ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice
Department of Cell and Developmental Biology; Department of Pathology
Medical Subject Headings
Animals; Apoptosis; Cell Cycle Proteins; *DNA Damage; DNA-Binding Proteins; Enzyme Activation; Intestine, Small; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mutation, Missense; Phosphorylation; Protein Stability; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-mdm2; Radiation Tolerance; Serine; Spleen; Thymus Gland; Time Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
Cell and Developmental Biology | Cell Biology
DNA damage induced by ionizing radiation activates the ATM kinase, which subsequently stabilizes and activates the p53 tumor suppressor protein. Although phosphorylation of p53 by ATM was found previously to modulate p53 levels and transcriptional activities in vivo, it does not appear to be a major regulator of p53 stability. We have utilized mice bearing altered Mdm2 alleles to demonstrate that ATM phosphorylation of Mdm2 serine 394 is required for robust p53 stabilization and activation after DNA damage. In addition, we demonstrate that dephosphorylation of Mdm2 Ser394 regulates attenuation of the p53-mediated response to DNA damage. Therefore, the phosphorylation status of Mdm2 Ser394 governs p53 protein levels and functions in cells undergoing DNA damage.
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Citation: Cancer Cell. 2012 May 15;21(5):668-79. Link to article on publisher's site