Cargando…

p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen

The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in d...

Descripción completa

Detalles Bibliográficos
Autores principales: Valente, Liz J., Tarangelo, Amy, Li, Albert Mao, Naciri, Marwan, Raj, Nitin, Boutelle, Anthony M., Li, Yang, Mello, Stephano Spano, Bieging-Rolett, Kathryn, DeBerardinis, Ralph J., Ye, Jiangbin, Dixon, Scott J., Attardi, Laura D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594498/
https://www.ncbi.nlm.nih.gov/pubmed/32886745
http://dx.doi.org/10.1083/jcb.201908212
_version_ 1783601653786607616
author Valente, Liz J.
Tarangelo, Amy
Li, Albert Mao
Naciri, Marwan
Raj, Nitin
Boutelle, Anthony M.
Li, Yang
Mello, Stephano Spano
Bieging-Rolett, Kathryn
DeBerardinis, Ralph J.
Ye, Jiangbin
Dixon, Scott J.
Attardi, Laura D.
author_facet Valente, Liz J.
Tarangelo, Amy
Li, Albert Mao
Naciri, Marwan
Raj, Nitin
Boutelle, Anthony M.
Li, Yang
Mello, Stephano Spano
Bieging-Rolett, Kathryn
DeBerardinis, Ralph J.
Ye, Jiangbin
Dixon, Scott J.
Attardi, Laura D.
author_sort Valente, Liz J.
collection PubMed
description The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.
format Online
Article
Text
id pubmed-7594498
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-75944982021-05-02 p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen Valente, Liz J. Tarangelo, Amy Li, Albert Mao Naciri, Marwan Raj, Nitin Boutelle, Anthony M. Li, Yang Mello, Stephano Spano Bieging-Rolett, Kathryn DeBerardinis, Ralph J. Ye, Jiangbin Dixon, Scott J. Attardi, Laura D. J Cell Biol Article The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer. Rockefeller University Press 2020-09-04 /pmc/articles/PMC7594498/ /pubmed/32886745 http://dx.doi.org/10.1083/jcb.201908212 Text en © 2020 Valente et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Valente, Liz J.
Tarangelo, Amy
Li, Albert Mao
Naciri, Marwan
Raj, Nitin
Boutelle, Anthony M.
Li, Yang
Mello, Stephano Spano
Bieging-Rolett, Kathryn
DeBerardinis, Ralph J.
Ye, Jiangbin
Dixon, Scott J.
Attardi, Laura D.
p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title_full p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title_fullStr p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title_full_unstemmed p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title_short p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
title_sort p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594498/
https://www.ncbi.nlm.nih.gov/pubmed/32886745
http://dx.doi.org/10.1083/jcb.201908212
work_keys_str_mv AT valentelizj p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT tarangeloamy p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT lialbertmao p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT nacirimarwan p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT rajnitin p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT boutelleanthonym p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT liyang p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT mellostephanospano p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT biegingrolettkathryn p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT deberardinisralphj p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT yejiangbin p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT dixonscottj p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen
AT attardilaurad p53deficiencytriggersdysregulationofdiversecellularprocessesinphysiologicaloxygen