XPC promotes MDM2-mediated degradation of the p53 tumor suppressor

Jing Yan Krzeszinski, Vitnary Choe, Jia Shao, Xin Bao, Haili Cheng, Shiwen Luo, Keke Huo, Hai Rao

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalMolecular Biology of the Cell
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2014

Fingerprint

Proteasome Endopeptidase Complex
Ubiquitin
DNA Repair
Proteolysis
Neoplasms
Carrier Proteins
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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.

In: Molecular Biology of the Cell, Vol. 25, No. 2, 15.01.2014, p. 213-221.

Research output: Contribution to journalArticle

Krzeszinski, JY, Choe, V, Shao, J, Bao, X, Cheng, H, Luo, S, Huo, K & Rao, H 2014, 'XPC promotes MDM2-mediated degradation of the p53 tumor suppressor', Molecular Biology of the Cell, vol. 25, no. 2, pp. 213-221. https://doi.org/10.1091/mbc.E13-05-0293
Krzeszinski JY, Choe V, Shao J, Bao X, Cheng H, Luo S et al. XPC promotes MDM2-mediated degradation of the p53 tumor suppressor. Molecular Biology of the Cell. 2014 Jan 15;25(2):213-221. https://doi.org/10.1091/mbc.E13-05-0293
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. In: Molecular Biology of the Cell. 2014 ; Vol. 25, No. 2. pp. 213-221.
@article{cb6f359d53b642a2a6fbb725ca20268c,
title = "XPC promotes MDM2-mediated degradation of the p53 tumor suppressor",
abstract = "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.",
author = "Krzeszinski, {Jing Yan} and Vitnary Choe and Jia Shao and Xin Bao and Haili Cheng and Shiwen Luo and Keke Huo and Hai Rao",
year = "2014",
month = "1",
day = "15",
doi = "10.1091/mbc.E13-05-0293",
language = "English (US)",
volume = "25",
pages = "213--221",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "2",

}

TY - JOUR

T1 - XPC promotes MDM2-mediated degradation of the p53 tumor suppressor

AU - Krzeszinski, Jing Yan

AU - Choe, Vitnary

AU - Shao, Jia

AU - Bao, Xin

AU - Cheng, Haili

AU - Luo, Shiwen

AU - Huo, Keke

AU - Rao, Hai

PY - 2014/1/15

Y1 - 2014/1/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84892528906&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892528906&partnerID=8YFLogxK

U2 - 10.1091/mbc.E13-05-0293

DO - 10.1091/mbc.E13-05-0293

M3 - Article

C2 - 24258024

AN - SCOPUS:84892528906

VL - 25

SP - 213

EP - 221

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 2

ER -