Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity
Wrighton, K.H., Prêle, C.M., Sunters, A. and Yeudall, W.A. (2004) Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity. International Journal of Cancer, 112 (5). pp. 760-770.
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Abstract
The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S- and G2 arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity.
Item Type: | Journal Article |
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Publisher: | Wiley-Liss Inc. |
Copyright: | © 2004 Wiley-Liss, Inc. |
URI: | http://researchrepository.murdoch.edu.au/id/eprint/64428 |
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