Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP
- Authors
- Li, Chengping; Jung, Samil; Lee, Soonduck; Jeong, Dongjun; Yang, Young; Kim, Keun-Il; Lim, Jong-Seok; Cheon, Chung-Il; Kim, Changjin; Kang, Young-Sook; Lee, Myeong-Sok
- Issue Date
- 10-Apr-2015
- Publisher
- Impact Journals
- Keywords
- Nutrient/serum starvation; apoptosis; TRIP-Br3; TRIP-Br1; XIAP
- Citation
- Oncotarget, v.6, no.10, pp 7522 - 7535
- Pages
- 14
- Journal Title
- Oncotarget
- Volume
- 6
- Number
- 10
- Start Page
- 7522
- End Page
- 7535
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/10724
- DOI
- 10.18632/oncotarget.3112
- ISSN
- 1949-2553
- Abstract
- 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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