Temporal dissection of p53 function in vitro and in vivo

MA Christophorou, D Martin-Zanca, L Soucek… - Nature …, 2005 - nature.com
MA Christophorou, D Martin-Zanca, L Soucek, ER Lawlor, L Brown-Swigart, EW Verschuren…
Nature genetics, 2005nature.com
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 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 …
Abstract
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 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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