Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2009-10-08Keywords
AnimalsBlotting, Western
Bone Neoplasms
Cells, Cultured
*DNA Damage
Embryo, Mammalian
Fibroblasts
Humans
Luciferases
Mice
Mice, Knockout
Mutation
Osteosarcoma
Phosphoprotein Phosphatases
Phosphorylation
Proto-Oncogene Proteins c-mdm2
Transfection
Tumor Suppressor Protein p53
Ubiquitination
Cell Biology
Metadata
Show full item recordAbstract
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.Source
Cancer Res. 2009 Oct 15;69(20):7960-8. Epub 2009 Oct 6. Link to article on publisher's siteDOI
10.1158/0008-5472.CAN-09-0634Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36008Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-09-0634