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Temporal dissection of p53 function in vitro and in vivo

Research output: Contribution to journalArticle

  • Maria A Christophorou
  • Dionisio Martin-Zanca
  • Laura Soucek
  • Elizabeth R Lawlor
  • Lamorna Brown-Swigart
  • Emmy W Verschuren
  • Gerard I Evan

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)718-26
Number of pages9
JournalNature Genetics
Volume37
Issue number7
DOIs
Publication statusPublished - Jul 2005

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.

    Research areas

  • Animals, Apoptosis, Cells, Cultured, DNA Damage, Embryo, Mammalian, Fibroblasts, Gamma Rays, Gene Expression Regulation, Neoplastic, Genes, p53, Genes, ras, Intestine, Small, Mice, Mice, Transgenic, Models, Animal, Neoplasms, Spleen, Tamoxifen, Thymus Gland, Time Factors, Tumor Suppressor Protein p53, Whole-Body Irradiation

ID: 17821827