Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial LPS stimulation of murine macrophages leads to increased tyrosine phosphorylation and activation of the 42- and 44-kDa mitogen-activated protein kinases (MAPK) and the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinase (JNK) and p38, related to the high osmolarity glycerol protein kinase in Saccharomyces cerevisiae (HOG1). LPS caused a rapid increase (10 min) in phosphotransferase activity toward myelin basic protein (MBP), a polypeptide that encompassed the first 169 residues of c-Jun fused to gluthathione S-transferase (GST-c-Jun (1-169)) and 27-kDa heat shock protein (hsp27). MonoQ fractionation of cell extracts resolved phosphotransferase activity peaks toward MBP, GST-c-Jun (1-169), and hsp27, which contained MAPK, SAPK/JNK, and MAPKAPK2, respectively, as indicated by immunoblotting data. In RAW 264.7 macrophages, LPS stimulation of MAPKAPK2, a substrate of p38 HOG1 and MAPK, appeared to occur predominantly via p38 HOG1 and not the MAPK. PMA, which activated the MAPK as potently as LPS, did not strongly activate MAPKAPK2, as assessed by hsp27 phosphorylation. Consistent with p38 HOG1-mediating LPS activation of MAPKAPK2, treatment with LPS, but not PMA, increased the tyrosine phosphorylation of p38 HOG1, a modification known to elevate the enzymatic capacity of this kinase. In LPS-treated cells, the activity of SAPK/JNK was increased 5- to 10-fold, as measured by precipitating SAPK/JNK with Abs or immobilized GST-c-Jun and performing an in vitro kinase assay. In addition, the kinases thought to be upstream of SAPK/JNK, SAPK/ERK kinase 1 (SEK1), and MAPK/ERK kinase kinase 1 (MEKK1), were activated following LPS, but not PMA, exposure (5-fold and 2.5-fold, respectively.
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PMID:Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. 866 21

We have previously reported that carbon tetrachloride (CCI4) stimulates c-fos, c-jun, and Ca(2+)-activated neutral protease gene expression in rat hepatic tissue (Zawaski et al., Biochem. Biophys. Res. Comm. 197, 585-590, 1993). The proteins c-Fos and c-Jun constitute inducible transcription factors in signal transduction and regulate the transcriptional activation of a battery of genes involved in cell growth and division. The present study was initiated to characterize the role of cytochrome P450 expression and metabolic activation on the magnitude of immediate-early (i.e. c-fos and c-jun) gene expression. Animals were treated either with diallyl sulfide, N-acetylcysteine, pyridine, or phenobarbital before treatment with CCI4. Total and poly(A)+ RNA were isolated, and c-fos and c-jun mRNA levels were analyzed by Northern blot and reverse transcriptase-polymerase chain reaction analyses. Treatment of animals with CCI4 increased c-fos and c-jun mRNA levels from below the limit of detection in control tissue to intense bands within 30 min of treatment, with maximal expression monitored at 1 and 2 hr posttreatment. Treatment of animals with diallyl sulfide alone also elevated c-fos and c-jun mRNA expression to detectable levels. However, pretreatment of animals with diallyl sulfide before treatment with CCI4 produced a 76-92% decrease in c-fos and c-jun mRNA levels, relative to that monitored for CCI4-treated animals. Pretreatment with N-acetylcysteine did not affect c-fos or c-jun mRNA levels and diminished CCI4-stimulated c-fos and c-jun gene expression by 44 and 55%, respectively, relative to the immediate-early gene mRNA levels monitored in the hepatic tissue of CCI4-treated animals. Pretreatment of animals with the CYP2E1 inducer pyridine for 24 hr had only a marginal effect on c-fos mRNA levels, but increased CCI4-stimulated c-fos and c-jun mRNA levels by an additional approximately 2- to approximately 4-fold over those monitored in the uninduced hepatic tissue of CCI4-treated animals. Whereas phenobarbital treatment alone enhanced c-fos expression only marginally, CCI4 treatment of phenobarbital-pretreated animals increased c-fos expression by up to an additional approximately 8-fold and c-jun mRNA levels by up to an additional approximately 5-fold over the respective levels monitored in the hepatic tissue of CCI4-treated animals. Enhanced CYP2E1 or CYP2B1/2B2 levels after treatment with pyridine or phenobarbital elevated c-fos mRNA over untreated controls. This increase was marginal, however, and detectable only with reverse transcriptase-polymerase chain reaction. Examination of nuclear levels of the heterodimeric c-Fos and c-Jun AP-1 transcription factor complex revealed a time-dependent increase in AP-1 levels. AP-1 transcription factor binding was confirmed using competitor consensus sequences and antibody supershifts. Nuclear levels of NF-kappa B, a transcription factor complex implicated in hepatocyte proliferation and apoptotic or programmed cell death, were also examined. NF-kappa B, which consists of the p50 and p65/Rel A polypeptides, was increased in hepatic nuclear extracts at 2 and 24 hr after CCI4 administration, with a concomitant decrease in the p50 polypeptide. Thus, the magnitude of CCI4 stimulation of the immediate-early genes c-fos and c-jun is dependent on metabolic activation by the P450s, and the magnitude of the effect is dependent on the levels and isozyme composition of P450s in the tissue. Furthermore, nuclear transcription factor levels of AP-1 and NF-kappa B are elevated in response to this toxicant.
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PMID:Cytochrome P4502E1- and cytochrome P4502B1/2B2-catalyzed carbon tetrachloride metabolism: effects on signal transduction as demonstrated by altered immediate-early (c-Fos and c-Jun) gene expression and nuclear AP-1 and NF-kappa B transcription factor levels. 882 85

Abasic sites in DNA are generated either spontaneously or after removal of altered bases during the base excision repair process. These as well as 3' damaged ends of DNA at single-strand breaks induced by reactive oxygen species are repaired by AP-endonucleases. The major human AP-endonuclease (named APE-1) has two unrelated activities. It may function as an activator of c-Fos and c-Jun transcription factors and as a repressor of the parathyroid hormone (PTH) gene by binding to the negative Ca(2+)-response elements (nCaRE) in its promoter. Preliminary studies indicate that the h-APE-1 gene is highly regulated. Analysis of its promoter activity by transient expression of the luciferase reporter gene in human, HeLa and TK6 cells suggested the presence of a negative regulatory element in the promoter. Two nCaRE-like sequences were identified in the promoter segment responsible for inhibiting reporter gene expression. Competitive electrophoretic mobility shift assay with HeLa nuclear extract indicated that the nCaRE sequences of the APE-1 and PTH genes are recognized by the APE-1 polypeptide. These results suggest that the APE-1 gene may be down-regulated by its own product.
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PMID:Negative regulation of the major human AP-endonuclease, a multifunctional protein. 894 27

Peripheral axotomy of adult rat sensory neurons causes induction of the transcription factor c-Jun and increased expression of the neuropeptides vasoactive intestinal polypeptide (VIP), galanin and neuropeptide Y. To determine whether VIP induction is dependent on transcriptional regulation by c-Jun, we exploited the fact that c-Jun and VIP are also induced in cultured sensory neurons. We blocked c-Jun synthesis by microinjecting antisense oligonucleotides and found that VIP expression, determined by quantitative immunofluorescence, was specifically reduced. Blockade of c-June expression also resulted in reduced neuropeptide Y expression but left galanin, substance P and calcitonin gene-related peptide unaffected. Since in vitro electrophoretic mobility shift assays showed that a nominal cyclic AMP responsive element (CRE) associated with the rat VIP gene could bind c-Jun-containing transcription factor complexes, we next investigated whether VIP expression in sensory neurons might depend on transcription factor binding to the CRE. When a DNA plasmid containing multiple copies of the CRE was injected into newly cultured sensory neurons to sequester transcription factors binding the endogenous CRE, there was a selective reduction in VIP expression. VIP induction in sensory neurons therefore probably results from transcriptional activation by c-Jun acting in combination with other factor(s), possibly acting through the CRE. These results show that c-Jun can regulate transcription of other genes affected by axotomy and imply that it could be a key regulator of the neuronal axotomy response.
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PMID:Regulation of VIP and other neuropeptides by c-Jun in sensory neurons: implications for the neuropeptide response to axotomy. 899 97

Pituitary adenylate-cyclase-activating polypeptide (PACAP) has been shown to possess mitogenic activity in various tumor cells. The present study was designed to investigate signal transduction mechanisms and expression of the proto-oncogenes c-fos and c-jun linked to the mitogenic effect of PACAP in the pancreatic carcinoma cell line AR4-2J. PACAP-(1-27)-peptide and PACAP-(1-38)-peptide, but not the structurally related vasoactive intestinal polypeptide (VIP), potently stimulated [3H]thymidine incorporation and cell number at doses of 0.1-10 nM. Both molecular forms of PACAP strongly increased formation of cAMP and inositol trisphosphate, elevated cytosolic Ca2+ levels and induced mitogen-activated protein (MAP) kinase activity. Quantitative reverse-transcription PCR revealed that PACAP-(1-27)-peptide and PACAP-(1-38)-peptide elevated c-fos mRNA levels 50-100-fold, whereas c-jun mRNA levels increased only moderately (2-3-fold). The effect of PACAP on c-fos and c-jun expression in AR4-2J cells was rapid (20 min), transient (1-2 h), dose-dependent IC50, 0.5 nM) and was abolished by the specific PACAP receptor antagonist PACAP-(6-38)-peptide or inhibitors of protein kinase C or tyrosine kinases. Compared with PACAP, epidermal growth factor and gastrin equipotently stimulated c-fos transcription whereas VIP, secretin, forskolin or phorbolester showed only marginal effects. Both PACAP (1-27)-peptide and PACAP-(1-38)-peptide strongly increased the DNA binding activity of the c-fos/ c-jun heterodimer transcription factor AP-1 at 10 nM and also stimulated AP-1 transcriptional activity up to 20-fold in AR4-2J cells. These findings indicate that the mitogenic effect of PACAP mediated via activation of the GTP-binding protein coupled PACAP/VIP-1 (PV1) receptor is linked to the MAP kinase cascade, increased expression of the proto-oncogenes c-fos and c-jun and activation of the heterodimeric transcription factor AP-1.
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PMID:Pituitary adenylate-cyclase-activating polypeptide stimulates proto-oncogene expression and activates the AP-1 (c-Fos/c-Jun) transcription factor in AR4-2J pancreatic carcinoma cells. 902 70

Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms.
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PMID:Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. 919 36

We have cloned a novel protein kinase from human cerebellum and named it LZK (leucine zipper-bearing kinase). The LZK cDNA encoded a 966-amino acid polypeptide that contains a kinase catalytic domain and double leucine/isoleucine zippers separated by a short spacer region. The amino acid sequence of the kinase catalytic domain was a hybrid between those in serine/threonine and tyrosine protein kinases, indicating that LZK belongs to the subfamily of the mixed lineage kinase (MLK) family. The kinase catalytic domain of LZK was most similar to DLK (Holtzman, L. B., Merritt, S.E., and Fan, G. (1994) J. Biol. Chem. 269, 30808-30817), MUK (Hirai, S., Izawa, M., Osada, S., Spyrou, G., and Ohno, S. (1996) Oncogene 12, 641-650), and ZPK (Reddy, U. R., and Presure, D. (1994) Biochem. Biophys. Res. Commun. 202, 613-620), which belong to the same subfamily of the MLK family. However, besides the kinase catalytic domain and double leucine/isoleucine zippers, there was no significant homology with known proteins. The recombinant LZK autophosphorylated in the presence of ATP and divalent cations, and exhibited serine/threonine kinase catalytic activity. Northern blot analysis revealed that LZK is expressed most strongly in the pancreas, with a pattern that differs from other MLKs. Expression of LZK in COS7 cells induced phosphorylation of c-Jun and activation of JNK-1, indicating the association of LZK in the c-Jun amino-terminal kinase/stress-activated protein kinase pathway. The expressed LZK was detected primarily in the membrane fraction, suggesting that LZK interacts with other cellular components in vivo.
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PMID:Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. 935 28

The alpha chain of the nascent polypeptide-associated complex (alpha-NAC) coactivator was shown to potentiate the activity of the homodimeric c-Jun activator, while transcription mediated by the c-Fos/c-Jun heterodimer was unaffected. The use of deletion mutants in pull-down assays revealed that alpha-NAC interacted with amino acids 1 to 89 of the c-Jun protein and that the coactivator could interact with both the unphosphorylated and the serine 73-phosphorylated form of c-Jun. N-terminal-deleted c-Jun protein failed to interact with alpha-NAC in mammalian two-hybrid assays, while mutant c-Jun proteins lacking the leucine zipper or the basic domain retained interaction with alpha-NAC in vivo. Kinetics studies with purified c-Jun homodimer and recombinant alpha-NAC proteins allowed determination of the mechanism of coactivation by alpha-NAC: the coactivator stabilized the AP-1 complex formed by the c-Jun homodimer on its DNA recognition sequence through an eightfold reduction in the dissociation constant (kd) of the complex. This effect of alpha-NAC was specific, because alpha-NAC could not stabilize the interactions of JunB or Sp1 with their cognate binding sites. Interestingly, the expression of alpha-NAC was first detected at 14.5 to 15 days postconception, concomitantly with the onset of ossification during embryogenesis. The alpha-NAC protein was specifically expressed in differentiated osteoblasts at the centers of ossification. Thus, the alpha-NAC gene product exhibits the properties of a developmentally regulated, bone-specific transcriptional coactivator.
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PMID:Bone-specific expression of the alpha chain of the nascent polypeptide-associated complex, a coactivator potentiating c-Jun-mediated transcription. 948 46

Vascular endothelial cells are important in a variety of physiological and pathophysiological processes. The growth and functions of vascular endothelial cells are regulated both by soluble mitogenic and differentiation factors and by interactions with the extracellular matrix; however, relatively little is known about the role of the matrix. In the present study, we investigate whether integrin-mediated anchorage to a substratum coated with the extracellular matrix protein fibronectin regulates growth factor signaling events in human endothelial cells. We show that cell adhesion to fibronectin and growth factor stimulation trigger distinct initial tyrosine phosphorylation events in endothelial cells. Thus, integrin-dependent adhesion of endothelial cells leads to tyrosine phosphorylation of both focal adhesion kinase and paxillin, but not of several growth factor receptors. Conversely, EGF stimulation causes receptor autophosphorylation, with no effect on focal adhesion kinase or paxillin tyrosine phosphorylation. Adhesion to fibronectin, in the absence of growth factors, leads to activation of MAPK. In addition, adhesion to fibronectin also potentiates growth factor signaling to MAPK. Thus, polypeptide growth factor activation of MAPK in anchored cells is far more effective than in cells maintained in suspension. Other agonists known to activate MAPK were also examined for their ability to activate MAPK in an anchorage-dependent manner. The neuropeptide bombesin, the bioactive lipid lysophosphatidic acid (LPA), and the cytokine tumor necrosis factor alpha, which signal through diverse mechanisms, were all able to activate MAPK to a much greater degree in fibronectin-adherent cells than in suspended cells. In addition, tumor necrosis factor alpha activation of c-Jun kinase (JNK) was also much more robust in anchored cells. Together, these data suggest a cooperation between integrins and soluble mitogens in efficient propagation of signals to downstream kinases. This cooperation may contribute to anchorage dependence of mitogenic cell cycle progression.
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PMID:Integrin-mediated signaling events in human endothelial cells. 969 60

Mixed lineage kinase-3 (MLK-3) is a mitogen-activated kinase kinase kinase that mediates stress-activating protein kinase (SAPK)/c-Jun NH2-terminal kinase activation. MLK-3 and other MLK family kinases are characterized by the presence of multiple protein-protein interaction domains including a tandem leucine/isoleucine zipper (LZs) motif. Leucine zippers are known to mediate protein dimerization raising the possibility that the tandem leucine/isoleucine zippers may function as a dimerization motif of MLK-3. Using both co-immunoprecipitation and nonreducing SDS-polyacrylamide gel electrophoresis, we demonstrated that MLK-3 forms disulfide bridged homo-dimers and that the LZs motif is sufficient for MLK-3 homodimerization. We next asked whether MLK-3 utilizes a dimerization-based activation mechanism analogous to that of receptor tyrosine kinases. We found that dimerization via the LZs motif is a prerequisite for MLK-3 autophosphorylation. We then demonstrated that co-expression of Cdc42 lead to a substantial increase in MLK-3 dimerization, indicating that binding by this GTPase may induce MLK-3 dimerization. Moreover, the LZs minus form of MLK-3 failed to activate the downstream target SAPK, and expression of a MLK-3 LZs polypeptide was found to block SAPK activation by wild type MLK-3. Taken together, these findings indicate that dimerization plays a pivotal role in MLK-3 activation.
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PMID:Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. 982 70


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