NDLI: Differential Roles of Insulin Receptor Substrates in the Anti-apoptotic Function of Insulin-like Growth Factor-1 and Insulin

Content Provider	Journal of Biological Chemistry (JBC)
Author	Tseng, Yu-Hua Ueki, Kohjiro Kriauciunas, Kristina M. Kahn, C. Ronald
Abstract	Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. Five hours after serum withdrawal, cells already began to undergo apoptosis. At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85–90%. After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. The biochemical basis of the defect in anti-apoptosis was not dependent on phosphorylation of mitogen-activated protein kinase; whereas phosphoinositide 3-kinase activity was decreased by 30% in IRS-1 KO cells. Akt phosphorylation was slightly reduced in these cells. Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms.
Related Links	http://www.jbc.org/content/277/35/31601.abstract
Ending Page	31611
Starting Page	31601
Page Count	11
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	35
Volume Number	277
DOI	10.1074/jbc.M202932200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2002-08-30
Access Restriction	Open
Subject Keyword	Insulin-like growth factor-1 (IGF-1) Insulin receptor substrate (IRS) Knockout (KO) Src homology 2 (SH2) Phosphoinositide 3-kinase (PI3K) CAMP response element-binding protein (CREB) Phosphotyrosine (pY) Mitogen-activated protein kinase (MAPK) Extracellular signal-regulated kinase (ERK) MAPK/ERK kinase (MEK) Fetal bovine serum (FBS) Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) Son of sevenless (SOS) Growth factor receptor binding protein 2 (Grb2) Pleckstrin homology (PH) Phosphotyrosine binding (PTB) CAMP response element (CRE) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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