4.7 Article

Differential effects of tumor necrosis factor-α on protein kinase C isoforms α and δ mediate inhibition of insulin receptor signaling

期刊

DIABETES
卷 51, 期 6, 页码 1921-1930

出版社

AMER DIABETES ASSOC
DOI: 10.2337/diabetes.51.6.1921

关键词

-

向作者/读者索取更多资源

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-alpha-inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-alpha, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. Insulin and TNF-alpha each caused tyrosine phosphorylation and activation of PKCs delta and alpha, but when TNF-alpha preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. Both PKCalpha and -delta are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. To further investigate the involvement of PKCs in inhibitory actions of TNF-alpha on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. We suggest that the effects of TNF-alpha on IR tyrosine phospborylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据