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Absence of Wip1 partially rescues Atm deficiency phenotypes in mice

Oncogene volume 31, pages 1155–1165 (2012)Cite this article

Abstract

Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared with Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm null mice. Finally, doubly null mice were partially rescued from gametogenesis defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

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References

  • Abraham RT . (2001). Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15: 2177–2196.

    Article  CAS  PubMed  Google Scholar 

  • Appella E, Anderson CW . (2001). Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268: 2764–2772.

    Article  CAS  PubMed  Google Scholar 

  • Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F et al. (1996). Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159–171.

    Article  CAS  PubMed  Google Scholar 

  • Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870.

    Article  CAS  PubMed  Google Scholar 

  • Belova GI, Demidov ON, Fornace AJ, Bulavin DV . (2005). Chemical inhibition of Wip1 phosphatase contributes to suppression of tumorigenesis. Cancer Biol Ther 4: 1154–1158.

    Article  CAS  PubMed  Google Scholar 

  • Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA et al. (2000). Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci USA 97: 3336–3341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA et al. (2002). Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 31: 210–215.

    Article  CAS  PubMed  Google Scholar 

  • Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW et al. (2004). Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 36: 343–350.

    Article  CAS  PubMed  Google Scholar 

  • Castellino RC, De Bortoli M, Lu X, Moon SH, Nguyen TA, Shepard MA et al. (2008). Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. J Neurooncol 86: 245–256.

    Article  CAS  PubMed  Google Scholar 

  • Choi J, Nannenga B, Demidov ON, Bulavin DV, Cooney A, Brayton C et al. (2002). Mice deficient for the wild-type p53-induced phosphatase gene (Wip1) exhibit defects in reproductive organs, immune function, and cell cycle control. Mol Cell Biol 22: 1094–1105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chun HH, Gatti RA . (2004). Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst) 3: 1187–1196.

    Article  CAS  Google Scholar 

  • Demidov ON, Timofeev O, Lwin HN, Kek C, Appella E, Bulavin DV . (2007). Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 1: 180–190.

    Article  CAS  PubMed  Google Scholar 

  • Ehrbrecht A, Muller U, Wolter M, Hoischen A, Koch A, Radlwimmer B et al. (2006). Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 208: 554–563.

    Article  CAS  PubMed  Google Scholar 

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 19: 817–825.

    Article  Google Scholar 

  • Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J et al. (1996). Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci USA 93: 13084–13089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiscella M, Zhang HL, Fan SJ, Sakaguchi K, Shen SF, Mercer WE et al. (1997). Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA 94: 6048–6053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujimoto H, Onishi N, Kato N, Takekawa M, Xu X, Kosugi A et al. (2006). Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. Cell Death Different 13: 1170–1180.

    Article  CAS  Google Scholar 

  • Gurley KE, Kemp CJ . (2001). Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis. Curr Biol 11: 191–194.

    Article  CAS  PubMed  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J . (2008). An oncogene-induced DNA damage model for cancer development. Science 319: 1352–1355.

    Article  CAS  PubMed  Google Scholar 

  • Harrison M, Li J, Degenhardt Y, Hoey T, Powers S . (2004). Wip1-deficient mice are resistant to common cancer genes. Trends Mol Med 10: 359–361.

    Article  CAS  PubMed  Google Scholar 

  • Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ . (1998). Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280: 1089–1091.

    Article  CAS  PubMed  Google Scholar 

  • Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T et al. (2003). Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 9: 1995–2004.

    CAS  PubMed  Google Scholar 

  • Jiang H, Reinhardt HC, Bartkova J, Tommiska J, Blomqvist C, Nevanlinna H et al. (2009). The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 23: 1895–1909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavin MF . (2008). Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9: 759–769.

    Article  CAS  PubMed  Google Scholar 

  • Le Guezennec X, Bulavin DV . (2009). WIP1 phosphatase at the crossroads of cancer and aging. Trends Biochem Sci 35: 109–114.

    Article  PubMed  Google Scholar 

  • Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven G, Nguyen KCQ et al. (2002). Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet 31: 133–134.

    Article  CAS  PubMed  Google Scholar 

  • Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z et al. (2010). The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci USA 107: 14188–14193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loukopoulos P, Shibata T, Katoh H, Kokubu A, Sakamoto M, Yamazaki K et al. (2007). Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: Identification of genetic indicators that predict patient outcome. Cancer Sci 98: 392–400.

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Ma O, Nguyen TA, Jones SN, Oren M, Donehower LA . (2007). The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 12: 342–354.

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Nannenga B, Donehower LA . (2005a). PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev 19: 1162–1174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu XB, Nguyen TA, Donehower LA . (2005b). Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D. Cell Cycle 4: 1060–1064.

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA . (2008). The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 27: 123–135.

    Article  PubMed  PubMed Central  Google Scholar 

  • Macurek L, Lindqvist A, Voets O, Kool J, Vos HR, Medema RH . (2010). Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. Oncogene 29: 2281–2291.

    Article  CAS  PubMed  Google Scholar 

  • Moon SH, Lin L, Zhang X, Nguyen TA, Darlington Y, Waldman AS et al. (2010). Wildtype p53-induced phosphatase 1 dephosphorylates histone variant {gamma}-H2AX and suppresses DNA double. J Biol Chem 285: 12935–12947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moretti P, Bouwknecht JA, Teague R, PaylorR, Zoghbi HY . (2005). Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 14: 205–220.

    Article  CAS  PubMed  Google Scholar 

  • Nannenga B, Lu X, Dumble M, Van Maanen M, Nguyen TA, Sutton R et al. (2006). Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Mol Carcinog 45: 594–604.

    Article  CAS  PubMed  Google Scholar 

  • Rao PH, Cigudosa JC, Ning Y, Calasanz MJ, Iida S, Tagawa S et al. (1998). Multicolor spectral karyotyping identifies new recurring breakpoints and translocations in multiple myeloma. Blood 92: 1743–1748.

    CAS  PubMed  Google Scholar 

  • Rayter S, Elliott R, Travers J, Rowlands MG, Richardson TB, Boxall K et al. (2008). A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene 27: 1036–1044.

    Article  CAS  PubMed  Google Scholar 

  • Rotman G, Shiloh Y . (1998). ATM: from gene to function. Hum Mol Genet 7: 1555–1563.

    Article  CAS  PubMed  Google Scholar 

  • Saito-Ohara F, Imoto I, Inoue J, Hosoi H, Nakagawara A, Sugimoto T et al. (2003). PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res 63: 1876–1883.

    CAS  PubMed  Google Scholar 

  • Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS et al. (1995). The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet 4: 2025–2032.

    Article  CAS  PubMed  Google Scholar 

  • Sedgwick RP, Boder E . (1991). Ataxia-Telangiectasia. In: deJong JMBE (ed). Hereditary Neuropathies and Spinocerebellar Atrophies. Elsevier: New York, pp 347–423 (Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of Clinical Neurology, Vol 16).

    Google Scholar 

  • Shen KC, Heng H, Wang Y, Lu S, Liu G, Deng CX et al. (2005). ATM and p21 cooperate to suppress aneuploidy and subsequent tumor development. Cancer Res 65: 8747–8753.

    Article  CAS  PubMed  Google Scholar 

  • Shiloh Y . (2003). ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3: 155–168.

    Article  CAS  PubMed  Google Scholar 

  • Shreeram S, Demidov ON, Hee WK, Yamaguchi H, Onishi N, Kek C et al. (2006a). Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol Cell 23: 757–764.

    Article  CAS  PubMed  Google Scholar 

  • Shreeram S, Hee WK, Demidov ON, Kek C, Yamaguchi H, Fornace AJ et al. (2006b). Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. J Exp Med 203: 2793–2799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H et al. (2000). p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J 19: 6517–6526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan DS, Lambros MB, Rayter S, Natrajan R, Vatcheva R, Gao Q et al. (2009). PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin Cancer Res 15: 2269–2280.

    Article  CAS  PubMed  Google Scholar 

  • Westphal CH, Rowan S, Schmaltz C, Elson A, Fisher DE, Leder P . (1997). Atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet 16: 397–401.

    Article  CAS  PubMed  Google Scholar 

  • Williamson CT, Muzik H, Turhan AG, Zamo A, O'Connor MJ, Bebb DG et al. (2010). ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther 9: 347–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia Y, Ongusaha P, Lee SW, Liou YC . (2009). Loss of Wip1 sensitizes cells to stress- and DNA damage-induced apoptosis. J Biol Chem 284: 17428–17437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D . (1996). Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10: 2411–2422.

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi H, Durell SR, Feng HQ, Bai YW, Anderson CW, Appella E . (2006). Development of a substrate-based cyclic phosphopeptide inhibitor of protein phosphatase 2C delta, Wip1. Biochemistry 45: 13193–13202.

    Article  CAS  PubMed  Google Scholar 

  • Yoda A, Toyoshima K, Watanabe Y, Onishi N, Hazaka Y, Tsukuda Y et al. (2008). Arsenic trioxide augments Chk2/p53-mediated apoptosis by inhibiting oncogenic Wip1 phosphatase. J Biol Chem 283: 18969–18979.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Corrine Spencer and Yi-Jue Zhao for technical assistance. This work was supported by NIH grants (R01 CA100420) to LAD and (R01 CA136549) to XL, and a DOD Breast Cancer Research Program Predoctoral Traineeship Award (BC050781) to T-AN

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Authors and Affiliations

  1. Interdepartmental Graduate Program in Cell and Molecular Biology, Houston, TX, USA

    Y Darlington, T-A Nguyen & L A Donehower

  2. Department of Molecular Virology and Microbiology,

    Y Darlington, T-A Nguyen, S-H Moon & L A Donehower

  3. Baylor College of Medicine, Houston, TX, USA

    Y Darlington, T-A Nguyen, S-H Moon & L A Donehower

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    S-H Moon & L A Donehower

  5. Department of Pathology and Immunology and Center for Comparative Medicine, Houston, TX, USA

    A Herron

  6. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    P Rao & L A Donehower

  7. Department of Immunology,

    C Zhu

  8. The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    C Zhu

  9. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    X Lu

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  1. Y Darlington
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Correspondence to L A Donehower.

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Darlington, Y., Nguyen, TA., Moon, SH. et al. Absence of Wip1 partially rescues Atm deficiency phenotypes in mice. Oncogene 31, 1155–1165 (2012). https://doi.org/10.1038/onc.2011.303

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