| Autor: |
Rosenzweig, Tovit, Braiman, Liora, Bak, Asia, Alt, Addy, Kuroki, Toshio, Sampson, Sanford R. |
| Předmět: |
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| Zdroj: |
Diabetes; Jun2002, Vol. 51 Issue 6, p1921-1930, 10p, 1 Diagram, 9 Graphs |
| Abstrakt: |
Tumor necrosis factor-α (TNF-α) 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-α inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-α, 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-α each caused tyrosine phosphorylation and activation of PKCs δ and α, but when TNF-α preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKCδ specifically to coprecipitate with IR, an effect blocked by TNF-α. Both PKCα and -δ are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKCα, it increased coprecipitation of IRS-1 with PKCδ. TNF-α 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-α on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. PKCα overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCδ overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-α on IR autophosphorylation and signaling to PI3-K. Blockade of PKCα antagonized the inhibitory effects of TNF-α on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. We suggest that the effects of TNF-α on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCδ and -α with upstream signaling molecules. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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