title: ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Gannon
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Woda
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: stephen.jones@umassmed.edu.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000528:radiation effects; D004789:Enzyme Activation; D007421:Intestine, Small / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000528:radiation effects; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D012694:Serine; D013154:Spleen / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D013950:Thymus Gland / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000528:radiation effects
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases