Protection of insulin receptor substrate-3 from staurosporine-induced apoptosis.
In primary adipocytes, insulin receptor substrate (IRS)-1 and -3 are expressed in a comparable amount and play distinct roles in insulin signaling. To examine the roles of these IRS in apoptosis inhibition, we evaluated staurosporine-induced apoptosis in Chinese hamster ovary (CHO) cells overexpressing human insulin receptor and IRS-1 or IRS-3. Overexpression of both IRS protected CHO cells from staurosporine-induced apoptosis. Overexpressed IRS-3 as well as IRS-1 enhanced phosphoinositide (PI) 3-kinase activity in response to insulin and increased phosphorylation of protein kinase B (PKB) at S473 and phosphorylation of one of the members of the forkhead transcription factor FKHRL1 on T32 in both insulin-untreated and -treated states. Treatment of these cells with a PI 3-kinase inhibitor LY294002 suppressed apoptosis-inhibitory effects of IRS-1 and IRS-3 as well as the phosphorylation of PKB and FKHRL1. These results indicate that both IRS-1 and IRS-3 take part in apoptosis inhibition through the PI 3-kinase/PKB/forkhead cascade.
Kaburagi
Yasushi
Y
The Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, 1-12-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. kaburagi@ri.imcj.go.jp
Satoh
Shinobu
S
Yamamoto-Honda
Ritsuko
R
Ito
Yuzuru
Y
Akanuma
Yasuo
Y
Sekihara
Hisahiko
H
Yasuda
Kazuki
K
Sasazuki
Takehiko
T
Kadowaki
Takashi
T
Yazaki
Yoshio
Y
D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000235:genetics; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine