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Papers In Press, published online ahead of print July 6, 2005
Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, NY, NY 10021
Corresponding Author: j-massague{at}ski.mskcc.org
DNA damage results in transcriptional induction of p53-target genes including the cyclin-dependent kinase (CDK) inhibitor p21Cip1 (CDKN1A) and the proapoptotic Bcl-2 family member PUMA, which cause cell cycle arrest and apoptosis, respectively depending on the cellular context. By imposing cell cycle arrest at the expense of apoptosis, p21Cip1 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 p21Cip1-deficient HCT116 colorectal cancer cells. DNA damage induced a similar level of p53 activation and PUMA induction in p21Cip1-deficient cells compared to wild-type isogenic counterparts. p21Cip1 did not act as a direct blocker of PUMA. However, only p21Cip1-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 p21Cip1-deficient HCT116 cells, p21Cip1, its family member p27Kip1 and the structurally unrelated CDK inhibitor p16Ink4a 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 suggests 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.
J. Biol. Chem, 10.1074/jbc.M504689200
Submitted on April 28, 2005
Revised on June 30, 2005
Accepted on July 6, 2005
CDK inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells
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