Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response.
MdmX and Mdm2 regulate p53 tumor suppressor functions by controlling p53 transcriptional activity and/or stability in cells exposed to DNA damage. Accumulating evidence indicates that ATM-mediated phosphorylation and degradation of Mdm2 and MdmX may be the initial driving force that induces p53 activity during the early phase of the DNA damage response. We have recently determined that a novel protein phosphatase, Wip1 (or PPM1D), contributes to p53 regulation by dephosphorylating Mdm2 to close the p53 activation loop initiated by the ATM/ATR kinases. In the present study, we determine that Wip1 directly dephosphorylates MdmX at the ATM-targeted Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser367. Wip1 inhibits the DNA damage-induced ubiquitination and degradation of MdmX, leading to the stabilization of MdmX and reduction of p53 activities. Our data suggest that Wip1 is an important component in the ATM-p53-MdmX regulatory loop.
Zhang
Xinna
X
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA.
Lin
Lin
L
Guo
Huarong
H
Yang
Jianhua
J
Jones
Stephen N
SN
Jochemsen
Aart
A
Lu
Xiongbin
X
D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D054875:Ubiquitination
D016159:Tumor Suppressor Protein p53; D008156:Luciferases; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C