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Journal article
An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model
Genes & development, v 30(8), pp 918-930
15 Apr 2016
PMID: 27034505
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model
- Creators
- Matthew Jennis - 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;Che-Pei Kung - The Wistar InstituteSubhasree Basu - The Wistar InstituteAnna Budina-Kolomets - The Wistar InstituteJulia I-Ju Leu - University of PennsylvaniaSakina Khaku - The Wistar InstituteJeremy P Scott - The Wistar InstituteKathy Q Cai - Fox Chase Cancer CenterMichelle R Campbell - National Institute of Environmental Health SciencesDevin K Porter - National Institute of Environmental Health SciencesXuting Wang - National Institute of Environmental Health SciencesDouglas A Bell - National Institute of Environmental Health SciencesXiaoxian Li - Emory UniversityDavid S Garlick - The Wistar InstituteQin Liu - The Wistar InstituteMonica Hollstein - University of LeedsDonna L George - University of PennsylvaniaMaureen E Murphy - The Wistar InstituteXuehang Wang - A.J. Drexel Nanomaterials Institute
- Publication Details
- Genes & development, v 30(8), pp 918-930
- Publisher
- American Physical Society (APS)
- Grant note
- Z01 ES100475 / Intramural NIH HHS R01 CA102184 / NCI NIH HHS R01 CA201430 / NCI NIH HHS P01 CA114046 / NCI NIH HHS P30 CA016520 / NCI NIH HHS CA010815 / NCI NIH HHS P30 CA010815 / NCI NIH HHS Z01-ES-100475 / NIEHS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Nanomaterials Institute
- Web of Science ID
- WOS:000374923500007
- Scopus ID
- 2-s2.0-84963814113
- Other Identifier
- 991019173468704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Developmental Biology
- Genetics & Heredity