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Author Notes:

Email: mmurphy@wistar.org

M.J., C.-P.K., S.B., A.B.-K., J.I.-J.L., D.A.B., Q.L., M.H., D.L.G., and M.E.M. conceived and designed the study.

K.Q.C., X.L., D.S.G., and M.H. provided reagents and expertise.

M.J., C.-P.K., S.B., A.B.-K., J.I.-J.L., S.K., J.P.S., M.R.C., D.K.P., X.W., D.A.B., Q.L., M.H., D.L.G., and M.E.M. acquired and analyzed the data.

M.J., D.L.G., and M.E.M. drafted the manuscript, and all authors provided critical revisions.

We acknowledge the Cell Culture Facility and Transgenic Facility at The Fox Chase Cancer Center as well as the members of the Microscopy Facility (Fred Keeney), the Genomics Facility (Tran Nguyen and Celia Chang), and the Laboratory Animal Facility at The Wistar Institute for assistance with these studies.

Subjects:

Research Funding:

Support for Core Facilities used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.

This research was funded by R01 CA102184 (M.E.M.) and PO1 CA114046 (to D.L.G). This work was supported in part by funding from the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health Z01-ES-100475 (to D.A.B.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Developmental Biology
  • Genetics & Heredity
  • p53
  • tumor suppression
  • metabolism
  • ferroptosis
  • polymorphism
  • Ser46 phosphorylation
  • INTERACTING PROTEIN KINASE-2
  • NONAPOPTOTIC CELL-DEATH
  • DNA-DAMAGE
  • P53-DEPENDENT APOPTOSIS
  • SER46 PHOSPHORYLATION
  • FERROPTOSIS
  • MUTATIONS
  • MICE
  • SENESCENCE
  • RESPONSES

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model

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Journal Title:

Genes and Development

Volume:

Volume 30, Number 8

Publisher:

, Pages 918-930

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016 Jennis et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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