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Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity

Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF). It is increasingly likely that p53-hotspot mutations may confer different types and magnitudes of GOF, but the ev...

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Autores principales: Xu, J, Wang, J, Hu, Y, Qian, J, Xu, B, Chen, H, Zou, W, Fang, J-Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973211/
https://www.ncbi.nlm.nih.gov/pubmed/24603336
http://dx.doi.org/10.1038/cddis.2014.75
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author Xu, J
Wang, J
Hu, Y
Qian, J
Xu, B
Chen, H
Zou, W
Fang, J-Y
author_facet Xu, J
Wang, J
Hu, Y
Qian, J
Xu, B
Chen, H
Zou, W
Fang, J-Y
author_sort Xu, J
collection PubMed
description Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF). It is increasingly likely that p53-hotspot mutations may confer different types and magnitudes of GOF, but the evidences are mainly supported by cellular and transgenic animal models. Here we combine large-scale cancer genomic data to characterize the prognostic significance of different p53 mutations in human cancers. Unexpectedly, only mutations on the Arg248 and Arg282 positions displayed significant association with shorter patient survival, but such association was not evident for other hotspot GOF mutations. Gene set enrichment analysis on these mutations revealed higher activity of drug-metabolizing enzymes, including the CYP3A4 cytochrome P450. Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs. Our results suggest that p53 mutations have unequal GOF activities in human cancers, and future evaluation of p53 as a cancer biomarker should consider which mutation is present in the tumor, rather than having comparison between wild-type and mutant genotypes.
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spelling pubmed-39732112014-04-02 Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity Xu, J Wang, J Hu, Y Qian, J Xu, B Chen, H Zou, W Fang, J-Y Cell Death Dis Original Article Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF). It is increasingly likely that p53-hotspot mutations may confer different types and magnitudes of GOF, but the evidences are mainly supported by cellular and transgenic animal models. Here we combine large-scale cancer genomic data to characterize the prognostic significance of different p53 mutations in human cancers. Unexpectedly, only mutations on the Arg248 and Arg282 positions displayed significant association with shorter patient survival, but such association was not evident for other hotspot GOF mutations. Gene set enrichment analysis on these mutations revealed higher activity of drug-metabolizing enzymes, including the CYP3A4 cytochrome P450. Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs. Our results suggest that p53 mutations have unequal GOF activities in human cancers, and future evaluation of p53 as a cancer biomarker should consider which mutation is present in the tumor, rather than having comparison between wild-type and mutant genotypes. Nature Publishing Group 2014-03 2014-03-06 /pmc/articles/PMC3973211/ /pubmed/24603336 http://dx.doi.org/10.1038/cddis.2014.75 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Xu, J
Wang, J
Hu, Y
Qian, J
Xu, B
Chen, H
Zou, W
Fang, J-Y
Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title_full Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title_fullStr Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title_full_unstemmed Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title_short Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
title_sort unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973211/
https://www.ncbi.nlm.nih.gov/pubmed/24603336
http://dx.doi.org/10.1038/cddis.2014.75
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