title: Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.
abstract: The inactivation of the p53 tumor suppressor pathway in many cancers often increases their resistance to anticancer therapy. Here we show that a previously proposed strategy directed to Wip1 inhibition could be ineffective in tumors lacking p53. On the contrary, Wip1 overexpression sensitized these tumors to chemotherapeutic agents. This effect was mediated through interaction between Wip1 and RUNX2 that resulted, in response to anticancer treatment, in RUNX2-dependent transcriptional induction of the proapoptotic Bax protein. The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53. The overexpression of Wip1 in normal tissues provided protection from cisplatin-induced apoptosis through decreased strength of upstream signaling to p53. Thus, Wip1 phosphatase promotes apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 866,  University of Burgundy, 21078 Dijon,  France.
authors: Anastasia R
authors: AR
authors: Goloudina
authors: Kan
authors: K
authors: Tanoue
authors: Arlette
authors: A
authors: Hammann
authors: Eric
authors: E
authors: Fourmaux
authors: Xavier
authors: X
authors: Le Guezennec
authors: Dmitry V
authors: DV
authors: Bulavin
authors: Sharlyn J
authors: SJ
authors: Mazur
authors: Ettore
authors: E
authors: Appella
authors: Carmen
authors: C
authors: Garrido
authors: Oleg N
authors: ON
authors: Demidov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D000071636:Protein Phosphatase 2C; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; C493709:RUNX2 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C