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Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway

Nature Genetics volume 36, pages 343–350 (2004)Cite this article

Abstract

Modulation of tumor suppressor activities may provide new opportunities for cancer therapy. Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 (also called Ink4a)–p19 (also called ARF) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts (MEFs) by oncogenes. Disruption of the gene Cdkn2a (encoding p16 and p19), but not of Trp53 (encoding p53), reconstituted cell transformation in Ppm1d-null MEFs. In vivo, deletion of Ppm1d in mice bearing mouse mammary tumor virus (MMTV) promoter–driven oncogenes Erbb2 (also called c-neu) or Hras1 impaired mammary carcinogenesis, whereas reduced expression of p16 and p19 by methylation-induced silencing or inactivation of p38 MAPK correlated with tumor appearance. We conclude that inactivation or depletion of the Wip1 phosphatase with resultant p38 MAPK activation suppresses tumor appearance by modulating the Cdkn2a tumor-suppressor locus.

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Figure 1: Resistance of Ppm1d-null MEFs to oncogene-induced transformation in vitro.
Figure 2: Induction of p53 and p16-p19 in Ppm1d-null MEFs.
Figure 3: The p16-p19 pathway rendered Ppm1d-null MEFs resistant to oncogenic transformation.
Figure 4: Deregulation of the p16-pRb pathway in mammary tissues of Ppm1d-null mice.
Figure 5: Ppm1d deficiency impaired mammary tumorigenesis in vivo.
Figure 6: Tumor formation in Ppm1d−/− MMTV-Erbb2 females correlated with lower levels of p16 and p19.
Figure 7: Inactivation of p38 MAPK reduced p16 and p19 expression and correlated with tumor formation in Ppm1d−/− Erbb2 mice.

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Acknowledgements

We thank C. Deng for discussions and comments, D. Medina for help with whole–mammary gland staining, P. Sicinski for pBabe-puro-NeuT, H. Varmus for MMTV-Wnt-1 transgenic mice and M. Roussel for p16-null and p16/p19-null MEFs. O.T. is a Ph.D. student at the Institute of Cytology, St. Petersburg, Russia; his fellowship was sponsored by the US National Institutes of Health Exchange Program. C.W.A. was supported in part by a US Army Breast Cancer Idea Award at the Brookhaven National Laboratory under contract with the US Department of Energy. B.N. was supported by a US Army Breast Cancer Research Training Grant.

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Authors and Affiliations

  1. Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Dmitry V Bulavin, Crissy Phillips, Oleg Timofeev & Albert J Fornace Jr.

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Bonnie Nannenga & Larry A Donehower

  3. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Larry A Donehower

  4. Biology Department, Brookhaven National Laboratory, Upton, 11973, New York, USA

    Carl W Anderson

  5. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ettore Appella

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Bulavin, D., Phillips, C., Nannenga, B. et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway. Nat Genet 36, 343–350 (2004). https://doi.org/10.1038/ng1317

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