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J. Biol. Chem., Vol. 283, Issue 9, 5466-5476, February 29, 2008

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S-Phase-specific Activation of PKC Induces Senescence in Non-small Cell Lung Cancer Cells^*

Jose L. Oliva¹², M. Cecilia Caino¹, Adrian M. Senderowicz, and Marcelo G. Kazanietz³

From the Department of Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160 and the CDER, Food and Drug Administration, Silver Spring, Maryland 20993

Protein kinase C (PKC) has been widely implicated in positive and negative control of cell proliferation. We have recently shown that treatment of non-small cell lung cancer (NSCLC) cells with phorbol 12-myristate 13-acetate (PMA) during G₁ phase inhibits the progression into S phase, an effect mediated by PKC-induced up-regulation of the cell cycle inhibitor p21^Cip1. However, PMA treatment in asynchronously growing NSCLC cells leads to accumulation of cells in G₂/M. Studies in post-G₁ phases revealed that PMA induced an irreversible G₂/M cell cycle arrest in NSCLC cells and conferred morphological and biochemical features of senescence, including elevated SA-β-Gal activity and reduced telomerase activity. Remarkably, this effect was phase-specific, as it occurred only when PKC was activated in S, but not in G₁, phase. Mechanistic analysis revealed a crucial role for the classical PKC isozyme as mediator of the G₂/M arrest and senescence, as well as for inducing p21^Cip1 an obligatory event for conferring the senescence phenotype. In addition to the unappreciated role of PKC isozymes, and specifically PKC, in senescence, our data introduce the paradigm that discrete PKCs trigger distinctive responses when activated in different phases of the cell cycle via a common mechanism that involves p21^Cip1 up-regulation.

Received for publication, September 10, 2007 , and in revised form, December 18, 2007.

^* This work was supported by Grants CA-89202 and CA-92537 from the National Institutes of Health (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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: Unidad de Biología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo, Km. 2 Majadahonda-28220 Madrid, Spain. E-mail: jloliva{at}isciii.es. ³ To whom correspondence may be addressed: Dept. of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Bldg. II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160. E-mail: marcelo{at}spirit.gcrc.upenn.edu.

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