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PMID: 17936559 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop.

Cancer cell ·Vol. 12 ·No. 4 ·2007-10-00 ·Pages 342-54

Lu X, Ma O, Nguyen TA, Jones SN, Oren M, Donehower LA

Abstract

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.

MeSH Terms

Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/genetics,metabolism Cell Line, Tumor DNA Damage DNA-Binding Proteins/deficiency,genetics,metabolism Fibroblasts/enzymology,metabolism,radiation effects Homeostasis Humans Mice Mice, Knockout Mutation Osteosarcoma/enzymology,genetics,metabolism Phosphoprotein Phosphatases/deficiency,genetics,metabolism Phosphorylation Proteasome Endopeptidase Complex/metabolism Protein Phosphatase 2C Protein Serine-Threonine Kinases/deficiency,genetics,metabolism Proto-Oncogene Proteins c-mdm2/genetics,metabolism RNA Interference RNA, Small Interfering/metabolism Serine/metabolism Signal Transduction/radiation effects Time Factors Transcription, Genetic Transfection Tumor Suppressor Protein p53/genetics,metabolism Tumor Suppressor Proteins/deficiency,genetics,metabolism Ubiquitin/metabolism Ubiquitin Thiolesterase/metabolism Ubiquitin-Specific Peptidase 7

Chemicals

Cell Cycle Proteins DNA-Binding Proteins RNA, Small Interfering TP53 protein, human Tumor Suppressor Protein p53 Tumor Suppressor Proteins Ubiquitin Serine MDM2 protein, human Mdm2 protein, mouse Proto-Oncogene Proteins c-mdm2 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases PPM1D protein, human Phosphoprotein Phosphatases Ppm1d protein, mouse Protein Phosphatase 2C USP7 protein, human Ubiquitin Thiolesterase Ubiquitin-Specific Peptidase 7 Proteasome Endopeptidase Complex

Authors & Affiliations

6 authors, click to expand affiliations / ORCID

Lu Xiongbin

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]

Ma Ou

Nguyen Thuy-Ai

Jones Stephen N

Oren Moshe

Donehower Lawrence A

Article Info

Journal

Cancer cell

Abbr.

Cancer Cell

ISSN

1535-6108

DOI

10.1016/j.ccr.2007.08.033

[email protected]

Published

2007-10-00

Pages

342-54

Language

English

Region

United States

NLM ID

101130617

Subset

External Links

PubMed source DOI: 10.1016/j.ccr.2007.08.033 View journal details

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The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop.

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