Cyclin-dependent kinase inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells Journal Article
| Authors: | Le, H. V.; Minn, A. J.; Massague, J. |
| Article Title: | Cyclin-dependent kinase inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells |
| Abstract: | 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 p53 up-regulated modulator of apoptosis (PUMA). Depending on the cellular context, p21CiP1 and PUMA mediate cell cycle arrest and apoptosis, respectively. 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 colorecial cancer cells. DNA damage induced a similar level of p53 activation and PUMA induction in p21Cip1- 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 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 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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; proto-oncogene proteins; neoplasms; colorectal cancer; cell cycle proteins; dna damage; cell cycle; protein bcl 2; apoptosis; enzyme inhibition; apoptosis regulatory proteins; enzyme activation; caspase; caspases; cell line, tumor; protein p53; dna; transcription regulation; tumors; cancer cell; tumor suppressor protein p53; cell cycle g2 phase; gene induction; cyclin-dependent kinase inhibitor p21; molecular biology; cyclin-dependent kinases; cyclin dependent kinase inhibitor; biochemistry; mitochondria; mitochondrion; polyploidy; caspase activation; cells; cdk inhibitors; cytochrome c; cytochromes c; cyclin dependent kinase inhibitor 1; membrane depolarization; dna damage-induced apoptotic events; p53 up-regulated modulator of apoptosis (puma); protein puma |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 280 |
| Issue: | 36 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2005-09-09 |
| Start Page: | 32018 |
| End Page: | 32025 |
| Language: | English |
| DOI: | 10.1074/jbc.M504689200 |
| PUBMED: | 16002406 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 24" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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