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EMBO J. 2002 Jun 17;21(12):3000-8.

DNA damage-induced apoptosis requires the DNA-dependent protein kinase, and is mediated by the latent population of p53.

Author information

  • 1Cancer Biology Research Group and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4N1.

Erratum in

  • EMBO J. 2004 Dec 8;23(24):4877.

Abstract

Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following gamma-irradiation, latent p53 formed a complex with the catalytic subunit of the DNA-dependent protein kinase (DNA-PK(CS)). The complex formation was DNase sensitive, suggesting that the proteins came together on the DNA, conceivably at strand breaks. This association was accompanied by phosphorylation of pre-existing, latent p53 at Ser18 (corresponding to Ser15 in human p53), which was not found in DNA-PK(CS)(-/-) cells. Most significantly, DNA damage-induced apoptosis was abolished in both DNA-PK(CS)(-/-) and p53(-/-) cells. In addition, blocking synthesis of inducible p53 by cycloheximide did not abrogate apoptosis, suggesting that the latent population of p53 is sufficient for executing the apoptotic program. Finally, E1A-expressing MEFs from a p53 "knock-in" mouse where Ser18 was mutated to an alanine had an attenuated apoptotic response, indicating that phosphorylation of this site by DNA-PK is a contributing factor for apoptosis.

PMID:
12065413
[PubMed - indexed for MEDLINE]
PMCID:
PMC126062
Free PMC Article
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