cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2.
The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic beta-cells, develop diabetes secondary to beta-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.
Jhala
Ulupi S
US
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Canettieri
Gianluca
G
Screaton
Robert A
RA
Kulkarni
Rohit N
RN
Krajewski
Stan
S
Reed
John
J
Walker
John
J
Lin
Xueying
X
White
Morris
M
Montminy
Marc
M
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014162:Transfection; D019076:Transgenes; D014407:Tumor Cells, Cultured
D017362:Cyclic AMP Response Element-Binding Protein; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010446:Peptide Fragments; D010750:Phosphoproteins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D005576:Colforsin; D007334:Insulin-Like Growth Factor I; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose