Radiation sensitivity and tumor susceptibility in ATM phospho-mutant ATF2 mice

Shuangwei Li, Sergei Ezhevsky, Antimone Dewing, Matthew H. Cato, Marzia Scortegagna, Anindita Bhoumik, Wolfgang Breitwieser, Demetrious Braddock, Alexey Eroshkin, Jianfei Qi, Meifan Chen, Jae Young Kim, Stephen Jones, Nic Jones, Robert Rickert, Ze'ev A. Ronai

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The transcription factor ATF2 was previously shown to be an ATM substrate. Upon phosphorylation by ATM, ATF2 exhibits a transcription-independent function in the DNA damage response through localization to DNA repair foci and control of cell cycle arrest. To assess the physiological significance of this phosphorylation, we generated ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2KI). ATF2KI mice are more sensitive to ionizing radiation (IR) than wild-type (ATF2 WT) mice: following IR, ATF2KI mice exhibited higher levels of apoptosis in the intestinal crypt cells and impaired hepatic steatosis. Molecular analysis identified impaired activation of the cell cycle regulatory protein p21Cip/Waf1 in cells and tissues of IR-treated ATF2KI mice, which was p53 independent. Analysis of tumor development in p53KO crossed with ATF2KI mice indicated a marked decrease in amount of time required for tumor development. Further, when subjected to two-stage skin carcinogenesis process, ATF2KI mice developed skin tumors faster and with higher incidence, which also progressed to the more malignant carcinomas, compared with the control mice. Using 3 mouse models, we establish the importance of ATF2 phosphorylation by ATM in the acute cellular response to DNA damage and maintenance of genomic stability.

Original languageEnglish (US)
Pages (from-to)316-330
Number of pages15
JournalGenes and Cancer
Volume1
Issue number4
DOIs
StatePublished - Dec 1 2010

Keywords

  • ATF2
  • DNA damage
  • Radiation
  • Tumorigenesis
  • p53

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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    Li, S., Ezhevsky, S., Dewing, A., Cato, M. H., Scortegagna, M., Bhoumik, A., Breitwieser, W., Braddock, D., Eroshkin, A., Qi, J., Chen, M., Kim, J. Y., Jones, S., Jones, N., Rickert, R., & Ronai, Z. A. (2010). Radiation sensitivity and tumor susceptibility in ATM phospho-mutant ATF2 mice. Genes and Cancer, 1(4), 316-330. https://doi.org/10.1177/1947601910370700