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

Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following γ‐irradiation, latent p53 formed a complex with the catalytic subunit of the DNA‐dependent protein kinase (DNA‐PKCS). The complex forma...

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Bibliographic Details
Published in:The EMBO journal 2002-06, Vol.21 (12), p.3000-3008
Main Authors: Woo, Richard A., Jack, Melissa T., Xu, Yang, Burma, Sandeep, Chen, David J., Lee, Patrick W.K.
Format: Article
Language:English
Subjects:
Animals
APOPTOSIS
Apoptosis - physiology
BASIC BIOLOGICAL SCIENCES
Cell Fractionation
Cells, Cultured
Cycloheximide - pharmacology
DNA
DNA Damage
DNA-Activated Protein Kinase
DNA-Binding Proteins
DNA-dependent protein kinase
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibroblasts - radiation effects
Gamma Rays
Humans
Mice
Mice, Transgenic
Nuclear Proteins
p53
Point Mutation
Protein Binding
Protein Synthesis Inhibitors - pharmacology
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
PROTEINS
Ser15
Space life sciences
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following γ‐irradiation, latent p53 formed a complex with the catalytic subunit of the DNA‐dependent protein kinase (DNA‐PKCS). 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‐PKCS−/− cells. Most significantly, DNA damage‐induced apoptosis was abolished in both DNA‐PKCS−/− 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.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/cdf307