title: Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis.
abstract: Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival.
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore;
authors.forename: Beng Hooi
authors.initials: BH
authors.lastname: Phang
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore;
authors.forename: Rashidah
authors.initials: R
authors.lastname: Othman
authors.affiliation: INSERM U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, Canceropole Nord-Ouest, France;
authors.forename: Gaelle
authors.initials: G
authors.lastname: Bougeard
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore;
authors.forename: Ren Hui
authors.initials: RH
authors.lastname: Chia
authors.affiliation: INSERM U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, Canceropole Nord-Ouest, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore 169608, Singapore;
authors.forename: Choong Leong
authors.initials: CL
authors.lastname: Tang
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore 169608, Singapore; Office of Clinical Sciences, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore 169857; Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore;
authors.forename: Peh Yean
authors.initials: PY
authors.lastname: Cheah
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore cmrksb@nccs.com.sg.
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: ATp53 mutants; acetylation; amino terminus; full-length p53; p47