Current Colorectal Cancer Reports

, Volume 5, Issue 4, pp 197–202 | Cite as

Wip1, an oncogene targeting tumor suppressors expressed in intestinal stem cells

  • Oleg N. Demidov
  • Hyukjin Cha
  • Dmitry V. Bulavin
  • Albert J. FornaceJrEmail author


Wip1 phosphatase (PPM1D) has oncogenic properties and is implicated in a variety of cancer types, including gastrointestinal. Like Mdm2, Wip1 normally functions to resolve stress responses, such as after DNA damage, and return the cell to its normal, unstressed state. It is expressed in somatic as well as stem cells, with relatively high expression in intestinal stem cells. Loss of normal APC function and other events early in the carcinogenic process trigger a stress-like state often referred to as oncogenic stress. Wip1 can dampen protective responses to such stress through dephosphorylation of key activating sites in important tumor suppressors, such as p53. Even normal levels of Wip1 affect tumor suppression, because Wip1-deficient mice are markedly tumor resistant in a variety of tumor-prone models, including APCmin. Unlike Mdm2-null mice, Wip1-null mice have a relatively mild phenotype, so development of Wip1 inhibitors may be well tolerated in vivo.


Intestinal Stem Cell Important Tumor Suppressor Intestinal Tumorigenesis Oncogenic Stress Wip1 Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Jones S, Chen WD, Parmigiani G, et al.: Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 2008, 105:4283–4288.CrossRefPubMedGoogle Scholar
  2. 2.
    Grady WM, Carethers JM: Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008, 135:1079–1099.CrossRefPubMedGoogle Scholar
  3. 3.
    Lowe SW, Cepero E, Evan G: Intrinsic tumour suppression. Nature 2004, 432:307–315.CrossRefPubMedGoogle Scholar
  4. 4.
    Bulavin DV, Fornace AJ Jr: p38 MAP kinase’s emerging role as a tumor suppressor. Adv Cancer Res 2004, 92:95–118.CrossRefPubMedGoogle Scholar
  5. 5.
    Wood LD, Parsons DW, Jones S, et al.: The genomic landscapes of human breast and colorectal cancers. Science 2007, 318:1108–1113.CrossRefPubMedGoogle Scholar
  6. 6.
    Kruse JP, Gu W: Modes of p53 regulation. Cell 2009, 137:609–622.CrossRefPubMedGoogle Scholar
  7. 7.
    Fiscella M, Zhang H, Fan S, et al.: Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci U S A 1997, 94:6048–6053.CrossRefPubMedGoogle Scholar
  8. 8.
    Clarke AR, Cummings MC, Harrison DJ: Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. Oncogene 1995, 11:1913–1920.PubMedGoogle Scholar
  9. 9.
    Fazeli A, Steen RG, Dickinson SL, et al.: Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas. Proc Natl Acad Sci U S A 1997, 94:10199–10204.CrossRefPubMedGoogle Scholar
  10. 10.
    Halberg RB, Katzung DS, Hoff PD, et al.: Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers. Proc Natl Acad Sci U S A 2000, 97:3461–3466.CrossRefPubMedGoogle Scholar
  11. 11.
    Reed KR, Meniel VS, Marsh V, et al.: A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer 2008, 8:162.CrossRefPubMedGoogle Scholar
  12. 12.
    Yamaguchi H, Durell SR, Feng H, et al.: Development of a substrate-based cyclic phosphopeptide inhibitor of protein phosphatase 2Cdelta, Wip1. Biochemistry 2006, 45:13193–13202.CrossRefPubMedGoogle Scholar
  13. 13.
    Shreeram S, Demidov ON, Hee WK, et al.: Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol Cell 2006, 23:757–764.CrossRefPubMedGoogle Scholar
  14. 14.
    Demidov ON, Timofeev O, Lwin HN, et al.: Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 2007, 1:180–190.CrossRefPubMedGoogle Scholar
  15. 15.
    Chuman Y, Kurihashi W, Mizukami Y, et al.: PPM1D430, a novel alternative splicing variant of the human PPM1D, can dephosphorylate p53 and exhibits specific tissue expression. J Biochem 2009, 145:1–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Bulavin DV, Demidov ON, Saito S, et al.: Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 2002, 31:210–215.CrossRefPubMedGoogle Scholar
  17. 17.
    Takekawa M, Adachi M, Nakahata A, et al.: p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J 2000, 19:6517–6526.CrossRefPubMedGoogle Scholar
  18. 18.
    Lu X, Nguyen TA, Moon SH, et al.: The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 2008, 27:123–135.CrossRefPubMedGoogle Scholar
  19. 19.
    Lu X, Nguyen TA, Zhang X, et al.: The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability. Cell Cycle 2008, 7:164–168.PubMedGoogle Scholar
  20. 20.
    Chew J, Biswas S, Shreeram S, et al.: WIP1 phosphatase is a negative regulator of NF-kappaB signalling. Nat Cell Biol 2009, 11:659–666.CrossRefPubMedGoogle Scholar
  21. 21.
    Lu X, Ma O, Nguyen TA, et al.: The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 2007, 12:342–354.CrossRefPubMedGoogle Scholar
  22. 22.
    Li J, Yang Y, Peng Y, et al.: Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet 2002, 31:133–134.CrossRefPubMedGoogle Scholar
  23. 23.
    Shreeram S, Hee WK, Demidov ON, et al.: Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. J Exp Med 2006, 203:2793–2799.CrossRefPubMedGoogle Scholar
  24. 24.
    Bulavin DV, Saito S, Hollander MC, et al.: Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 1999, 18:6845–6854.CrossRefPubMedGoogle Scholar
  25. 25.
    Fuku T, Semba S, Yutori H, et al.: Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma. Pathol Int 2007, 57:566–571.CrossRefPubMedGoogle Scholar
  26. 26.
    Oshima T, Sasaki M, Kataoka H, et al.: Wip1 protects hydrogen peroxide-induced colonic epithelial barrier dysfunction. Cell Mol Life Sci 2007, 64:3139–3147.CrossRefPubMedGoogle Scholar
  27. 27.
    Hartmann DP, Kallakury BVS, Luka J, et al.: Immunohistochemical expression of the PPM1D/wip-1 protein correlates with aggressive tumor behavior in invasive colorectal carcinomas (CRCS) [abstract 479]. Presented at the Annual Meeting of the United States and Canadian Academy of Pathology. San Antonio, TX; February 26–March 4, 2005.Google Scholar
  28. 28.
    Choi J, Nannenga B, Demidov ON, et al.: 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 2002, 22:1094–1105.CrossRefPubMedGoogle Scholar
  29. 29.
    Nannenga B, Lu X, Dumble M, et al.: Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Mol Carcinog 2006, 45:594–604.CrossRefPubMedGoogle Scholar
  30. 30.
    Bulavin DV, Phillips C, Nannenga B, et al.: Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 2004, 36:343–350.CrossRefPubMedGoogle Scholar
  31. 31.
    Potten CS, Ellis JR: Adult small intestinal stem cells: identification, location, characteristics, and clinical applications. Ernst Schering Res Found Workshop 2006, 81–98.Google Scholar
  32. 32.
    Morrison SJ, Kimble J: Asymmetric and symmetric stemcell divisions in development and cancer. Nature 2006, 441:1068–1074.CrossRefPubMedGoogle Scholar
  33. 33.
    Bulavin DV, Kovalsky O, Hollander MC, et al.: Abrogation of oncogenic H-ras-induced cell-cycle arrest and p38 MAPK activation by disruption of Gadd45a. Mol Cell Biol 2003, 23:3859–3871.CrossRefPubMedGoogle Scholar
  34. 34.
    Mendrysa SM, O’Leary KA, McElwee MK, et al.: Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 2006, 20:16–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Qiu W, Carson-Walter EB, Kuan SF, et al.: PUMA suppresses intestinal tumorigenesis in mice. Cancer Res 2009, 69:4999–5006.CrossRefPubMedGoogle Scholar
  36. 36.
    Ito K, Hirao A, Arai F, et al.: Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 2006, 12:446–451.CrossRefPubMedGoogle Scholar
  37. 37.
    Ventura JJ, Tenbaum S, Perdiguero E, et al.: p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet 2007, 39:750–758.CrossRefPubMedGoogle Scholar
  38. 38.
    Cha H, Wang X, Li H, Fornace AJ Jr: A functional role for p38 MAP kinase in modulating mitotic transit in the absence of stress. J Biol Chem 2007, 282:22984–22992.CrossRefPubMedGoogle Scholar
  39. 39.
    Guo YL, Yang B: Altered cell adhesion and cell viability in a p38alpha mitogen-activated protein kinase-deficient mouse embryonic stem cell line. Stem Cells Dev 2006, 15:655–664.CrossRefPubMedGoogle Scholar
  40. 40.
    Sharpless NE, DePinho RA: How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007, 8:703–713.CrossRefPubMedGoogle Scholar
  41. 41.
    Park IK, Qian D, Kiel M, et al.: Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003, 423:302–305.CrossRefPubMedGoogle Scholar
  42. 42.
    Molofsky AV, Slutsky SG, Joseph NM, et al.: Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006, 443:448–452.CrossRefPubMedGoogle Scholar
  43. 43.
    Lee JS, Lee MO, Moon BH, et al.: Senescent growth arrest in mesenchymal stem cells is bypassed by Wip1-mediated downregulation of intrinsic stress signaling pathways. Stem Cells 2009, 27:1963–1975.CrossRefPubMedGoogle Scholar
  44. 44.
    Zhu YH, Zhang CW, Lu L, et al.: Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control. Stem Cells 2009, 27:1433–1442.CrossRefPubMedGoogle Scholar
  45. 45.
    Wong ES, Le Guezennec X, Demidov ON, et al.: p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell 2009, 17:142–149.CrossRefPubMedGoogle Scholar
  46. 46.
    Saito-Ohara F, Imoto I, Inoue J, et al.: PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res 2003, 63:1876–1883.PubMedGoogle Scholar
  47. 47.
    Belova GI, Demidov ON, Fornace AJ Jr, et al.: Chemical inhibition of Wip1 phosphatase contributes to suppression of tumorigenesis. Cancer Biol Ther 2005, 4:1154–1158.PubMedCrossRefGoogle Scholar
  48. 48.
    Rayter S, Elliott R, Travers J, et al.: A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene 2008, 27:1036–1044.CrossRefPubMedGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Oleg N. Demidov
  • Hyukjin Cha
  • Dmitry V. Bulavin
  • Albert J. FornaceJr
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular and Cellular Biology, and Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashington, DCUSA

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