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J. Biol. Chem., Vol. 280, Issue 35, 31091-31100, September 2, 2005

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Protein Phosphatase 2A Regulates Apoptosis in Intestinal Epithelial Cells^*

Ramesh M. Ray, Sujoy Bhattacharya, and Leonard R. Johnson

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Polyamine depletion prevents apoptosis by increasing serine/threonine phosphorylation leading to either inactivation or activation of pro- and anti-apoptotic proteins, respectively. Despite evidence that protein kinases are regulators of apoptosis, a specific role for protein phosphatases in regulating cell survival has not been established. In this study, we show that polyamine depletion inhibits serine/threonine phosphatase 2A (PP2A). Inhibition of PP2A in cells depleted of polyamines correlated well with increased phosphorylation of Bad at Ser¹¹². Bad Ser¹¹² phosphorylation in response to tumor necrosis factor (TNF)- treatment decreased with time in cells grown in control as well as those grown in the presence of -difluoromethylornithine plus putrescine. However, a sustained increase in the levels of Bad Ser¹¹² phosphorylation was maintained in response to TNF- treatment in cells grown in the presence of -difluoromethylornithine. Inhibition of PP2A by okadaic acid and fostriecin or PP2A small interfering RNA transfection significantly decreased TNF--induced apoptosis in control and polyamine-depleted cells. Inhibition of PP2A by okadaic acid: 1) increased Bad and Bcl-2 phosphorylation at Ser¹¹² and Ser⁷⁰, respectively; 2) increased ERK activity; 3) prevented JNK activation; 4) prevented cytochrome c release, and activation of caspases-9 and -3 in response to TNF-. Inhibition of MEK1 by U0126 prevented phosphorylation of Bad at Ser¹¹². These results indicate that polyamines regulate PP2A activity, and inhibition of PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation and thereby prevents cytochrome c release, caspase-9, and caspase-3 activation.

Received for publication, March 18, 2005 , and in revised form, June 28, 2005.

^* This work was supported by NIDDK National Institutes of Health Grant DK-16505 and a Thomas A. Gerwin Endowment. 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: Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-7168; Fax: 901-448-7126; E-mail: rray{at}physio1.utmem.edu.

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