Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP
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Chengping Li1,*, Samil Jung1,*, Soonduck Lee1, Dongjun Jeong2, Young Yang1, Keun-Il Kim1, Jong-Seok Lim1, Chung-Il Cheon1, Changjin Kim2, Young-Sook Kang3, Myeong-Sok Lee1
1Department of Life Systems, Sookmyung Women’s University, Seoul, 140–742, South Korea
2Department of Pathology, College of Medicine, Soonchunhyang University, Chonan, 330–090, South Korea
3College of Pharmacy, Sookmyung Women’s University, Seoul, 140–742, South Korea
*These authors have contributed equally to this work
Myeong-Sok Lee, e-mail: email@example.com
Keywords: Nutrient/serum starvation, apoptosis, TRIP-Br3, TRIP-Br1, XIAP
Abbreviations: TRIP-Br1 or 3, Transcriptional Regulator Interacting with the PHD-Bromo-domain 1 or 3, XIAP, X-linked inhibitor of apoptosis protein
Received: November 27, 2014 Accepted: January 08, 2015 Published: February 21, 2015
TRIP-Br3 and TRIP-Br1 have shown to have important biological functions. However, the function of TRIP-Br3 in tumorigenesis is not well characterized compared to oncogenic TRIP-Br1. Here, we investigated the function of TRIP-Br3 in tumorigenesis by comparing with that of TRIP-Br1. Under nutrient/serum starvation, TRIP-Br3 expression was down-regulated slightly in cancer cells and significantly in normal cells. Unexpectedly, TRIP-Br1 expression was greatly up-regulated in cancer cells but not in normal cells. Moreover, TRIP-Br3 activated autophagy while TRIP-Br1 inactivated it under serum starvation. In spite of different expression and roles of TRIP-Br3 and TRIP-Br1, both of them alleviate cell death by directly binding to and stabilizing XIAP, a potent apoptosis inhibitor, through blocking its ubiquitination. Taken together, we propose that TRIP-Br3 primarily activates the autophagy and suppresses apoptosis in nutrient sufficient condition. However, the prolonged extreme stressful condition of nutrient starvation causes a dramatic decrease of TRIP-Br3, which in turn induces apoptosis by destabilizing XIAP. Up-regulated TRIP-Br1 in cancer cells compensates this effect and delays apoptosis. This can be explained by the competitive alternative binding of TRIP-Br3 and TRIP-Br1 to the BIR2 domain of XIAP. In an extended study, our immunohistochemical analysis revealed a markedly lower level of TRIP-Br3 protein in human carcinoma tissues compared to normal epithelial tissues, implying the role of TRIP-Br3 as a tumor suppressor rather than onco-protein.
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