PMID- 12031982
OWN - NLM
STAT- MEDLINE
DCOM- 20020624
LR  - 20190515
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 51
IP  - 6
DP  - 2002 Jun
TI  - Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms 
      alpha and delta mediate inhibition of insulin receptor signaling.
PG  - 1921-30
AB  - 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.
FAU - Rosenzweig, Tovit
AU  - Rosenzweig T
AD  - Faculty of Life Sciences, Gonda-Goldschmied Center, Bar-Ilan University, 
      Ramat-Gan, Israel.
FAU - Braiman, Liora
AU  - Braiman L
FAU - Bak, Asia
AU  - Bak A
FAU - Alt, Addy
AU  - Alt A
FAU - Kuroki, Toshio
AU  - Kuroki T
FAU - Sampson, Sanford R
AU  - Sampson SR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Isoenzymes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.- (Prkcd protein, mouse)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.13 (Prkca protein, mouse)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression
MH  - Immunosorbent Techniques
MH  - Insulin/pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Isoenzymes/antagonists & inhibitors/genetics/*metabolism
MH  - Mice
MH  - Muscle, Skeletal/metabolism
MH  - Mutagenesis
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Phosphotyrosine/metabolism
MH  - Protein Kinase C/antagonists & inhibitors/genetics/*metabolism
MH  - Protein Kinase C-alpha
MH  - Protein Kinase C-delta
MH  - Receptor, Insulin/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2002/05/29 10:00
MHDA- 2002/06/25 10:01
CRDT- 2002/05/29 10:00
PHST- 2002/05/29 10:00 [pubmed]
PHST- 2002/06/25 10:01 [medline]
PHST- 2002/05/29 10:00 [entrez]
AID - 10.2337/diabetes.51.6.1921 [doi]
PST - ppublish
SO  - Diabetes. 2002 Jun;51(6):1921-30. doi: 10.2337/diabetes.51.6.1921.