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J. Biol. Chem., Vol. 280, Issue 42, 35310-35317, October 21, 2005

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Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms^*

Evan J. Ryer, Kenji Sakakibara, Chunjie Wang, Devanand Sarkar, Paul B. Fisher1, Peter L. Faries, K. Craig Kent, and Bo Liu2

From the Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital and Weill Medical College, Cornell University, New York, New York 10021 and the Departments of Pathology, Neurosurgery, and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032

Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. In the present study, we examined the novel PKC isoform protein kinase C delta (PKC) and its role in vascular SMC apoptosis. In A10 SMCs, overexpression of PKC was sufficient to induce apoptosis, whereas inhibition of PKC diminished H₂O₂-induced apoptosis. Moreover, evidence is provided that the tumor suppressor p53 is an essential mediator of PKC-induced apoptosis in SMCs. Activation of PKC led to accumulation as well as phosphorylation of p53 in SMCs; this induction correlated with apoptosis. Furthermore, blocking p53 induction with small interference RNA or targeted gene deletion prevented PKC-induced apoptosis, whereas restoring p53 expression rescued the ability of PKC to induce apoptosis in p53 null SMCs. We also establish that PKC regulates p53 at both transcriptional and post-translational levels. Specifically, the transcriptional regulation required p38 MAPK, whereas the post-translational modification, at least for serine 46, did not involve MAPK. Additionally, PKC, p38 MAPK, and p53 co-associate in cells under conditions favoring apoptosis. Together, our data suggest that SMC apoptosis proceeds through a pathway that involves PKC, the intermediary p38 MAPK, and the downstream target tumor suppressor p53.

Received for publication, July 1, 2005 , and in revised form, August 11, 2005.

^* This work was supported in part by a NHLBI, National Institutes of Health Grant HL-68673 (to K. C. K. and B. L.), American Heart Association Heritage Foundation Grant-in-aid 0455859T (to B. L.), and National Institutes of Health Training Grant T32 CA68971-07 (to E. J. R.). Additional support for these studies was provided in part by the Samuel Waxman Cancer Research Foundation and the Chernow 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.

¹ A Michael and Stella Chernow Urological Cancer Research Scientist and a Samuel Waxman Cancer Research Foundation Investigator.

² To whom correspondence should be addressed: Dept. of Surgery, New York Presbyterian Hospital, 525 E. 68th St., Payson 707, New York, NY 10021. Tel.: 212-746-5192; Fax: 212-746-5812; E-mail: bol2001{at}med.cornell.edu.

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