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J. Biol. Chem., Vol. 280, Issue 36, 32018-32025, September 9, 2005

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Cyclin-dependent Kinase Inhibitors Uncouple Cell Cycle Progression from Mitochondrial Apoptotic Functions in DNA-damaged Cancer Cells^*

Hong-Van Le, Andy J. Minn¶, and Joan Massagué||

From the Cancer Biology and Genetics Program, Howard Hughes Medical Institute, and ^¶Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

DNA damage results in transcriptional induction of p53 target genes, including the cyclin-dependent kinase (CDK) inhibitor p21^Cip1 (CDKN1A) and the proapoptotic Bcl-2 family member p53 up-regulated modulator of apoptosis (PUMA). Depending on the cellular context, p21^Cip1 and PUMA mediate cell cycle arrest and apoptosis, respectively. By imposing cell cycle arrest at the expense of apoptosis, p21^Cip1 can sharply reduce the effectiveness of DNA-damaging anticancer agents in colorectal cancer cells. We investigated the link between cell cycle progression and the onset of apoptosis in DNA-damaged cells by analyzing the activation of the apoptotic cascade in p21^Cip1-deficient HCT116 colorectal cancer cells. DNA damage induced a similar level of p53 activation and PUMA induction in p21^Cip1-deficient cells compared with wild-type isogenic counterparts. p21^Cip1 did not act as a direct blocker of PUMA. However, only p21^Cip1-deficient cells showed extensive cytochrome c release, mitochondrial membrane depolarization, and caspase activation. An increase in caspase activation occurred as these cells reached M-phase and incurred polyploidy. When ectopically expressed in p21^Cip1-deficient HCT116 cells, p21^Cip1, its family member p27^Kip1, and the structurally unrelated CDK inhibitor p16^Ink4a were similarly effective at causing cell cycle arrest and inhibiting DNA damage-induced apoptotic events such as cytochrome c release, mitochondrial membrane depolarization, and activation of the caspase cascade. These observations suggest that by blocking dysregulated cell cycle progression, CDK inhibitors can influence the sensitivity of the mitochondria to proapoptotic signals in DNA damage-induced cancer cells.

Received for publication, April 28, 2005 , and in revised form, June 30, 2005.

^* 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.

^|| An investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel.: 212-639-8975; E-mail: j-massague{at}mskcc.org.

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