Decreasing IRS-2 expression in pancreatic beta-cells (INS-1) promotes apoptosis, which can be compensated for by introduction of IRS-4 expression.
IRS-2 plays a pivotal role in the control of pancreatic beta-cell growth. Here, the effect of altering IRS-2 expression levels in the pancreatic beta-cell line, INS-1, was examined. Adenoviral-mediated increased in IRS-2 protein levels protected against fatty acid (FFA)-induced apoptosis, associated with increased activation of PKB and decreased levels of activated caspase-9. Conversely, decreasing endogenous IRS-2 in INS-1 cells, using adenoviral-mediated expression of IRS-2 antisense, caused a three-fold increase in baseline apoptosis that was further enhanced in the presence of FFA. This was associated with decreased activation of PKB and increased caspase-9 activation. Although IRS-4 is not normally expressed in beta-cells, it was found that adenoviral-mediated introduction of IRS-4 into INS-1 cells enhanced glucose/IGF-1 induced mitogenesis, and protected against FFA-induced apoptosis, similarly to IRS-2. Moreover, expression of IRS-4 in INS-1 cells depleted of IRS-2 levels by IRS-2 antisense, was able to compensate for the lack of IRS-2 and reduce apoptosis in these cells back to normal. Thus, in beta-cells IRS-4 and -2 have similar biological functions. Also, this study further emphasizes the importance of IRS-2 signaling in control of beta-cell survival.
Lingohr
Melissa K
MK
Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
Dickson
Lorna M
LM
Wrede
Christian E
CE
Briaud
Isabelle
I
McCuaig
Jill F
JF
Myers
Martin G
MG
Rhodes
Christopher J
CJ
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000633:toxicity; D005822:Genetic Vectors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D064413:3-Phosphoinositide-Dependent Protein Kinases; D053453:Caspase 9; D020169:Caspases; D005230:Fatty Acids, Nonesterified; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; C491532:IRS4 protein, rat; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; C506435:Casp9 protein, rat