Journal article
Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity
International Journal of Cancer, Vol.112(5), pp.760-770
2004
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.
Details
- Title
- Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity
- Authors/Creators
- K.H. Wrighton (Author/Creator) - King's College LondonC.M. Prêle (Author/Creator) - The University of Western AustraliaA. Sunters (Author/Creator) - Hammersmith HospitalW.A. Yeudall (Author/Creator) - King's College London
- Publication Details
- International Journal of Cancer, Vol.112(5), pp.760-770
- Publisher
- Wiley-Liss Inc.
- Identifiers
- 991005541468107891
- Copyright
- © 2004 Wiley-Liss, Inc.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis
- 1.25.656 P53
- Web Of Science research areas
- Oncology
- ESI research areas
- Clinical Medicine