cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2

  1. Ulupi S. Jhala1,
  2. Gianluca Canettieri1,
  3. Robert A. Screaton1,
  4. Rohit N. Kulkarni4,
  5. Stan Krajewski2,
  6. John Reed2,
  7. John Walker3,
  8. Xueying Lin4,
  9. Morris White4, and
  10. Marc Montminy1,5
  1. 1The Salk Institute for Biological Studies, La Jolla, California 92037, USA
  2. 2The Burnham Institute, La Jolla, California 92037, USA
  3. 3The Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
  4. 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.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1097103.

  • Corresponding author.

  • 5 E-MAIL montminy{at}salk.edu; FAX (858) 625-9045.

    • Accepted May 13, 2003.
    • Received March 26, 2003.
| Table of Contents

Life Science Alliance