Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Katharine H. Wrighton; Cecilia M. Prele; Andrew Sunters; W. Andrew Yeudall

doi:10.1002/ijc.20446

journal article Aug 04, 2004

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Katharine H. Wrighton Cecilia M. Prele Andrew Sunters W. Andrew Yeudall

International Journal of Cancer Vol. 112 No. 5 pp. 760-770 · Wiley

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Abstract

AbstractThe 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. © 2004 Wiley‐Liss, Inc.

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Details

Published: Aug 04, 2004
Vol/Issue: 112(5)
Pages: 760-770
License: View

Authors

K

Katharine H. Wrighton

C

Cecilia M. Prele

Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia 6009, Australia.; Institute for Respiratory Health, Centre for Respiratory Health, School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia 6009, Australia.

Funding

Concern Foundation

Cite This Article

Katharine H. Wrighton, Cecilia M. Prele, Andrew Sunters, et al. (2004). Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity. International Journal of Cancer, 112(5), 760-770. https://doi.org/10.1002/ijc.20446

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

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