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J. Biol. Chem., Vol. 282, Issue 33, 24352-24363, August 17, 2007

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G₁₂ Stimulates Apoptosis in Epithelial Cells through JNK1-mediated Bcl-2 Degradation and Up-regulation of IB^*

From the Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Apoptosis is an essential mechanism for the maintenance of somatic tissues, and when dysregulated can lead to numerous pathological conditions. G proteins regulate apoptosis in addition to other cellular functions, but the roles of specific G proteins in apoptosis signaling are not well characterized. G₁₂ stimulates protein phosphatase 2A (PP2A), a serine/threonine phosphatase that modulates essential signaling pathways, including apoptosis. Herein, we examined whether G₁₂ regulates apoptosis in epithelial cells. Inducible expression of G₁₂ or constitutively active (QL)₁₂ in Madin-Darby canine kidney cells led to increased apoptosis with expression of QL₁₂, but not G₁₂. Inducing QL₁₂ led to degradation of the anti-apoptotic protein Bcl-2 (via the proteasome pathway), increased JNK activity, and up-regulated IB protein levels, a potent stimulator of apoptosis. Furthermore, the QL₁₂-stimulated activation of JNK was blocked by inhibiting PP2A. To characterize endogenous G₁₂ signaling pathways, non-transfected MDCK-II and HEK293 cells were stimulated with thrombin. Thrombin activated endogenous G₁₂ (confirmed by GST-tetratricopeptide repeat (TPR) pull-downs) and stimulated apoptosis in both cell types. The mechanisms of thrombin-stimulated apoptosis through endogenous G₁₂ were nearly identical to the mechanisms identified in QL₁₂-MDCK cells and included loss of Bcl-2, JNK activation, and up-regulation of IB. Knockdown of the PP2A catalytic subunit in HEK293 cells inhibited thrombin-stimulated apoptosis, prevented JNK activation, and blocked Bcl-2 degradation. In summary, G₁₂ has a major role in regulating epithelial cell apoptosis through PP2A and JNK activation leading to loss of Bcl-2 protein expression. Targeting these pathways in vivo may lead to new therapeutic strategies for a variety of disease processes.

Received for publication, April 2, 2007 , and in revised form, June 4, 2007.

^* This work was supported by National Institutes of Health NIGMS Grant GM-55223, NIDDK Polycystic Kidney Disease Center Grant P50 DK074030 (Project 1) (to B. M. D.), and a Harvard College Research Fellowship (to V. Y.). 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.

¹ To whom correspondence should be addressed: 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5809; Fax: 617-525-5830; E-mail: bdenker{at}rics.bwh.harvard.edu.

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