The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop
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UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2007-10-16Keywords
AnimalsCell Cycle Proteins
Cell Line, Tumor
DNA Damage
DNA-Binding Proteins
Fibroblasts
Homeostasis
Humans
Mice
Mice, Knockout
Mutation
Osteosarcoma
Phosphoprotein Phosphatases
Phosphorylation
Proteasome Endopeptidase Complex
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-mdm2
RNA Interference
RNA, Small Interfering
Serine
*Signal Transduction
Time Factors
Transcription, Genetic
Transfection
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Ubiquitin
Ubiquitin Thiolesterase
Cell Biology
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Show full item recordAbstract
The tumor suppressor p53 is a transcription factor that responds to cellular stresses by initiating cell cycle arrest or apoptosis. One transcriptional target of p53 is Mdm2, an E3 ubiquitin ligase that interacts with p53 to promote its proteasomal degradation in a negative feedback regulatory loop. Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. Dephosphorylated Mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation. Thus, Wip1 acts as a gatekeeper in the Mdm2-p53 regulatory loop by stabilizing Mdm2 and promoting Mdm2-mediated proteolysis of p53.Source
Cancer Cell. 2007 Oct;12(4):342-54. Link to article on publisher's siteDOI
10.1016/j.ccr.2007.08.033Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36013Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.ccr.2007.08.033
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