Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response
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Abstract
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.
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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 [59]
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 [59]
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 [44]
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References 34 · Cited by 67
Research works printed but not linked: 1
- [30]Parant J Chavez-Reyes A Little NA Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53 Nat Genet 2001 29 92 5 11528400
- Authors
- Zhang, X., Lin, L., Guo, H., Yang, J., Jones, S. N., Jochemsen, A., & Lu, X.
- Affiliations
- 1Department of Biological Sciences and
- Baylor College of Medicine (US)
- University of Massachusetts Chan Medical School (US)
- Leiden University Medical Center (NL)
- University of South Carolina (US)
- Venue
- Cancer Research
- Published
- 2009-10-14
- Volume
- 69
- Issue
- 20
- Pages
- 7960-7968
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2763051
- OpenAlex
- W2115078294
- Cited by
- 67
- References
- 34
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 5 · 2012: 8
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- American Federation for Aging Research
- National Institutes of Health
- National Cancer Institute (R01CA136549, R01CA077735)
- 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 › DNA Repair Mechanisms
- Keywords
- MDMX, Wip1 phosphatase, PPM1D, p53 regulation, DNA damage response, ATM kinase, protein dephosphorylation, ubiquitination, protein degradation, MDM2, p53 stabilization, tumor suppressor
- MeSH terms
- Protein Phosphatase 2C, Animals, Bone Neoplasms, Cells, Cultured, DNA Damage, Embryo, Mammalian, Fibroblasts, Humans, Luciferases, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Osteosarcoma, Transfection, Blotting, Western, Tumor Suppressor Protein p53, Mice, Knockout, Mice, Proto-Oncogene Proteins c-mdm2, Ubiquitination
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