1. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint
- Author
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René H. Medema, Jan Benada, Zdenek Kleibl, Jiri Bartek, Soňa Pecháčková, Libor Macurek, Indra A. Shaltiel, Jan evčík, Pavel Dundr, Petr Pohlreich, Emile E. Voest, and Petra Kleiblova
- Subjects
Cell cycle checkpoint ,DNA damage ,Biology ,medicine.disease_cause ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Report ,Cell Line, Tumor ,Neoplasms ,Phosphoprotein Phosphatases ,medicine ,Humans ,Genetic Predisposition to Disease ,Research Articles ,030304 developmental biology ,0303 health sciences ,Mutation ,Oncogene ,Cell Cycle ,G1 Phase ,Cancer ,Cell Biology ,Cell cycle ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Protein Phosphatase 2C ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Tumor Suppressor Protein p53 ,Carcinogenesis ,DNA Damage ,HeLa Cells - Abstract
Mutations in PPM1D/Wip1 phosphatase impair the DNA damage-induced checkpoint and may predispose cells to tumorigenesis., The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress and represent an intrinsic barrier preventing cancer development. The serine/threonine phosphatase PPM1D/Wip1 inactivates p53 and promotes termination of the DDR pathway. Wip1 has been suggested to act as an oncogene in a subset of tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1. Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline. We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer.
- Published
- 2013
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