Wip1 confers G2 checkpoint recovery competence by counteracting p53‐dependent transcriptional repression
Open accessAbstract
Activation of the DNA damage checkpoint causes a cell-cycle arrest through inhibition of cyclin-dependent kinases (cdks). To successfully recover from the arrest, a cell should somehow be maintained in its proper cell-cycle phase. This problem is particularly eminent when a cell arrests in G2, as cdk activity is important to establish a G2 state. Here, we identify the phosphatase Wip1 (PPM1D) as a factor that maintains a cell competent for cell-cycle re-entry during an ongoing DNA damage response in G2. We show that Wip1 function is required throughout the arrest, and that Wip1 acts by antagonizing p53-dependent repression of crucial mitotic inducers, such as Cyclin B and Plk1. Our data show that the primary function of Wip1 is to retain cellular competence to divide, rather than to silence the checkpoint to promote recovery. Our findings uncover Wip1 as a first in class recovery competence gene, and suggest that the principal function of Wip1 in cellular transformation is to retain proliferative capacity in the face of oncogene-induced stress.
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PPM1D (WIP1) is also a p53 target and encodes for a phosphatase that confers a negative feedback loop through p53 dephosphorylation and cell cycle checkpoint abrogation.
“PPM1D (WIP1) is also a p53 target and encodes for a phosphatase that confers a negative feedback loop through p53 dephosphorylation and cell cycle checkpoint abrogation.40, 220, 221”
From Census and evaluation of p53 target genes (2017) · cites this paper as [221]
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- Authors
- Lindqvist, A., de Bruijn, M., Macurek, L., Brás, A., Mensinga, A., Bruinsma, W., Voets, O., Kranenburg, O., & Medema, R. H.
- Affiliations
- Cancer Genomics Centre (NL)
- Spanish National Cancer Research Centre (ES)
- University Medical Center Utrecht (NL)
- Corresponding author
- Medema, René H
- Venue
- The EMBO Journal
- Published
- 2009-08-27
- Volume
- 28
- Issue
- 20
- Pages
- 3196-3206
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2771084
- OpenAlex
- W2102207006
- Cited by
- 75
- References
- 53
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 5 · 2021: 3 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 6 · 2013: 7 · 2012: 5
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wenner-Gren Foundation
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (916.86.083)
- Ministerio de Economía y Competitividad
- KWF Kankerbestrijding
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Wip1, PPM1D, G2 checkpoint, DNA damage response, cell cycle arrest, cell cycle re-entry, cyclin B, PLK1, cyclin-dependent kinases, cell transformation
- MeSH terms
- Protein Phosphatase 2C, Polo-Like Kinase 1, Flow Cytometry, Humans, Microscopy, Phosphoprotein Phosphatases, Proto-Oncogene Proteins, Blotting, Western, Tumor Suppressor Protein p53, G2 Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin B, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor
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