title: p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis.
abstract: Mutations in the oligomerization domain of p53 are genetically linked to cancer susceptibility in Li-Fraumeni Syndrome. These mutations typically alter the oligomeric state of p53 and impair its transcriptional activity. Activation of p53 through tetramerization is required for its tumor suppressive function by inducing transcriptional programs that lead to cell fate decisions such as cell cycle arrest or apoptosis. How p53 chooses between these cell fate outcomes remains unclear. Here, we use 5 oligomeric variants of p53, including 2 novel p53 constructs, that yield either monomeric, dimeric or tetrameric forms of p53 and demonstrate that they induce distinct cellular activities and gene expression profiles that lead to different cell fate outcomes. We report that dimeric p53 variants are cytostatic and can arrest cell growth, but lack the ability to trigger apoptosis in p53-null cells. In contrast, p53 tetramers induce rapid apoptosis and cell growth arrest, while a monomeric variant is functionally inactive, supporting cell growth. In particular, the expression of pro-arrest CDKN1A and pro-apoptotic P53AIP1 genes are important cell fate determinants that are differentially regulated by the oligomeric state of p53. This study suggests that the most abundant oligomeric species of p53 present in resting cells, namely p53 dimers, neither promote cell growth or cell death and that shifting the oligomeric state equilibrium of p53 in cells toward monomers or tetramers is a key parameter in p53-based cell fate decisions.
authors.affiliation: a Department of Medical Biophysics , University of Toronto , Toronto , Ontario , Canada.|b Physical Sciences, Sunnybrook Research Institute , Toronto , Ontario , Canada.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Fischer
authors.affiliation: a Department of Medical Biophysics , University of Toronto , Toronto , Ontario , Canada.|b Physical Sciences, Sunnybrook Research Institute , Toronto , Ontario , Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Prodeus
authors.affiliation: a Department of Medical Biophysics , University of Toronto , Toronto , Ontario , Canada.|c Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada.|d Division of Haematology/Oncology, Hospital for Sick Children , Toronto , Ontario , Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: a Department of Medical Biophysics , University of Toronto , Toronto , Ontario , Canada.|b Physical Sciences, Sunnybrook Research Institute , Toronto , Ontario , Canada.|e Department of Pharmaceutical Sciences , University of Toronto , Toronto , Ontario , Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gariépy
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D055503:Protein Multimerization; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: apoptosis; cell cycle arrest; cell fate; oligomerization; p53; tumor suppressor