Regulation of Rad17 Protein Turnover Unveils an Impact of Rad17-APC Cascade in Breast Carcinogenesis and Treatment

Zhuan Zhou; Chao Jing; Liyong Zhang; Fujita Takeo; Hyun Kim; Yi Huang; Zhihua Liu; Yong Wan

doi:10.1074/jbc.M113.456962

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Regulation of Rad17 Protein Turnover Unveils an Impact of Rad17-APC Cascade in Breast Carcinogenesis and Treatment

Journal article

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Peer reviewed

Regulation of Rad17 Protein Turnover Unveils an Impact of Rad17-APC Cascade in Breast Carcinogenesis and Treatment

Zhuan Zhou, Chao Jing, Liyong Zhang, Fujita Takeo, Hyun Kim, Yi Huang, Zhihua Liu and Yong Wan

The Journal of biological chemistry, Vol.288(25), pp.18134-18145

06/21/2013

DOI: 10.1074/jbc.M113.456962

PMCID: PMC3689957

PMID: 23637229

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Abstract

Aberrant regulation of DNA damage checkpoint function leads to genome instability that in turn can predispose cellular tissues to become cancerous. Previous works from us and others demonstrated the role of Rad17 in either activation or termination of DNA damage checkpoint function. In the current study, we have revealed the unexpected accumulation of Rad17 in various types of breast cancer cell lines as well as human breast cancer tissues. We observed that Rad17 protein turnover rate in breast epithelial cells is much faster than in breast cancer cells, where the turnover of Rad17 is regulated by the Cdh1/APC pathway. We further observed that Rad17-mediated checkpoint function is modulated by proteolysis. Stabilization of Rad17 disrupts cellular response to chemotherapeutic drug-induced DNA damage and enhances cellular transformation. In addition, manipulation of Rad17 by RNA interference or stabilization of Rad17 significantly sensitize breast cancer cell to various chemotherapeutic drugs. Our present results indicate the manipulation of Rad17 proteolysis could be a valuable approach to sensitize breast cancer cell to the chemotherapeutic treatment despite of the critical role in governing DNA damage response and cellular recovery from genotoxic stress. Abrogated Rad17-APC axis is involved in genome instability and tumorigenesis. Proteolytic regulation of Rad17 is involved in breast tumorigenesis and could be targeted for chemosensitization. Regulation of Rad17 turnover is important in the maintenance of genome stability and carcinogenesis. Demonstration of impact of Rad17 turnover regulation in genome stability, tumorigenesis, and chemosensitization.

APC

Carcinogenesis

Chromosomes/non-histone Chromosomal Proteins

DNA Binding Protein

Genome Instability

Protein Dynamics

Protein Stability

Protein Turnover

Rad17

Details

Title: Subtitle: Regulation of Rad17 Protein Turnover Unveils an Impact of Rad17-APC Cascade in Breast Carcinogenesis and Treatment
Creators: Zhuan Zhou - UPMC Hillman Cancer Center
Chao Jing - Chinese Academy of Medical Sciences & Peking Union Medical College
Liyong Zhang - UPMC Hillman Cancer Center
Fujita Takeo - UPMC Hillman Cancer Center
Hyun Kim - UPMC Hillman Cancer Center
Yi Huang - University of Pittsburgh
Zhihua Liu - Chinese Academy of Medical Sciences & Peking Union Medical College
Yong Wan - UPMC Hillman Cancer Center
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(25), pp.18134-18145
DOI: 10.1074/jbc.M113.456962
PMID: 23637229
PMCID: PMC3689957
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Language: English
Date published: 06/21/2013
Academic Unit: Internal Medicine
Record Identifier: 9984383312902771

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