TY - JOUR
T1 - p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen
AU - Valente, Liz J.
AU - Tarangelo, Amy
AU - Li, Albert Mao
AU - Naciri, Marwan
AU - Raj, Nitin
AU - Boutelle, Anthony M.
AU - Li, Yang
AU - Mello, Stephano Spano
AU - Bieging-Rolett, Kathryn
AU - Deberardinis, Ralph J.
AU - Ye, Jiangbin
AU - Dixon, Scott J.
AU - Attardi, Laura D.
N1 - Funding Information:
We thank the following people for the provision of reagents and/ or advice with the development of new protocols: Monte M. Winslow, Ian Winters, Edward LaGory, Ejung Moon, Jan Skotheim, and Matt Footer. We are grateful to Lauren Zacharias at the Children’s Medical Center Research Institute’s Metabolomics Facility at UT Southwestern for running our metabolomics analysis. We thank Julien Sage and Alyssa Kaiser for critical reading of the manuscript. This study was supported by funding to L.D. Attardi from National Institutes of Health grant R35CA197591, and to R.J. DeBerardinis from National Institutes of Health grant R35CA22044901.
Funding Information:
This study was supported by funding to L.D. Attardi from National Institutes of Health grant R35CA197591, and to R.J. DeBerardinis from National Institutes of Health grant R35CA22044901. The authors declare no competing financial interests.
Publisher Copyright:
© 2020 Valente et al.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201908212
DO - 10.1083/jcb.201908212
M3 - Article
C2 - 32886745
AN - SCOPUS:85090506286
SN - 0021-9525
VL - 219
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 11
M1 - e201908212
ER -