Temporal dissection of p53 function in vitro and in vivo.

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 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.

• Authors: Maria A Christophorou, Dionisio Martin-Zanca, Laura Soucek, Elizabeth R Lawlor, Lamorna Brown-Swigart, Emmy W Verschuren, Gerard I Evan
• Journal: Nature genetics (Nat Genet) Vol. 37 Issue 7 Pg. 718-26 (Jul 2005) ISSN: 1061-4036 [Print] United States
• PMID: 15924142 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Tumor Suppressor Protein p53
• Tamoxifen
• afimoxifene

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Cells, Cultured
• DNA Damage (drug effects)
• Embryo, Mammalian (cytology)
• Fibroblasts (metabolism)
• Gamma Rays
• Gene Expression Regulation, Neoplastic
• Genes, p53
• Genes, ras (genetics)
• Intestine, Small (drug effects, pathology, radiation effects)
• Mice
• Mice, Transgenic
• Models, Animal
• Neoplasms (genetics, metabolism, pathology)
• Spleen (drug effects, pathology, radiation effects)
• Tamoxifen (analogs & derivatives, pharmacology)
• Thymus Gland (drug effects, pathology, radiation effects)
• Time Factors
• Tumor Suppressor Protein p53 (genetics, physiology)
• Whole-Body Irradiation