Temporal dissection of p53 function in vitro and in vivo.
To 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 p53ER(TAM), 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.
Christophorou
Maria A
MA
Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California 94143-0875, USA.
Martin-Zanca
Dionisio
D
Soucek
Laura
L
Lawlor
Elizabeth R
ER
Brown-Swigart
Lamorna
L
Verschuren
Emmy W
EW
Evan
Gerard I
GI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D011905:Genes, ras / Q000235:genetics; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014916:Whole-Body Irradiation
D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene