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Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF

 Aram Ko  ;  Su Yeon Han  ;  Chel Hun Choi  ;  Hanbyoul Cho  ;  Min-Sik Lee  ;  Soo-Youl Kim  ;  Joon Seon Song  ;  Kyeong-Man Hong  ;  Han-Woong Lee  ;  Stephen M Hewitt  ;  Joon-Yong Chung  ;  Jaewhan Song 
 Cell Death and Differentiation, Vol.25(6) : 1050-1062, 2018 
Journal Title
 Cell Death and Differentiation 
Issue Date
Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by inducing the transcription of ubiquitin-specific protease 10 (USP10). USP10, in turn, mediated the deubiquitination of p14ARF, preventing its proteasome-dependent degradation. USP10-null mouse embryonic fibroblasts and human primary cells depleted of USP10 bypassed c-Myc-induced senescence via the destabilization of p14ARF, and these cells displayed accelerated hyper-proliferation and transformation. Clinically the c-Myc-USP10-p14ARF axis was disrupted in non-small cell lung cancer patients, resulting in significantly worse overall survival. Our studies indicate that USP10 induced by c-Myc has a crucial role in OIS by maintaining the stability of key tumor suppressor p14ARF.
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1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Hanbyoul(조한별) ORCID logo https://orcid.org/0000-0002-6177-1648
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