529회

DNA DAMAGE CAUSES p27Kip1 ACCUMULATION THROUGH COP1 SIGNALING

최현호 교수 (Sun Yat-sen University, China)

p27 is a critical CDK inhibitor involved in cell cycle regulation, but its response to DNA damage remains unclear. Constitutive photomorphogenesis 1 (COP1), a p53-targeting E3 ubiquitin ligase, is downregulated by DNA damage, but the biological consequences of this phenomenon are poorly understood. Here, we report that p27 levels were elevated after DNA damage, with concurrent reduction of COP1 levels. Mechanistic studies showed that COP1 directly interacted with p27 through a VP motif on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated degradation of p27. Also, COP1 overexpression lead to cytoplasmic distribution of p27, thereby accelerating p27 degradation. COP1 overexpression resulted in elevation of Aurora A kinase. COP1 and Aurora A levels were positively correlated in patient samples and associated with poor overall survival. We found that COP1 expression promoted cell proliferation, cell transformation, and tumor progression, manifesting its role in cancer promotion whereas p27 negatively regulated COP1 function and prevented tumor growth in a mouse xenograft model of human cancer. Together, these findings define a mechanism for posttranslational regulation of p27 after DNA damage that can explain the correlation between COP1 overexpression and p27 downregulation during tumorigenesis.

학력 및 약력

2005년             석사, 고려대학교 식품공학과

2011년             석사, Univ. of Texas Health Science Center-MD Anderson Cancer Center, U.S.A

2014 년             박사, Texas A&M University , U.S.A

2014 - 2017         Postdoctoral Fellow. The University of Texas MD Anderson Cancer Center

2017 - 현재         부교수, Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou, China

주요발표논문

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Choi HH, Phan L, Chou PC, Su CH, Yeung SC, Chen JS, Lee MH. COP1 enhances ubiquitin-mediated degradation of  p27Kip1 to promote cancer cell growth. Oncotarget. 2015 Aug 14;6(23):19721-34.

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Choi HH, Su CH, Fang L, Zhang  J, Yeung  SC, Lee MH. CSN6 deregulation impairs genome integrity in a COP1-dependent pathway. Oncotarget. 2015 May 20;6(14):11779-93.