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Cited by 44Cancer-related Molecular PathwaysProtein Tyrosine PhosphatasesUbiquitin and proteasome pathways

The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability

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Lu, Xiongbin, Nguyen, Thuy-Ai, Zhang, Xinna, Donehower, Lawrence A.·2008·Cell Cycle
DOI 10.4161/cc.7.2.5299
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Abstract

The p53 tumor suppressor is essential in maintaining genomic integrity in response to cellular stresses. In response to DNA damage, p53 is activated and stabilized largely through post-translational modifications, including phosphorylation by DNA damage responsive kinases such as ATM and ATR. Activated p53 transactivates a battery of genes that can mediate either cell cycle arrest or apoptosis. In those instances where p53 facilitates cell cycle arrest, a means to return the cell to a pre-stress state with low p53 levels is important. The E3 ubiquitin ligase Mdm2 is one p53 transcriptional target that accumulates after damage and promotes p53 ubiquitination and degradation. Thus, p53 and Mdm2 form a critical negative feedback regulatory loop that helps to maintain appropriate p53 levels in the presence or absence of stress. We propose here that Wip1 (Wildtype p53-Induced Phosphatase 1), also known as PPM1D, plays an important role in the p53-Mdm2 autoregulatory loop. We have recently shown that Wip1, also a p53 target gene, dephosphorylates Mdm2 at Ser395 (an ATM target site), resulting in stabilization of Mdm2, enhanced Mdm2-p53 binding, and enhanced ubiquitination of p53 by Mdm2. Thus, Wip1 facilitates Mdm2-mediated degradation of p53. The p53 inhibitory role of Wip1 implicates it as a potential oncogene and indeed Wip1 is amplified and overexpressed in a number of human cancers. Wip1 may inhibit p53 signaling by multiple mechanisms, but our data suggests that its largest effects are due to dephosphorylation of Mdm2.

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  • Reversal of Mdm2 and Mdmx phosphorylation should inhibit p53 function, and studies of the Wip1 phosphatase suggest this is the case.

    “A corollary from the above is that reversal of Mdm2 and Mdmx phosphorylation should inhibit p53 function, and studies of the Wip1 phosphatase suggest this is the case [59,60].”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [60]

  • Wip1 can specifically dephosphorylate Mdm2 at Ser395 and Mdmx at Ser403 and indirectly at Ser342 and Ser367, which increases their stability in order to inhibit p53 function.

    “In addition to dephosphorylating p53, Wip1 can specifically dephosphorylate Mdm2 at Ser395 and Mdmx at Ser403 and indirectly at Ser342 and Ser367, which increases their stability in order to inhibit p53 function [59,60].”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [60]

  • PPM1D can dephosphorylate both MDM2 and MDMX, thereby contributing to its oncogenic function.

    “Indeed, protein phosphatase 1D (PPM1D) can dephosphorylate both MDM2 and MDMX, thereby contributing to its oncogenic function43,44.”

    From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [43]

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Authors
Lu, X., Nguyen, T.-A., Zhang, X., & Donehower, L. A.
Affiliations
  • University of South Carolina (US)
  • Baylor College of Medicine (US)
ORCID
Venue
Cell Cycle
Publisher
Informa UK Limited
Published
2008-01-15
Volume
7
Issue
2
Pages
164-168
ISSN
  • 1538-4101 (ISSN-L)
  • 1551-4005
DOI
10.4161/cc.7.2.5299
OpenAlex
W2017058074
Cited by
44
References
0
Citations by year
2025: 3 · 2024: 1 · 2023: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 8
FWCI
1.93
Type
journal article
Language
en
Open access
Locations
  • Cell Cycle (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
Wip1 phosphatase, MDM2, p53 stabilization, p53 ubiquitination, p53 degradation, ATM, DNA damage response, E3 ubiquitin ligase, oncogenes
MeSH terms
Protein Phosphatase 2C, Animals, DNA Damage, Humans, Phosphoprotein Phosphatases, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2

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