Participation of p53 Protein in the Cellular Response to DNA Damage

Michael B. Kastan, Onyinye Onyekwere, David Sidransky, Bert Vogelstein, Ruth W. Craig

Research output: Contribution to journalArticle

Abstract

The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of MI -1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, -»-irradiationor actinomycin D, causes a transient inhibition of replicative DNA synthesis via both (., and (F. arrests. Levels of p53 protein in MI -I cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the Gãarrest. In contrast, the S-phase arrest of MI -1 cells caused by exposure to the anti-metabolite, cytosino arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the (F, arrest and the induction of p53 protein after f-irradiation, thus suggesting that blocking the induction of pS3 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike MI -I cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the pS3 gene do not exhibit a (., arrest after -y-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type pS3 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.

Original languageEnglish (US)
Pages (from-to)6304-6311
Number of pages8
JournalCancer Research
Volume51
StatePublished - Dec 1991

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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