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

International Journal of Cancer. Journal International Du Cancer
Katharine H WrightonW A Yeudall

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 G(2) 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-...Continue Reading

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Citations

Jul 1, 2011·European Journal of Cell Biology·Mohammad Poorgholi BelverdiPetra Knaus
Mar 31, 2010·Carcinogenesis·Huixin WangW Andrew Yeudall
Jul 29, 2021·Journal of Biochemical and Molecular Toxicology·Rasha M Hussein, Saed M Al-Dalain
Apr 26, 2007·Chemical Reviews·Yongwon Jung, Stephen J Lippard

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