title: Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint.
abstract: 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.
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, CZ-12853 Prague, Czech Republic.
authors: Petra
authors: P
authors: Kleiblova
authors: Indra A
authors: IA
authors: Shaltiel
authors: Jan
authors: J
authors: Benada
authors: Jan
authors: J
authors: Ševčík
authors: Soňa
authors: S
authors: Pecháčková
authors: Petr
authors: P
authors: Pohlreich
authors: Emile E
authors: EE
authors: Voest
authors: Pavel
authors: P
authors: Dundr
authors: Jiri
authors: J
authors: Bartek
authors: Zdenek
authors: Z
authors: Kleibl
authors: René H
authors: RH
authors: Medema
authors: Libor
authors: L
authors: Macurek
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000502:physiology*; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
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