title: An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.
abstract: A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA; Program in Molecular and Cellular Biology and Genetics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA;
authors.forename: Matthew
authors.initials: M
authors.lastname: Jennis
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Che-Pei
authors.initials: CP
authors.lastname: Kung
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Subhasree
authors.initials: S
authors.lastname: Basu
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Anna
authors.initials: A
authors.lastname: Budina-Kolomets
authors.affiliation: Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Julia I-Ju
authors.initials: JI
authors.lastname: Leu
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Sakina
authors.initials: S
authors.lastname: Khaku
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Scott
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA;
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Campbell
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Devin K
authors.initials: DK
authors.lastname: Porter
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Li
authors.affiliation: The Wistar Institute Cancer Center, Philadelphia, Pennsylvania 19104, USA;
authors.forename: David S
authors.initials: DS
authors.lastname: Garlick
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.affiliation: Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Donna L
authors.initials: DL
authors.lastname: George
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Maureen E
authors.identifier: http://orcid.org/0000-0001-7644-7296
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000818:Animals; D044383:Black People / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003062:Codon / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D012307:Risk Factors; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D003062:Codon; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
keywords: Ser46 phosphorylation; ferroptosis; metabolism; p53; polymorphism; tumor suppression