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J. Biol. Chem., Vol. 280, Issue 37, 32107-32114, September 16, 2005

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Protein Kinase C Stimulates Apoptosis by Initiating G₁ Phase Cell Cycle Progression and S Phase Arrest^*

Ademi E. Santiago-Walker1, Aphrothiti J. Fikaris, Gary D. Kao, Eric J. Brown¶, Marcelo G. Kazanietz, and Judy L. Meinkoth2

From the Departments of Pharmacology, Radiation Oncology, and ^¶Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6061

Overexpression of protein kinase C (PKC) stimulates apoptosis in a wide variety of cell types through a mechanism that is incompletely understood. PKC-deficient cells are impaired in their response to DNA damage-induced apoptosis, suggesting that PKC is required to mount an appropriate apoptotic response under conditions of stress. The mechanism through which it does so remains elusive. In addition to effects on cell survival, PKC elicits pleiotropic effects on cellular proliferation. We now provide the first evidence that the ability of PKC to stimulate apoptosis is intimately linked to its ability to stimulate G₁ phase cell cycle progression. Using an adenoviral-based expression system to express PKC,-, and - in epithelial cells, we demonstrate that a modest increase in PKC activity selectively stimulates quiescent cells to initiate G₁ phase cell cycle progression. Rather than completing the cell cycle, PKC-infected cells arrest in S phase, an event that triggers caspase-dependent apoptotic cell death. Apoptosis was preceded by the activation of cell cycle checkpoints, culminating in the phosphorylation of Chk-1 and p53. Strikingly, blockade of S phase entry using the phosphatidylinositol 3-kinase inhibitor LY294002 prevented checkpoint activation and apoptosis. In contrast, inhibitors of mitogen-activated protein kinase cascades failed to prevent apoptosis. These findings demonstrate that the biological effects of PKC can be extended to include positive regulation of G₁ phase cell cycle progression. Importantly, they reveal the existence of a novel, cell cycle-dependent mechanism through which PKC stimulates cell death.

Received for publication, April 22, 2005 , and in revised form, July 25, 2005.

^* This work was supported by Public Health Service Grant DK-45696 from NIDDK,National Institutes of Health (NIH) and Grant CA-109543 from NCI, NIH (to J. L. M.) and by Grants CA-89202 and CA-92537 from NCI, NIH (to M. G. K.). 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 Supported by a minority training grant supplement to Grant DK-45696.

² To whom correspondence should be addressed: Dept. of Pharmacology, University ofPennsylvania School of Medicine, Rm. 1251 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6061. Tel.: 215-898-1909; Fax: 215-746-8941; E-mail: meinkoth{at}pharm.med.upenn.edu.

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