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)

Platelet-derived growth factors (PDGFs) specifically bind to PDGF receptors (PDGFRs), resulting in their activation via autophosphorylation and subsequent triggering of a cascade of phosphorylation events that include mitogen-activated protein (MAP) kinases. Most of our knowledge concerning MAP kinase activation comes from studies of cultured cells in vitro, and little is known about their activation in vivo. In the present study, we determined PDGF and PDGFR levels and MAP kinase activities, including extracellular signal-regulated protein kinases (ERK) and c-Jun NH2-terminal protein kinases (JNK) or stress-activated protein kinases (SAPK) in brain of young and older mice. Both PDGF and PDGFR proteins were most abundant in protein extracts from brain (cerebral cortex) among tissues of heart, liver, spleen, lung and kidney, as determined by Western blot analysis. PDGFR proteins in brain differed significantly between young (1 or 8 weeks) and older (14 months) mice and PDGFR phosphorylation was seen in all age groups examined by a specific antibody against phosphotyrosine. The highest activity ERK2 was also observed in brain tissues, and this activity declined with age, although ERK1 and ERK2 protein levels were not significantly altered during development and aging. Furthermore, the activity and amount of JNK/SAPK proteins were the most abundant in brain tissues and did not change with age. Thus, our findings demonstrate that the highest levels of PDGFs and PDGFRs existed in brain, and constitutive activation of MAP kinases declined with age, suggesting that signal pathways mediated by PDGF-MAP kinase cascades are important components in coordinating growth and differentiation of neurone and glial cells during development and aging.
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PMID:Abundance of platelet-derived growth factors (PDGFs), PDGF receptors and activation of mitogen-activated protein kinases in brain decline with age. 947 86

Shp-2 is a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains. A targeted mutant allele of the Shp-2 gene with a deletion of 65 amino acids in the NH2-terminal SH2 domain was created that leads to embryonic lethality at mid-gestation in homozygous mutant mice. To define the Shp-2 function in cell signaling, we have established mutant fibroblast cell lines, and have examined the effect of the Shp-2 mutation on extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. Insulin-like growth factor (IGF)-I-induced ERK activation was completely abolished, while ERK activity upon platelet-derived growth factor and epidermal growth factor stimulation was significantly reduced and shortened in mutant cells. Stimulation of ERK by phorbol 12-myristate 13-acetate was not affected in mutant cells, but the phorbol 12-myristate 13-acetate-induced ERK activity decayed much faster compared with that in wild-type cells. In contrast, JNK activation upon heat shock was significantly enhanced in Shp-2 mutant cells. Based on these results, we conclude that Shp-2 plays differential positive regulatory roles in various mitogenic signaling pathways leading to ERK activation, and that Shp-2 is a negative effector in JNK activation by cellular stress. This is the first evidence that a tyrosine phosphatase has opposite effects in mediating the activation of ERK and JNK MAP kinases.
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PMID:The Shp-2 tyrosine phosphatase has opposite effects in mediating the activation of extracellular signal-regulated and c-Jun NH2-terminal mitogen-activated protein kinases. 947 33

The aim of this study was to elucidate the upstream signaling mechanism that mediates the fluid shear stress activation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinases (ERKs), in vascular endothelial cells (ECs). Our results indicate that p60src is rapidly activated by fluid shear stress in bovine aortic endothelial cells (BAECs). Shear stress induction of the hemagglutinin (HA) epitope-tagged HA-JNK1 and the Myc epitope-tagged Myc-ERK2 was significantly attenuated by v-src(K295R) and c-src(K295R), the kinase-defective mutants ofv-src and c-src, respectively. HA-JNK1 and Myc-ERK2 were activated by c-src(F527), a constitutively activated form of p60src, and the activation was abolished by RasN17, a dominant-negative mutant of p2lras. In contrast, although HA-JNK1 and Myc-ERK2 were also activated by RasL61, an activated form of p21ras, the activation was not affected by v-src(K295R). These results indicate that p60src is upstream to the Ras-JNK and Ras-ERK pathways in response to shear stress. The shear stress inductions of the promoters of monocyte chemotactic protein-1 (MCP-1) and c-fos, driven by TPA-responsive element (TRE) and serum-responsive element (SRE), respectively, were attenuated by v-src(K295R). This attenuation is associated with decreased transcriptional activities of c-Jun and Elk-1, the transcription factors targeting TRE and SRE, respectively. Thus, p60src plays a critical role in the shear stress activation of MAPK pathways and induction of Activating Protein-1 (AP- 1)/TRE and Elk-1/SRE-mediated transcription in ECs.
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PMID:Shear stress activates p60src-Ras-MAPK signaling pathways in vascular endothelial cells. 948 87

Activation of stress-activated protein kinases, including the p38 and the c-Jun NH2-terminal kinases (JNK), have been associated with the onset of cardiac hypertrophy and cell death in response to hemodynamic overload and ischemia/reperfusion injury. Upon infection of cultured neonatal rat cardiac myocytes with recombinant adenoviral vectors expressing a wild type and a constitutively active mutant of MKK7 (or JNKK2), JNK was specifically activated without affecting other mitogen-activated protein kinases, including extracellular signal-regulated protein kinases and p38. Specific activation of the JNK pathway in cardiac myocytes induced characteristic features of hypertrophy, including an increase in cell size, elevated expression of atrial natriuretic factor, and induction of sarcomere organization. In contrast, co-activation of both JNK (by MKK7) and p38 (by MKK3 or MKK6) in cardiomyocytes led to an induction of cytopathic responses and suppression of hypertrophic responses. These data provide the first direct evidence that activation of JNK alone is sufficient to induce characteristic features of cardiac hypertrophy, thereby supporting an active role for the JNK pathway in the development of cardiac hypertrophy. The cytopathic response, as a result of co-activation of both JNK and p38, may contribute to the loss of contractile function and viability of cardiomyocytes following hemodynamic overload and cardiac ischemia/reperfusion injury.
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PMID:Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. 948 59

Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces the matrix metalloproteinases collagenase, 92-kD gelatinase, and stromelysin, which degrade skin connective tissue and may contribute to premature skin aging (photoaging). Pretreatment of skin with all-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism of tRA inhibition of UV induction of matrix metalloproteinases in human skin in vivo. Exposure of human skin in vivo to low doses of UV activated EGF receptors, the GTP-binding regulatory protein p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which bound to the c-Jun promoter and upregulated c-Jun gene expression. Elevated c-Jun, in association with constitutively expressed c-Fos, formed increased levels of transcription factor activator protein (AP) 1, which is required for transcription of matrix metalloproteinases. Pretreatment of human skin with tRA inhibited UV induction of c-Jun protein and, consequently, AP-1. c-Jun protein inhibition occurred via a posttranscriptional mechanism, since tRA did not inhibit UV induction of c-Jun mRNA. These data demonstrate, for the first time, activation of MAP kinase pathways in humans in vivo, and reveal a novel posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin.
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PMID:Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. 950 86

Thyroid gland is known to be higher sensitive to carcinogenic effects of external ionizing radiation (IR) than other tissues. To clarify the cell-specific response following irradiation, activations of c-Jun NH2-terminal kinases (JNKs), which is one of mitogen-activated protein kinases (MAPKs) family members, and extracellular signal-regulated kinase (ERK) were examined in primary cultured human thyroid cells in comparison with human diploid fibroblast cells, WI-38. Although UV exposure strikingly induced JNK activity in both cells, the dose-response increase following IR exposure was observed in thyroid cells with the maximal JNK activity (3.5 fold induction) obtained at 10 Gy exposure, but no increase in WI-38 cells. The JNK activity was reached a maximum of 2.2 fold induction at 30 min after 5 Gy exposure and then sustained for at least 12 hr. On the other hand, ERK activity was not stimulated in thyroid cells following irradiation. The effects of 12-O-tetradecanoylphorbol beta-acetate (TPA) mimicked those of radiation on JNK cascade and 1-(5-isoquinolinesulphonyl)-2,5-dimethylpiperazine 2HCl (H7) and pretreatment with TPA blocked JNK activation following irradiation. Our results demonstrate that IR stimulates JNK activity in cultured human thyroid cells but not in fibroblasts indicating distinct activation and regulation mechanisms of JNK cascade. The JNK activation following IR exposure is mediated at least partially through a PKC-dependent pathway.
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PMID:Ionizing radiation activates c-Jun NH2-terminal kinase (JNK/SAPK) via a PKC-dependent pathway in human thyroid cells. 951 79

"Stress-regulated" mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H2O2) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H2O2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H2O2 in both cases was observed at 0.5 mM. Whereas activation of p38-MAPK by H2O2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H2O2. MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H2O2 to a similar extent as with ischemia or ischemia/reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SR-MAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-alpha-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.
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PMID:Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. 951 15

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that elicits a large number of biological effects. However, the intracellular signaling mechanisms that are responsible for the TNF-alpha effects remain largely unknown. We have previously demonstrated that cultured mouse Sertoli cells, after TNF-alpha treatment, increase the surface expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) production (Riccioli, A., Filippini, A., De Cesaris, P., Barbacci, E., Stefanini, M., Starace, G., and Ziparo, E. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 5808-5812). Here, we show that, in cultured Sertoli cells, TNF-alpha activates the mitogen-activated protein kinase pathway (p38, c-Jun N-terminal protein kinase/stress-activated protein kinase, and the p42/p44 mitogen-activated protein kinases) as revealed by an increased phosphorylation of p38, activating transcription factor-2, c-Jun, and Elk-1. Furthermore, our data indicate that the biological effects induced by TNF-alpha in Sertoli cells (enhancement of ICAM-1, VCAM-1, and IL-6 expression) depend on the activation of different signaling pathways. SB203580, a highly specific p38 inhibitor, does not affect ICAM-1 and VCAM-1 expression, but strongly inhibits IL-6 production. Moreover, interferon-gamma, which up-regulates adhesion molecule expression and reduces IL-6 production, does not induce phosphorylation of p38. Our data strongly support the hypothesis that, in response to TNF-alpha, activation of p38 leads to IL-6 production, whereas ICAM-1 and VCAM-1 expression could be induced by activation of the c-Jun N-terminal protein kinase/stress-activated protein kinase pathway.
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PMID:Tumor necrosis factor-alpha induces interleukin-6 production and integrin ligand expression by distinct transduction pathways. 951 59

Anisomycin, a translational inhibitor secreted by Streptomyces spp., strongly activates the stress-activated mitogen-activated protein (MAP) kinases JNK/SAPK (c-Jun NH2-terminal kinase/stress-activated protein kinase) and p38/RK in mammalian cells, resulting in rapid induction of immediate-early (IE) genes in the nucleus. Here, we have characterized this response further with respect to homologous and heterologous desensitization of IE gene induction and stress kinase activation. We show that anisomycin acts exactly like a signalling agonist in eliciting highly specific and virtually complete homologous desensitization. Anisomycin desensitization of a panel of IE genes (c-fos, fosB, c-jun, junB, and junD), using epidermal growth factor (EGF), basic fibroblast growth factor, (bFGF), tumor necrosis factor alpha (TNF-alpha), anisomycin, tetradecanoyl phorbol acetate (TPA), and UV radiation as secondary stimuli, was found to be extremely specific both with respect to the secondary stimuli and at the level of individual genes. Further, we show that anisomycin-induced homologous desensitization is caused by the fact that anisomycin no longer activates the JNK/SAPK and p38/RK MAP kinase cascades in desensitized cells. In anisomycin-desensitized cells, activation of JNK/SAPKs by UV radiation and hyperosmolarity is almost completely lost, and that of the p38/RK cascade is reduced to about 50% of the normal response. However, all other stimuli produced normal or augmented activation of these two kinase cascades in anisomycin-desensitized cells. These data show that anisomycin behaves like a true signalling agonist and suggest that the anisomycin-desensitized signalling component(s) is not involved in JNK/SAPK or p38/RK activation by EGF, bFGF, TNF-alpha, or TPA but may play a significant role in UV- and hyperosmolarity-stimulated responses.
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PMID:Anisomycin selectively desensitizes signalling components involved in stress kinase activation and fos and jun induction. 952 56

Several cytokines and LPS regulate the population of the B1 receptors (B1Rs) for kinins; these are responsive to des-Arg9-bradykinin (BK) and Lys-des-Arg9-BK. B1R activation contributes to inflammatory vascular changes and pain. Aortic rings isolated from normal rabbits and incubated in vitro in Krebs physiological medium were used as a model of tissue injury. From a null level of response, these rings exhibit a time- and protein synthesis-dependent increase in the maximal contractile response to des-Arg9-BK. Exposure to exogenous IL-1beta or epidermal growth factor (EGF) considerably increases the process of sensitization to the kinins. Freshly isolated control aortic rings showed high mitogen-activated protein (MAP) kinase activities (persistent activation of p38, but less prolonged for extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase pathways) relatively to the basal activities found in various types of cultured cells. IL-1beta or EGF further increased the activities of the extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase MAP kinases. The inhibitor of the p38 MAP kinase, SB 203580 (10 microM), massively (approximately 75%) and selectively inhibited the spontaneous sensitization to des-Arg9-BK over 6 h. SB 203580 also significantly reduced the development of the response to des-Arg9-BK as stimulated by IL-1 or EGF. Both spontaneous and IL-1beta-stimulated up-regulation of responsiveness to des-Arg9-BK were significantly inhibited by the MAP kinase extracellular signal-regulated kinase kinase 1 inhibitor PD 98059 (approximately 40%). The protein kinase inhibitors failed to inhibit protein synthesis and to acutely inhibit the contractile effect of des-Arg9-BK, suggesting that they do not influence B1 receptor transduction mechanisms. In cultured aortic smooth muscle cells stimulated with EGF, MAP kinase activation preceded B1R mRNA induction. Protein kinase inhibitors reveal the role of cell injury-controlled MAP kinase pathways, and singularly of the p38 pathway, in the induction of B1R.
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PMID:Role of the mitogen-activated protein kinases in the expression of the kinin B1 receptors induced by tissue injury. 957 May 62


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