title: Cell-type, dose, and mutation-type specificity dictate mutant p53 functions in vivo.
abstract: The specific roles of mutant p53's dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using "knockin" mouse strains expressing varying R246S mutant levels, we show that the DN effect on transactivation is universally observed after acute p53 activation, whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53's DN effect protected against radiation-induced death but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53(-/-) mice in various models, even when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53's DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore.
authors.forename: Ming Kei
authors.initials: MK
authors.lastname: Lee
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Teoh
authors.forename: Beng Hooi
authors.initials: BH
authors.lastname: Phang
authors.forename: Wei Min
authors.initials: WM
authors.lastname: Tong
authors.forename: Zhao Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D055879:Gene Knock-In Techniques / Q000379:methods; D051379:Mice; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2