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

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 functi...

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Autores principales: Basu, Subhasree, Gnanapradeepan, Keerthana, Barnoud, Thibaut, Kung, Che-Pei, Tavecchio, Michele, Scott, Jeremy, Watters, Andrea, Chen, Qing, Kossenkov, Andrew V., Murphy, Maureen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859965/
https://www.ncbi.nlm.nih.gov/pubmed/29463573
http://dx.doi.org/10.1101/gad.309062.117
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author Basu, Subhasree
Gnanapradeepan, Keerthana
Barnoud, Thibaut
Kung, Che-Pei
Tavecchio, Michele
Scott, Jeremy
Watters, Andrea
Chen, Qing
Kossenkov, Andrew V.
Murphy, Maureen E.
author_facet Basu, Subhasree
Gnanapradeepan, Keerthana
Barnoud, Thibaut
Kung, Che-Pei
Tavecchio, Michele
Scott, Jeremy
Watters, Andrea
Chen, Qing
Kossenkov, Andrew V.
Murphy, Maureen E.
author_sort Basu, Subhasree
collection PubMed
description 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.
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spelling pubmed-58599652018-08-01 Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α Basu, Subhasree Gnanapradeepan, Keerthana Barnoud, Thibaut Kung, Che-Pei Tavecchio, Michele Scott, Jeremy Watters, Andrea Chen, Qing Kossenkov, Andrew V. Murphy, Maureen E. Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2018-02-01 /pmc/articles/PMC5859965/ /pubmed/29463573 http://dx.doi.org/10.1101/gad.309062.117 Text en © 2018 Basu et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ 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/.
spellingShingle Research Paper
Basu, Subhasree
Gnanapradeepan, Keerthana
Barnoud, Thibaut
Kung, Che-Pei
Tavecchio, Michele
Scott, Jeremy
Watters, Andrea
Chen, Qing
Kossenkov, Andrew V.
Murphy, Maureen E.
Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title_full Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title_fullStr Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title_full_unstemmed Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title_short Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α
title_sort mutant p53 controls tumor metabolism and metastasis by regulating pgc-1α
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859965/
https://www.ncbi.nlm.nih.gov/pubmed/29463573
http://dx.doi.org/10.1101/gad.309062.117
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