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XPC promotes MDM2-mediated degradation of the p53 tumor suppressor

Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association wit...

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Autores principales: Krzeszinski, Jing Yan, Choe, Vitnary, Shao, Jia, Bao, Xin, Cheng, Haili, Luo, Shiwen, Huo, Keke, Rao, Hai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890342/
https://www.ncbi.nlm.nih.gov/pubmed/24258024
http://dx.doi.org/10.1091/mbc.E13-05-0293
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author Krzeszinski, Jing Yan
Choe, Vitnary
Shao, Jia
Bao, Xin
Cheng, Haili
Luo, Shiwen
Huo, Keke
Rao, Hai
author_facet Krzeszinski, Jing Yan
Choe, Vitnary
Shao, Jia
Bao, Xin
Cheng, Haili
Luo, Shiwen
Huo, Keke
Rao, Hai
author_sort Krzeszinski, Jing Yan
collection PubMed
description Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis.
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spelling pubmed-38903422014-03-30 XPC promotes MDM2-mediated degradation of the p53 tumor suppressor Krzeszinski, Jing Yan Choe, Vitnary Shao, Jia Bao, Xin Cheng, Haili Luo, Shiwen Huo, Keke Rao, Hai Mol Biol Cell Articles Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis. The American Society for Cell Biology 2014-01-15 /pmc/articles/PMC3890342/ /pubmed/24258024 http://dx.doi.org/10.1091/mbc.E13-05-0293 Text en © 2014 Krzeszinski et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Krzeszinski, Jing Yan
Choe, Vitnary
Shao, Jia
Bao, Xin
Cheng, Haili
Luo, Shiwen
Huo, Keke
Rao, Hai
XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title_full XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title_fullStr XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title_full_unstemmed XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title_short XPC promotes MDM2-mediated degradation of the p53 tumor suppressor
title_sort xpc promotes mdm2-mediated degradation of the p53 tumor suppressor
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890342/
https://www.ncbi.nlm.nih.gov/pubmed/24258024
http://dx.doi.org/10.1091/mbc.E13-05-0293
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