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J. Biol. Chem., Vol. 283, Issue 1, 388-397, January 4, 2008

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Pivotal Role of the Cyclin-dependent Kinase Inhibitor p21^WAF1/CIP1 in Apoptosis and Autophagy^*

Keishi Fujiwara¹, Shigeru Daido¹, Akitsugu Yamamoto, Ryuji Kobayashi^¶, Tomohisa Yokoyama, Hiroshi Aoki, Eiji Iwado, Naoki Shinojima, Yasuko Kondo, and Seiji Kondo^||**2

From the Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, the Department of Cell Biology and Bioscience, The Nagahama Institute of Bioscience and Technology, Nagahama, Shiga 526-0829, Japan, the ^¶Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, the ^||University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, and the ^**Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030

Programmed cell death (PCD) is involved in a variety of biologic events. Based on the morphologic appearance of the cells, there are two types of PCD as follows: apoptotic (type I) and autophagic (type II). However, the molecular machinery that determines the type of PCD is poorly defined. The purpose of this study was to show whether the presence of the cyclin-dependent kinase (CDK) inhibitor p21^WAF1/CIP1, a modulator of apoptosis, determines which type of PCD the cell undergoes. Treatment with C₂-ceramide was associated with both the cleavage of caspase-3 and poly(ADP-ribose) polymerase and the degradation of autophagy-related Beclin 1 and Atg5 proteins, without a change in the cyclin-CDK activity, which culminated in apoptosis in p21^+/+ mouse embryonic fibroblasts (MEFs). On the other hand, C₂-ceramide did not cleave caspase-3 or poly(ADP-ribose) polymerase and kept Beclin 1 and Atg5 proteins stable in p21^-/- MEFs, events that this time culminated in autophagy. When expression of the p21 protein was inhibited by small interfering RNA or when the overexpression of Beclin 1 or Atg5 was induced, autophagy rather than apoptosis was initiated in the p21^+/+ MEFs treated with C₂-ceramide. In contrast, the exogenous expression of p21 or the silencing of Beclin 1 and Atg5 with small interfering RNA increased the number of apoptotic cells and decreased the number of autophagic cells among C₂-ceramide-treated p21^-/- MEFs. -Irradiation, which endogenously generates ceramide, induced a similar tendency in these MEFs. These results suggest that p21 plays an essential role in determining the type of cell death, positively for apoptosis and negatively for autophagy.

Received for publication, November 30, 2006 , and in revised form, October 24, 2007.

^* This work was supported in part by a start-up fund from the University of Texas M. D. Anderson Cancer Center (to S. K.), by a generous donation from the Anthony D. Bullock III Foundation (to Y. K. and S. K.), and by Cancer Center Support Grant (CCSG)/Shared Resources CA-16672. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Neurosurgery, the University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit BSRB 1004, Houston, TX 77030. Tel.: 713-834-6215; Fax: 713-834-6257; E-mail: seikondo{at}mdanderson.org.

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