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

US Jhala, G Canettieri, RA Screaton… - Genes & …, 2003 - genesdev.cshlp.org
US Jhala, G Canettieri, RA Screaton, RN Kulkarni, S Krajewski, J Reed, J Walker, X Lin…
Genes & development, 2003genesdev.cshlp.org
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 …
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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