Nature Genetics
37, 718 - 726 (2005)
Published online: 29 May 2005; | doi:10.1038/ng1572
Temporal dissection of p53 function in vitro and in vivoMaria A Christophorou1, 4, Dionisio Martin-Zanca1, 2, 4, Laura Soucek1, Elizabeth R Lawlor1, 3, Lamorna Brown-Swigart1, Emmy W Verschuren1, 3
& Gerard I Evan11
Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California
94143-0875, USA. 2
Instituto de Microbiologia Bioquimica CSIC/Universidad de Salamanca, Campus "Miguel de Unamuno,"
37007
Salamanca, Spain. 3
Present addresses: University of Southern California Keck School of Medicine, Division of Hematology/Oncology, Children's Hospital of Los Angeles, 4650 Sunset Blvd, Los Angeles, California
90027, USA (E.R.L.); Stanford University, Pathology Department, 300 Pasteur Drive, MC 5324, Stanford, California
94305, USA (E.W.V.). 4
These authors contributed equally to this work.
Correspondence should be addressed to Gerard I Evan gevan@cc.ucsf.eduTo investigate the functions of the p53 tumor suppressor, we created a new knock-in gene replacement mouse model in which the endogenous Trp53 gene is substituted by one encoding p53ERTAM, a p53 fusion protein whose function is completely dependent on ectopic provision of 4-hydroxytamoxifen. We show here that both tissues in vivo and cells in vitro derived from such mice can be rapidly toggled between wild-type and p53 knockout states. Using this rapid perturbation model, we define the kinetics, dependence, persistence and reversibility of p53-mediated responses to DNA damage in tissues in vivo and to activation of the Ras oncoprotein and stress in vitro. This is the first example to our knowledge of a new class of genetic model that allows the specific, rapid and reversible perturbation of the function of a single endogenous gene in vivo.
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