cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2
- Ulupi S. Jhala1,
- Gianluca Canettieri1,
- Robert A. Screaton1,
- Rohit N. Kulkarni4,
- Stan Krajewski2,
- John Reed2,
- John Walker3,
- Xueying Lin4,
- Morris White4, and
- Marc Montminy1,5
- 1The Salk Institute for Biological Studies, La Jolla, California 92037, USA
- 2The Burnham Institute, La Jolla, California 92037, USA
- 3The Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
- 4Howard Hughes Medical Institute, The Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
Abstract
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 β-cells, develop diabetes secondary to β-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.
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Footnotes
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Supplemental material is available at http://www.genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1097103.
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Corresponding author.
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↵5 E-MAIL montminy{at}salk.edu; FAX (858) 625-9045.
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- Accepted May 13, 2003.
- Received March 26, 2003.
- Cold Spring Harbor Laboratory Press