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Article

  • The EMBO Journal (2005) 24, 3093 - 3103
  • doi:10.1038/sj.emboj.7600769

Published online: 18 August 2005

G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv

Gilles Doumont1,2,a, Alain Martoriati1,2,a, Chantal Beekman1, Sven Bogaerts1, Patrick J Mee3, Fabrice Bureau4, Emanuela Colombo5,6, Myriam Alcalay5,6, Eric Bellefroid2, Francesco Marchesi7, Eugenio Scanziani7, Pier Giuseppe Pelicci5,6 and Jean-Christophe Marine1

  1. Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Ghent, Belgium
  2. Unit of Molecular Embryology, Free University of Brussels (ULB-IBMM), Gosselies, Belgium
  3. Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UK
  4. Unit of Immunology, Free University of Brussels (ULB-IBMM), Gosselies, Belgium
  5. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
  6. FIRC Institute of Molecular Oncology, Milan, Italy
  7. Department of Veterinary Pathology, University of Milan, Milan, Italy

Correspondence to:

Jean-Christophe Marine, Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), Technologiepark, 927, 9052 Ghent, Belgium. Tel.: +32 9 3313640; Fax: +32 9 331360; E-mail: chris.marine@dmbr.ugent.be

aThese authors contributed equally to this work

Received 18 March 2005; Accepted 13 July 2005

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo.

  • Keywords:

    • DNA damage,
    • growth arrest,
    • p53,
    • Ptprv,
    • skin carcinogenesis