Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling.
| Autor: | Rosenzweig, Tovit, Braiman, Liora, Bak, Asia, Alt, Addy, Kuroki, Toshio, Sampson, Sanford R |
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| Předmět: |
TYROSINE metabolism
ANIMAL experimentation ANIMAL populations BIOCHEMISTRY CARRIER proteins CELL culture CELL receptors CELLULAR signal transduction COMPARATIVE studies ENZYME inhibitors GENE expression GENETIC techniques IMMUNOADSORPTION INSULIN ISOENZYMES PHENOMENOLOGY RESEARCH methodology MEDICAL cooperation MICE GENETIC mutation PHOSPHOPROTEINS PHOSPHORYLATION PHOSPHOTRANSFERASES RESEARCH TRANSFERASES TUMOR necrosis factors EVALUATION research SKELETAL muscle CHEMICAL inhibitors PHARMACODYNAMICS |
| Zdroj: | Diabetes; Jun2002, Vol. 51 Issue 6, p1921-1930, 10p |
| Abstrakt: | 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 phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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