title: Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis.
abstract: ATM phosphorylation of Mdm2-S394 is required for robust p53 stabilization and activation in DNA-damaged cells. We have now utilized Mdm2(S394A) knockin mice to determine that phosphorylation of Mdm2-S394 regulates p53 activity and the DNA damage response in lymphatic tissues in vivo by modulating Mdm2 stability. Mdm2-S394 phosphorylation delays lymphomagenesis in Eμ-myc transgenic mice, and preventing Mdm2-S394 phosphorylation obviates the need for p53 mutation in Myc-driven tumorigenesis. However, irradiated Mdm2(S394A) mice also have increased hematopoietic stem and progenitor cell functions, and we observed decreased lymphomagenesis in sub-lethally irradiated Mdm2(S394A) mice. These findings document contrasting effects of ATM-Mdm2 signaling on p53 tumor suppression and reveal that destabilizing Mdm2 by promoting its phosphorylation by ATM would be effective in treating oncogene-induced malignancies, while inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies.
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Michael I
authors: MI
authors: Carr
authors: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Justine E
authors: JE
authors: Roderick
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Hugh S
authors: HS
authors: Gannon
authors: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Michelle A
authors: MA
authors: Kelliher
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: stephen.jones@umassmed.edu.
authors: Stephen N
authors: SN
authors: Jones
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology / Q000528:radiation effects; D063646:Carcinogenesis / Q000378:metabolism* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000528:radiation effects; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008822:Mice, Transgenic; D009857:Oncogenes; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D055550:Protein Stability / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D051736:Proto-Oncogene Proteins c-mdm2; D064007:Ataxia Telangiectasia Mutated Proteins