Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α

  1. Maureen E. Murphy1
  1. 1Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  2. 2Graduate Group in Biochemistry and Biophysics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104;
  3. 3Program in Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  4. 4Program in Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
  1. Corresponding author: mmurphy{at}wistar.org
  1. 7 These authors contributed equally to this work.

  • Present addresses: 5Washington University, St Louis, MO 63110, USA; 6Mitochondrial Medicine Laboratory, Lund University, Lund SE 221 00, Sweden.

Abstract

Mutant forms of p53 protein often possess protumorigenic functions, conferring increased survival and migration to tumor cells via their “gain-of-function” activity. Whether and how a common polymorphism in TP53 at amino acid 72 (Pro72Arg; referred to here as P72 and R72) impacts this gain of function has not been determined. We show that mutant p53 enhances migration and metastasis of tumors through the ability to bind and regulate PGC-1α and that this regulation is markedly impacted by the codon 72 polymorphism. Tumor cells with the R72 variant of mutant p53 show increased PGC-1α function along with greatly increased mitochondrial function and metastatic capability. Breast cancers containing mutant p53 and the R72 variant show poorer prognosis compared with P72. The combined results reveal PGC-1α as a novel “gain-of-function” partner of mutant p53 and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis.

Keywords

Footnotes

  • Received October 30, 2017.
  • Accepted January 22, 2018.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

Related Article

| Table of Contents

Life Science Alliance