the ATP-dependent binding of LT to the origin core by approximately 7-fold. Furthermore, c-Jun was found to interact directly with LT, but not with replication protein A. The activities of c-Jun to stimulate unwinding and origin binding of LT were found to be harbored within the N-terminal region of c-Jun, which is distinct from the DNA binding domain. We speculate that certain transcription factors may possess specific DNA replication domains that function to stimulate the loading of replication factors at the origin during the initiation of DNA synthesis.
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PMID:c-Jun stimulates origin-dependent DNA unwinding by polyomavirus large Tantigen. 889 57

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

Heterodimerization among the basic-leucine zipper (bZIP) proteins or among the basic-helix-loop-helix-leucine zipper (bHLHZip) proteins confers a multitude of combinational activities to these transcription factors. To further examine the function of the bHLHZip protein, USF, we screened for cellular proteins which could directly interact with USF using the yeast two-hybrid system. A bZip protein, Fra1, was found to efficiently interact with USF. USF specifically interacts with Fra1 but not with other closely related family members, c-Fos, Fra2, FosB, or with c-Jun. Both the bHLHZip and the N-terminal regions of Fra1 are required for efficient interaction with USF. In vivo association between USF and Fra1 has been demonstrated by co-immunoprecipitation. Expression of exogenous USF led to a decrease in AP1-dependent transcription in F9 cells. Co-expression of exogenous Fra1 restored the AP1 activity in a dose-dependent manner. These data show that USF and Fra1 physically and functionally interact demonstrating that cross-talk occurs between factors of distantly related transcription families.
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PMID:Cross-family interaction between the bHLHZip USF and bZip Fra1 proteins results in down-regulation of AP1 activity. 916 Aug 89


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