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)

Polyomavirus middle-sized tumor antigen (MT) increases the expression of c-jun through a phorbol 12-O-tetradecanoate 13-acetate response element in the c-jun promoter. To investigate the cellular signaling pathways affected by MT, we studied the role of the c-Ras and Raf-1 proteins in MT-induced transactivation of c-jun and cell transformation. There was an increase in GTP complexed to Ras in MT-expressing cells, indicating an increase in Ras activity. Coexpression of dominant inhibitory mutants of Ha-ras and raf-1 with MT inhibited MT-mediated transactivation and focus formation. Studies of the phosphorylation of c-Jun showed that MT expression increased the phosphorylation of Ser-63 and Ser-73 in the transactivation domain and decreased the phosphorylation of a peptide containing Ser-243, Ser-249, and Thr-231 in the DNA binding domain. MT increased the transcriptional activating ability of c-Jun but failed to increase the transcriptional activating ability of c-Jun mutants with Ser-63 and Ser-73 changed to nonphosphorylatable Ala, indicating that MT modulates c-Jun activity through phosphorylation. The dominant inhibitory mutants of Ha-ras and raf-1 interfered with the ability of MT to activate c-Jun. The results indicate that MT induces a phosphorylation cascade through the activation of c-Ras and Raf-1 and that c-Jun is one of the downstream targets that may cause changes in gene expression leading to cell transformation.
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PMID:Polyomavirus middle-sized tumor antigen modulates c-Jun phosphorylation and transcriptional activity. 793 38

DNA damage inducing treatment of cultured mammalian cells triggers the activation of transcription factors and the prolongation of the half life of p53. As the earliest event detectable in the nucleus (5 min), AP-1 (c-Jun/c-Fos) is post-translationally modified. Triggering this early event and triggering subsequent transcription factor dependent processes requires extra-nuclear components of signal transduction such as Src, Ras, Raf-1 and MAP-2 kinase. Recent efforts have concentrated on examining whether DNA damage or other secondary effects of the damaging agent generate the signal then passed on to transcription factors. Further, it has been studied whether a pathway of reverse signalling exists that originates in the nucleus and reaches the cell surface. At the cell surface the UV induced signalling chain can be interrupted experimentally. Beyond this step DNA damage and signal transduction induced by phorbol esters and growth factors merge and reach the nuclear proteins through common components.
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PMID:The mammalian UV response: mechanism of DNA damage induced gene expression. 794 83

The indol alkaloid staurosporine is a potent inhibitor of protein kinase C, but has also been shown to have certain effects paradoxically similar to those of protein kinase C-activating phorbol esters. We show here that collagenase mRNA expression is stimulated by 10 nM staurosporine in normal and ras-oncogene-transformed rat fibroblasts. The kinetics of collagenase mRNA induction by staurosporine were slow compared to induction by phorbol ester. Staurosporine induction of the collagenase promoter appeared to be mediated via the TPA response element (TRE). Induction did not involve any increase in jun mRNA expression and did not require expression of c-Jun. Prolonged treatment with phorbol ester to deplete protein kinase C did not inhibit stimulation of the collagenase promoter by staurosporine. Instead, involvement of cAMP-dependent protein kinase (PKA) was indicated by inhibition of staurosporine induction by the PKA inhibitor H-89. In addition, raised levels of cAMP were observed during the first hour of staurosporine treatment. Altogether, our data indicate that staurosporine induces a PKA-dependent pathway leading to c-Jun-independent activation of the collagenase TRE element.
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PMID:Induction of the collagenase phorbol ester response element by staurosporine. 796 79

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytokines with pleiotropic biological activities, exerting a broad range of overlapping biological functions. The redundancy of TNF and IL-1 activities may be based on the utilization of shared key components of intracellular signaling pathways. Two lipid second messengers have been found to transmit TNF and IL-1 intracellular signals: 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C, and ceramide, generated by sphingomyelinase (SMase). DAG is a well established activator of the important signaling system protein kinase C (PKC), which appears to mediate various cellular responses to TNF or IL-1. In addition, it is obvious that DAG also activates other enzyme systems like acidic sphingomyelinase. SMases have been implicated in a number of TNF responses, including stimulation of cell growth and differentiation, as well as triggering cytotoxicity and apoptosis. The metabolic active cleavage product of SMase, ceramide, is a novel multifunctional lipid second messenger capable of inducing various signaling systems. Both cytokines, TNF and IL-1, stimulate a neutral,plasma membrane-associated SMase that leads to stimulation of a protein kinase and eventually to activation of the mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Ceramide is also capable of stimulating a cytosolic protein phosphatase. PKC plays a role in activation of the nuclear transcription factor AP-1, and the DAG-regulated acidic SMase is involved in transducing TNF signals to the cell nucleus via activation of the nuclear transcription factor NF-kappa B.
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PMID:The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. 796 60

JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and Thr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Here we describe the molecular cloning of a second member of the JNK group, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furthermore, JNK protein kinase activation is observed in cells treated with tumor necrosis factor. Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1. This difference in c-Jun phosphorylation correlates with increased binding of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemical properties of these JNK isoforms suggest that they may have different functions in vivo. Evidence in favor of this hypothesis was obtained from the observation that JNK1, but not JNK2, complements a defect in the expression of the mitogen-activated protein kinase HOG1 in the yeast Saccharomyces cerevisiae. Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.
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PMID:Signal transduction by tumor necrosis factor mediated by JNK protein kinases. 796 72

The stress-activated protein kinases (SAPKs), which are distantly related to the MAP kinases, are the dominant c-Jun amino-terminal protein kinases activated in response to a variety of cellular stresses, including treatment with tumour-necrosis factor-alpha and interleukin-beta (refs 1, 2). SAPK phosphorylation of c-Jun probably activates the c-Jun transactivation function. SAPKs are part of a signal transduction cascade related to, but distinct from, the MAPK pathway. We have now identified a novel protein kinase, called SAPK/ERK kinase-1 (SEK1), which is structurally related to the MAP kinase kinases (MEKs). SEK1 is a potent activator of the SAPKs in vitro and in vivo. An inactive SEK1 mutant blocks SAPK activation by extracellular stimuli without interfering with the MAPK pathway. Although alternative mechanisms of SAPK activation may exist, as an immediate upstream activator of the SAPKs, SEK1 further defines a signalling cascade that couples cellular stress agonists to the c-Jun transcription factor.
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PMID:Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. 799 69

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax. Chimeric fusion proteins consisting of the DNA-binding domain of the yeast transcription factor Gal4 and the amino-terminal domain (residues 1 to 66) of ATF3 were able to mediate Tax-dependent transactivation of a Gal4-responsive promoter, which suggests a direct involvement of this region of ATF3. Recombinant fusion proteins of glutathione S-transferase with either the amino- or carboxy-terminal (residues 139 to 181) domain of ATF3 were able to specifically interact with Tax. Furthermore, specific antisera directed against Tax coimmunoprecipitated ATF3 only in the presence of Tax.
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PMID:Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. 800 91

A number of signalling pathways stimulate transcription of target genes through nuclear factors whose activities are primarily regulated by phosphorylation. Cyclic AMP regulates the expression of numerous genes, for example, through the protein kinase-A (PKA)-mediated phosphorylation of transcription factor CREB at Ser 133. Although phosphorylation may stimulate transcriptional activators by modulating their nuclear transport or DNA-binding affinity, CREB belongs to a class of proteins whose phosphorylation appears specifically to enhance their trans-activation potential. Recent work describing a phospho-CREB binding protein (CBP) which interacts specifically with the CREB trans-activation domain prompted us to examine whether CBP is necessary for cAMP regulated transcription. We report here that microinjection of an anti-CBP antiserum into fibroblasts can inhibit transcription from a cAMP responsive promoter. Surprisingly, CBP also cooperates with upstream activators such as c-Jun, which are involved in mitogen responsive transcription. We propose that CBP is recruited to the promoter through interaction with certain phosphorylated factors, and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptor to the transcriptional apparatus.
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PMID:Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. 802 57

Ras proteins exert their mitogenic and oncogenic effects through activation of downstream protein kinases. An important question is how Ras-generated signals reach the nucleus to activate downstream target genes. AP-1, a heterodimeric complex of Jun and Fos proteins, which activates mitogen-inducible genes, is a major nuclear target of Ras. Ras can stimulate AP-1 activity by inducing c-fos transcription, a process which is probably mediated by the ERK1 and -2 mitogen-activated protein (MAP) kinases, which phosphorylate the transcription factor Elk-1/TCF. Besides inducing transcription from fos and jun genes, mitogens and Ras proteins enhance AP-1 activity through phosphorylation of c-Jun. Phosphorylation of the c-Jun activation domain leads to c-jun induction through an autoregulatory loop. Ras- and ultra-violet-responsive protein kinases that phosphorylate c-Jun on serine residues at positions 63 and 73 and stimulate its transcriptional activity have been identified. These proline-directed kinases, termed JNKs, are novel MAP kinases. It is not clear, however, whether c-Jun is the only recipient and JNK the only transducer of the Ras signal to AP-1 proteins. A short sequence surrounding the major JNK phosphorylation site of c-Jun is conserved in c-Fos and is part of its activation domain, suggesting that c-Fos may be similarly regulated. Here we show that Ras does indeed augment the transcriptional activity of c-Fos through phosphorylation at Thr 232, the homologue of Ser 73 of c-Jun. However, this is mediated by a novel Ras- and mitogen-responsive proline-directed protein kinase that is different from JNKs and ERKs. Therefore, at least three types of proline-directed kinases transmit Ras- and mitogen-generated signals to the transcriptional machinery.
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PMID:c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK. 807 47

The mechanisms by which pX, the transactivator of the Hepatitis B Virus (HBV), exerts its effects on transcription of viral and cellular genes have not yet been fully clarified. While previous reports suggested the possibility of a direct interaction of pX, which lacks intrinsic DNA-binding activity, with components of the cellular transcription machinery, more recent investigations support the hypothesis that pX might activate cellular kinases involved in transcriptional regulation and growth control. We analysed the mechanisms of c-Jun transcription factor activation by pX and in particular the role of cellular proteins involved in the transduction of mitogenic signals (namely Ha-Ras and Raf-1). In both HeLa and undifferentiated F9 cells pX was able to increase the activity of exogenous transfected c-Jun but not of c-Jun proteins bearing mutations in the serine residues located in the amino-terminal transcriptional activation domain. We show by use of Ha-Ras and Raf-1 dominant negative mutants that both Ha-Ras and Raf-1 are required for pX-induced activation of c-Jun transcriptional activity. In addition we show that pX is able to cooperate with Raf-1 in c-Jun activation. Our results are consistent with the hypothesis that at least one site of action of pX is peripheral and is located upstream of the Ras genes products.
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PMID:Ras- and Raf-dependent activation of c-jun transcriptional activity by the hepatitis B virus transactivator pX. 808 89


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