G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv.
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.
Doumont
Gilles
G
Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Ghent, Belgium.
Martoriati
Alain
A
Beekman
Chantal
C
Bogaerts
Sven
S
Mee
Patrick J
PJ
Bureau
Fabrice
F
Colombo
Emanuela
E
Alcalay
Myriam
M
Bellefroid
Eric
E
Marchesi
Francesco
F
Scanziani
Eugenio
E
Pelicci
Pier Giuseppe
PG
Marine
Jean-Christophe
JC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens; D002478:Cells, Cultured; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D002273:Carcinogens; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D044767:Ubiquitin-Protein Ligases; D017027:Protein Tyrosine Phosphatases; C474713:Ptprv protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3