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

TitleG1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv.
Publication TypeJournal Article
Year of Publication2005
AuthorsDoumont G, Martoriati A, Beekman C, Bogaerts S, Mee PJ, Bureau F, Colombo E, Alcalay M, Bellefroid E, Marchesi F, Scanziani E, Pelicci PGiuseppe, Marine J-C
JournalEMBO J
Volume24
Issue17
Pagination3093-103
Date Published2005 Sep 7
ISSN0261-4189
Keywords9,10-Dimethyl-1,2-benzanthracene, Amino Acid Sequence, Animals, Apoptosis, Carcinogens, Cells, Cultured, DNA Damage, Embryo, Mammalian, Epithelial Cells, Fibroblasts, G1 Phase, Intestinal Mucosa, Intestine, Small, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Papilloma, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Skin Neoplasms, Transcription, Genetic, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Abstract

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.

DOI10.1038/sj.emboj.7600769
Alternate JournalEMBO J.
PubMed ID16107883
PubMed Central IDPMC1201350
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