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J. Biol. Chem., Vol. 279, Issue 15, 14828-14834, April 9, 2004

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Cyclic AMP Activation of the Extracellular Signal-regulated Kinases 1 and 2

IMPLICATIONS FOR INTESTINAL CELL SURVIVAL THROUGH THE TRANSIENT INHIBITION OF APOPTOSIS^*

Jeffrey A. Rudolph, Julia L. Poccia, and Mitchell B. Cohen

From the Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039

The proliferative compartment of the intestinal crypt is critical in the process of intestinal epithelial cell homeostasis. The ability of these progenitor crypt cells to resist apoptosis and ensure restitution during a potentially lethal insult, but retain the ability to remove damaged or altered cells afterward, is necessary for preservation of the crypt-villus unit. We have examined the ability of cAMP to transiently inhibit apoptosis via the extracellular signal-regulated kinases 1 and 2 (ERK1/2), in T84 cells, an intestinal crypt-like cell line. Using the cAMP analog 8-bromo-cAMP and cholera toxin (CT), cAMP-mediated ERK1/2 activation was first measured by Western blot analysis of the phosphorylated (activated) and total (activated and inactivated) forms of ERK1/2. Cyclic AMP activated ERK1/2 in a time- and dose-dependent manner, and the effect was inhibited by PD098059, an inhibitor of the ERK1/2 signaling pathway. However, inhibition of protein kinase A (PKA) did not alter the activation of ERK1/2. CT transiently inhibited both staurosporine and Fas antibody mediated apoptosis as measured by a caspase-3 activation assay and the detection of nucleosomes in an apoptosis based enzyme-linked immunosorbent assay. This inhibitory effect was reversed by the simultaneous addition of PD098059. Our data suggest that in the T84 cell line, cAMP activates ERK1/2 in a PKA independent fashion and a physiological consequence of this activated pathway is the transient inhibition of apoptosis. These findings suggest a novel pathway that intestinal cells use to protect against injury while maintaining the overall ability to remove damaged cells and preserve intestinal homeostasis.

Received for publication, September 16, 2003 , and in revised form, December 29, 2003.

^* This work was supported by the National Institutes of Health Grant DK47318 (to M. B. C.), the American Digestive Health Foundation and Procter Scholar Research Award (to J. A. R.), and the Crohn's and Colitis Foundation of America Award (to J. L. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039. Tel.: 513-636-4415; Fax: 513-636-5581; E-mail: jeff.rudolph{at}cchmc.org.

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