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)

Previously we showed that rat mesangial cells are normally resistant to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. They are made susceptible to the apoptotic effect of TNF-alpha when pretreated with actinomycin D, cycloheximide or vanadate. A sustained c-Jun N-terminal protein kinase (JNK) activation was closely correlated with the initiation of apoptosis under these conditions. We proposed that a TNF-alpha-inducible phosphatase was responsible for preventing a sustained activation of JNK and consequent apoptosis in these cells (Guo, Y.-L., Baysal, K., Kang, B. , Yang, L.-J., and Williamson, J. R. (1998) J. Biol. Chem. 273, 4027-4034). In the present study we provide further evidence to support this hypothesis. Ro318220, although originally identified as a specific inhibitor of protein kinase C, was subsequently found to be a strong inhibitor of MKP-1 expression. In rat mesangial cells, pretreatment of the cells with Ro318220 blocked expression of MKP-1 induced by TNF-alpha. This treatment also prolonged JNK activation and caused apoptosis. Taken together, our results support the currently controversial hypothesis that the JNK pathway is involved in TNF-alpha-induced apoptosis. In addition, we provide a mechanistic explanation for how mesangial cells in primary culture achieve resistance to TNF-alpha cytotoxicity. Specifically, induction of MKP-1 by TNF-alpha appears to be responsible for protection of the cells from apoptosis by preventing a prolonged activation of JNK.
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PMID:Inhibition of the expression of mitogen-activated protein phosphatase-1 potentiates apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells. 955 92

We reported previously that Ro-318220 blocked expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) induced by tumor necrosis factor-alpha (TNF-alpha) and subsequently caused apopotosis in mesangial cells (Y.-L. Guo, B. Kang, and J. R. Williamson. J. Biol. Chem. 273: 10362-10366, 1998). These data support our hypothesis that a TNF-alpha-inducible phosphatase may be responsible for preventing sustained activation of c-Jun NH2-terminal protein kinase (JNK) and consequent cell death in these cells (Y.-L. Guo, K. Baysal, B. Kang, L.-J. Yang, and J. R. Williamson. J. Biol. Chem. 273: 4027-4034, 1998). In this study, we investigated the involvement of protein kinase C (PKC) in regulation of MKP-1 expression in mesangial cells together with effects on viability. Although originally characterized as a PKC inhibitor, Ro-318220 inhibited TNF-alpha-induced MKP-1 expression through a mechanism other than blocking the PKC pathway. Furthermore, inhibition of the PKC pathway neither significantly affected TNF-alpha-induced MKP-1 expression nor made cells susceptible to toxic effect of TNF-alpha. Thus PKC activation is not essential for cells to achieve the resistance to TNF-alpha cytotoxicity displayed by normal mesangial cells. However, activation of PKC by phorbol 12-myristate 13-acetate (PMA) dramatically increased cellular resistance to the apoptotic effect of TNF-alpha. Coincidentally, PMA stimulated MKP-1 expression and suppressed JNK activation. Therefore, PMA-induced MKP-1 expression may contribute to the protective effect of PMA. These results provide a mechanistic explanation for previous documentation that PKC activation can rescue some cells from apopotosis.
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PMID:Resistance to TNF-alpha cytotoxicity can be achieved through different signaling pathways in rat mesangial cells. 995 Jul 71

Although almost two decades of study point to a central role for aberrant ErbB2 activation in breast cancer, many cellular and biochemical mechanisms underlying ErbB2-induced tumor initiation and progression remain to be resolved. A study by Guo et al. published recently in Cell indicates that the signaling function of beta4 integrin actively contributes to the initiation, growth, and invasion of ErbB2-induced mammary tumors in transgenic mice by promoting the activation of c-Jun and STAT3. These observations offer novel mechanistic insight into ErbB2 action and highlight the notion that ErbB2 co-opts the functions of other signaling proteins to elicit tumor progression.
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PMID:Co-opted integrin signaling in ErbB2-induced mammary tumor progression. 1690 7

Insulin resistance is one of the major factors contributing to metabolic diseases, but the underlying mechanisms are still poorly understood. As an important cofactor, B-cell translocation gene 1 (BTG1) is involved in many physiologic processes; however, the direct effect of BTG1 on insulin sensitivity has not been described. In our study, BTG1 overexpression or knockdown improved or impaired insulin signaling in vitro, respectively. In addition, adenovirus-mediated BTG1 overexpression improved insulin sensitivity in wild-type (WT) and insulin-resistant leptin-receptor mutated (db/db) mice. In addition, transgenic BTG1-overexpressing mice were resistant to high-carbohydrate diet-induced insulin resistance. Adenovirus-mediated BTG1 knockdown consistently impaired insulin sensitivity in WT and insulin-sensitive leucine-deprived mice. Moreover, hepatic BTG1 expression was increased by leucine deprivation via the mammalian target of rapamycin/ribosomal protein S6 kinase 1 pathway. Furthermore, c-Jun expression was up-regulated by BTG1, and adenovirus-mediated c-Jun knockdown blocked BTG1-improved insulin signaling and insulin sensitivity in vitro and in vivo. Finally, BTG1 promoted c-Jun expression via stimulating c-Jun and retinoic acid receptor activities. Taken together, these results identify a novel function for BTG1 in the regulation of hepatic insulin sensitivity and provide important insights into the nutritional regulation of BTG1 expression.- Xiao, F., Deng, J., Yu, J., Guo, Y., Chen, S., Guo, F. A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun.
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PMID:A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun. 2639 36

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that causes cardiovascular toxicity. The phenotypic transformation of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic phenotype is a hallmark of vascular response to injury. However, the precise role and molecular mechanism of TCDD in vascular remodeling remains unknown. In the present study, we found that TCDD treatment promoted VSMC phenotypic transition from contractile to synthetic phenotype and exaggerated vascular neointimal hyperplasia after wire injury in mice. TCDD treatment enhanced VSMC entry into cell cycle from G0/G1 phase to S and G2/M phase. The expression of cyclin D1, cyclin-dependent kinase 4 (CDK4), and its phosphorylation were coordinately increased in response to TCDD treatment. Knocking down of aryl hydrocarbon receptor (AHR) inhibited VSMC phenotypic transition induced by TCDD and promoted S/G2 phase cell cycle arrest. TCDD treatment markedly increased oncogenic c-Jun gene expression in VSMCs. ChIP assay revealed the direct binding of AHR on the promoter of c-Jun to up-regulate the mRNA expression of c-Jun. Silencing of c-Jun gene enhanced the expression of p53 and p21, whereas attenuated the expression of CDK4 and cyclin D1 leading to the decrease in the TCDD-stimulated VSMC proliferation and synthetic phenotype transition in vitro. In vivo study showed that genetic ablation of c-Jun in VSMCs restricted injury-induced neointimal hyperplasia in TCDD-treated mice. Thus, TCDD exposure exaggerated injury-induced vascular remodeling by the activation of AHR and up-regulation of the expression of its target gene c-Jun, indicating that inhibition of AHR may be a promising prevention strategy for TCDD-associated cardiovascular diseases.-Guo, S., Zhang, R., Liu, Q., Wan, Q., Wang, Y., Yu, Y., Liu, G., Shen, Y., Yu, Y., Zhang, J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice. 3121 22