Top

Published in:

Open Access 01-06-2008

The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways

Authors: Xiongbin Lu, Thuy-Ai Nguyen, Sung-Hwan Moon, Yolanda Darlington, Matthias Sommer, Lawrence A. Donehower

Published in: Cancer and Metastasis Reviews | Issue 2/2008

Abstract

The Wild-type p53-induced phosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cδ), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16^INK4a and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.

Abraham, R. T. (2001). Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes & Development, 15, 2177–2196.CrossRef

Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nature Reviews Cancer, 3, 155–168.PubMedCrossRef

Kim, S. T., Lim, D. S., Canman, C. E., & Kastan, M. B. (1999). Substrate specificities and identification of putative substrates of ATM kinase family members. Journal of Biological Chemistry, 274, 37538–37543.PubMedCrossRef

Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald 3rd, E. R., Hurov, K. E., Luo, J., et al. (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science, 316, 1160–1166.PubMedCrossRef

Gorgoulis, V. G., Vassiliou, L. V., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., et al. (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature, 434, 907–913.PubMedCrossRef

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.PubMedCrossRef

Shreeram, S., Demidov, O. N., Hee, W. K., Yamaguchi, H., Onishi, N., Kek, C., et al. (2006). Wip1 phosphatase modulates ATM-dependent signaling pathways. Molecular Cell, 23, 757–764.PubMedCrossRef

Lu, X., Ma, O., Nguyen, T. A., Jones, S. N., Oren, M., & Donehower, L. A. (2007). The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell, 12, 342–354.PubMedCrossRef

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

10.

Lu, X., Nannenga, B., & Donehower, L. A. (2005). PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes & Development, 19, 1162–1174.CrossRef

11.

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 Journal, 19, 6517–6526.PubMedCrossRef

12.

Bulavin, D. V., Phillips, C., Nannenga, B., Timofeev, O., Donehower, L. A., Anderson, C. W., et al. (2004). Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nature Genetics, 36, 343–350.PubMedCrossRef

13.

Fiscella, M., Zhang, H., Fan, S., Sakaguchi, K., Shen, S., Mercer, W. E., et al. (1997). Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proceedings of the National Academy of Sciences of the United States of America, 94, 6048–6053.PubMedCrossRef

14.

Yoda, A., Xu, X. Z., Onishi, N., Toyoshima, K., Fujimoto, H., Kato, N., et al. (2006). Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. Journal of Biological Chemistry, 281, 24847–24862.PubMedCrossRef

15.

Yamaguchi, H., Minopoli, G., Demidov, O. N., Chatterjee, D. K., Anderson, C. W., Durell, S. R., et al. (2005). Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. Biochemistry, 44, 5285–5294.PubMedCrossRef

16.

Choi, J., Appella, E., & Donehower, L. A. (2000). The structure and expression of the murine wildtype p53-induced phosphatase 1 (Wip1) gene. Genomics, 64, 298–306.PubMedCrossRef

17.

Bulavin, D. V., Demidov, O. N., Saito, S., Kauraniemi, P., Phillips, C., Amundson, S. A., et al. (2002). Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nature Genetics, 31, 210–215.PubMedCrossRef

18.

Barford, D., Das, A. K., & Egloff, M. P. (1998). The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annual Review of Biophysics and Biomolecular Structure, 27, 133–164.PubMedCrossRef

19.

Moorhead, G. B., Trinkle-Mulcahy, L., & Ulke-Lemee, A. (2007). Emerging roles of nuclear protein phosphatases. Nature Reviews Molecular Cell Biology, 8, 234–244.PubMedCrossRef

20.

Barford, D. (1996). Molecular mechanisms of the protein serine/threonine phosphatases. Trends in Biochemical Sciences, 21, 407–412.PubMedCrossRef

21.

Jackson, M. D., & Denu, J. M. (2001). Molecular reactions of protein phosphatases—insights from structure and chemistry. Chemical Reviews, 101, 2313–2340.PubMedCrossRef

22.

Takekawa, M., Maeda, T., & Saito, H. (1998). Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO Journal, 17, 4744–4752.PubMedCrossRef

23.

Hanada, M., Kobayashi, T., Ohnishi, M., Ikeda, S., Wang, H., Katsura, K., et al. (1998). Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells. FEBS Letters, 437, 172–176.PubMedCrossRef

24.

Yamaguchi, H., Durell, S. R., Feng, H., Bai, Y., Anderson, C. W., & Appella, E. (2006). Development of a substrate-based cyclic phosphopeptide inhibitor of protein phosphatase 2Cdelta, Wip1. Biochemistry, 45, 13193–13202.PubMedCrossRef

25.

Lu, X., Bocangel, D., Nannenga, B., Yamaguchi, H., Appella, E., & Donehower, L. A. (2004). The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Molecular Cell, 15, 621–634.PubMedCrossRef

26.

Lu, X., Nguyen, T. A., & Donehower, L. A. (2005). Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D. Cell Cycle, 4, 1060–1064.PubMed

27.

Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., & Kastan, M. B. (1997). DNA damage induces phosphorylation of the amino terminus of p53. Genes & Development, 11, 3471–3481.CrossRef

28.

Bulavin, D. V., Saito, S., Hollander, M. C., Sakaguchi, K., Anderson, C. W., Appella, E., et al. (1999). Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO Journal, 18, 6845–6854.PubMedCrossRef

29.

Liu, Q., Guntuku, S., Cui, X. S., Matsuoka, S., Cortez, D., Tamai, K., et al. (2000). Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes & Development, 14, 1448–1459.CrossRef

30.

Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y., & Prives, C. (2000). The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes & Development, 14, 289–300.

31.

Maya, R., Balass, M., Kim, S. T., Shkedy, D., Leal, J. F., Shifman, O., et al. (2001). ATM-dependent phosphorylation of Mdm2 on serine 395: Role in p53 activation by DNA damage. Genes & Development, 15, 1067–1077.CrossRef

32.

Derijard, B., Raingeaud, J., Barrett, T., Wu, I. H., Han, J., Ulevitch, R. J., et al. (1995). Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science, 267, 682–685.PubMedCrossRef

33.

Raingeaud, J., Gupta, S., Rogers, J. S., Dickens, M., Han, J., Ulevitch, R. J., et al. (1995). Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. Journal of Biological Chemistry, 270, 7420–7426.PubMedCrossRef

34.

She, Q. B., Chen, N., & Dong, Z. (2000). ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. Journal of Biological Chemistry, 275, 20444–20449.PubMedCrossRef

35.

Huang, C., Ma, W. Y., Maxiner, A., Sun, Y., & Dong, Z. (1999). p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. Journal of Biological Chemistry, 274, 12229–12235.PubMedCrossRef

36.

Krokan, H. E., Drablos, F., & Slupphaug, G. (2002). Uracil in DNA—occurrence, consequences and repair. Oncogene, 21, 8935–8948.PubMedCrossRef

37.

Rual, J. F., Venkatesan, K., Hao, T., Hirozane-Kishikawa, T., Dricot, A., Li, N., et al. (2005). Towards a proteome-scale map of the human protein-protein interaction network. Nature, 437, 1173–1178.PubMedCrossRef

38.

Lu, X., Nguyen, T. A., Appella, E., & Donehower, L. A. (2004). Homeostatic regulation of base excision repair by a p53-induced phosphatase: Linking stress response pathways with DNA repair proteins. Cell Cycle, 3, 1363–1366.PubMed

39.

Bartek, J., & Lukas, J. (2003). Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell, 3, 421–429.PubMedCrossRef

40.

Zhao, H., & Piwnica-Worms, H. (2001). ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Molecular Cell Biology, 21, 4129–4139.CrossRef

41.

Karlsson-Rosenthal, C., & Millar, J. B. (2006). Cdc25: mechanisms of checkpoint inhibition and recovery. Trends in Cell Biology, 16, 285–292.PubMedCrossRef

42.

Melchionna, R., Chen, X. B., Blasina, A., & McGowan, C. H. (2000). Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nature Cell Biology, 2, 762–765.PubMedCrossRef

43.

Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K., & Elledge, S. J. (2000). Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proceedings of the National Academy of Sciences of the United States of America, 97, 10389–10394.PubMedCrossRef

44.

Ahn, J. Y., Schwarz, J. K., Piwnica-Worms, H., & Canman, C. E. (2000). Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Research, 60, 5934–5936.PubMed

45.

Gatei, M., Sloper, K., Sorensen, C., Syljuasen, R., Falck, J., Hobson, K., et al. (2003). Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation. Journal of Biological Chemistry, 278, 14806–14811.PubMedCrossRef

46.

Hirao, A., Cheung, A., Duncan, G., Girard, P. M., Elia, A. J., Wakeham, A., et al. (2002). Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Molecular Cell Biology, 22, 6521–6532.CrossRef

47.

Cuadrado, M., Martinez-Pastor, B., & Fernandez-Capetillo, O. (2006). “ATR activation in response to ionizing radiation: still ATM territory”. Cell Division, 1, 7.PubMedCrossRef

48.

Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C., Lukas, J., et al. (2006). ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nature Cell Biology, 8, 37–45.PubMedCrossRef

49.

Nannenga, B., Lu, X., Dumble, M., Van Maanen, M., Nguyen, T. A., Sutton, R., et al. (2006). Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Molecular Carcinogenesis, 45, 594–604.PubMedCrossRef

50.

Oliva-Trastoy, M., Berthonaud, V., Chevalier, A., Ducrot, C., Marsolier-Kergoat, M. C., Mann, C., et al. (2007). The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene, 26, 1449–1458.PubMedCrossRef

51.

Fuku, T., Semba, S., Yutori, H., & Yokozaki, H. (2007). Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma. Pathology International, 57, 566–571.PubMedCrossRef

52.

Horn, H. F., & Vousden, K. H. (2007). Coping with stress: Multiple ways to activate p53. Oncogene, 26, 1306–1316.PubMedCrossRef

53.

Olivier, M., Hussain, S. P., Caron de Fromentel, C., Hainaut, P., & Harris, C. C. (2004). TP53 mutation spectra and load: A tool for generating hypotheses on the etiology of cancer. IARC Scientific Publications, 157, 247–270.PubMed

54.

Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery Jr., C. A., Butel, J. S., et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature, 356, 215–221.PubMedCrossRef

55.

Bond, G. L., Hu, W., & Levine, A. J. (2005). MDM2 is a central node in the p53 pathway: 12 years and counting. Current Cancer Drug Targets, 5, 3–8.PubMedCrossRef

56.

Shieh, S. Y., Ikeda, M., Taya, Y., & Prives, C. (1997). DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell, 91, 325–334.PubMedCrossRef

57.

Shreeram, S., Hee, W. K., Demidov, O. N., Kek, C., Yamaguchi, H., Fornace Jr., A. J., et al. (2006). Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. Journal of Experimental Medicine, 203, 2793–2799.PubMedCrossRef

58.

Ostman, A., Hellberg, C., & Bohmer, F. D. (2006). Protein-tyrosine phosphatases and cancer. Nature Reviews Cancer, 6, 307–320.PubMedCrossRef

59.

Arroyo, J. D., & Hahn, W. C. (2005). Involvement of PP2A in viral and cellular transformation. Oncogene, 24, 7746–7755.PubMedCrossRef

60.

Li, J., Yang, Y., Peng, Y., Austin, R. J., van Eyndhoven, W. G., Nguyen, K. C., et al. (2002). Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nature Genetics, 31, 133–134.PubMedCrossRef

61.

Momand, J., Jung, D., Wilczynski, S., & Niland, J. (1998). The MDM2 gene amplification database. Nucleic Acids Research, 26, 3453–3459.PubMedCrossRef

62.

Rauta, J., Alarmo, E. L., Kauraniemi, P., Karhu, R., Kuukasjarvi, T., & Kallioniemi, A. (2006). The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Research and Treatment, 95, 257–263.PubMedCrossRef

63.

Yu, E., Ahn, Y. S., Jang, S. J., Kim, M. J., Yoon, H. S., Gong, G., et al. (2007). Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. Breast Cancer Research and Treatment, 101, 269–278.PubMedCrossRef

64.

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. Clinical Cancer Research, 9, 1995–2004.PubMed

65.

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 Research, 63, 1876–1883.PubMed

66.

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 Science, 98, 392–400.PubMedCrossRef

67.

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. Journal of Pathology, 208, 554–563.PubMedCrossRef

68.

Mendrzyk, F., Radlwimmer, B., Joos, S., Kokocinski, F., Benner, A., Stange, D. E., et al. (2005). Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. Journal of Clinical Oncology, 23, 8853–8862.PubMedCrossRef

69.

Castellino, C., De Bortoli, M., Moon S. H., Lu, X., Skapura, D. G., Lin, L. L., et al. (2007). Medulloblastomas overexpress the p53-Inactivating oncogene Wip1/PPM1D. J. Neuro-Onc. (in press).

70.

Demidov, O. N., Kek, C., Shreeram, S., Timofeev, O., Fornace, A. J., Appella, E., et al. (2007). The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene, 26, 2502–2506.PubMedCrossRef

71.

Choi, J., Nannenga, B., Demidov, O. N., Bulavin, D. V., 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. Molecular Cell Biology, 22, 1094–1105.CrossRef

72.

Belova, G. I., Demidov, O. N., Fornace Jr., A. J., & Bulavin, D. V. (2005). Chemical inhibition of Wip1 phosphatase contributes to suppression of tumorigenesis. Cancer Biology and Therapy, 4, 1154–1158.PubMedCrossRef

73.

Rayter, S., Elliott, R., Travers, J., Rowlands, M. G., Richardson, T. B., Boxall, K., et al. (2007). A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene (in press).

74.

Proia, D. A., Nannenga, B. W., Donehower, L. A., & Weigel, N. L. (2006). Dual roles for the phosphatase PPM1D in regulating progesterone receptor function. Journal of Biological Chemistry, 281, 7089–7101.PubMedCrossRef

75.

Schito, M. L., Demidov, O. N., Saito, S., Ashwell, J. D., & Appella, E. (2006). Wip1 phosphatase-deficient mice exhibit defective T cell maturation due to sustained p53 activation. Journal of Immunology, 176, 4818–4825.

Title: The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways
Authors: Xiongbin Lu
Thuy-Ai Nguyen
Sung-Hwan Moon
Yolanda Darlington
Matthias Sommer
Lawrence A. Donehower
Publication date: 01-06-2008
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 2/2008
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-008-9127-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2008

Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development

Biography - Stephen M. Keyse

The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer

Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis

Targeted therapy for oesophageal cancer: an overview

Dual-specificity MAP kinase phosphatases (MKPs) and cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer