Murdoch University Research Repository

Welcome to the Murdoch University Research Repository

The Murdoch University Research Repository is an open access digital collection of research
created by Murdoch University staff, researchers and postgraduate students.

Learn more

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.

Free to read: https://doi.org/10.1002/ijc.20446
*No subscription required

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
Publisher: Wiley-Liss Inc.
Copyright: © 2004 Wiley-Liss, Inc.
URI: http://researchrepository.murdoch.edu.au/id/eprint/64428
Item Control Page Item Control Page