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

Katharine H. Wrighton, Cecilia M. Prêle, Andrew Sunters, W. Andrew Yeudall

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (HI79L), 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 HI79L-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, HI79L 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.

Original languageEnglish (US)
Pages (from-to)760-770
Number of pages11
JournalInternational Journal of Cancer
Volume112
Issue number5
DOIs
StatePublished - Dec 10 2004

Fingerprint

Cisplatin
DNA Damage
Down-Regulation
Cyclin A
Apoptosis
Cyclin B1
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Aptitude
Propidium
In Situ Nick-End Labeling
Amino Acid Substitution
Cell Cycle Checkpoints
S Phase
Histidine
Codon
Leucine
Caspase 3
Flow Cytometry
Phosphotransferases

Keywords

  • Apoptosis
  • Cell cycle
  • Cisplatin
  • Cyclin
  • Kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aberrant p53 alters DNA damage checkpoints in response to cisplatin : Downregulation of CDK expression and activity. / Wrighton, Katharine H.; Prêle, Cecilia M.; Sunters, Andrew; Yeudall, W. Andrew.

In: International Journal of Cancer, Vol. 112, No. 5, 10.12.2004, p. 760-770.

Research output: Contribution to journalArticle

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