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Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP.

Li C, Jung S, Lee S, Jeong D, Yang Y, Kim KI, Lim JS, Cheon CI, Kim C, Kang YS, Lee MS - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, 140-742, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Summary model showing the coordinated regulation by TRIP-Br3 and TRIP-Br1 with anti-apoptotic functions in normal and cancer cells in response to serum deprived condition
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Figure 7: Summary model showing the coordinated regulation by TRIP-Br3 and TRIP-Br1 with anti-apoptotic functions in normal and cancer cells in response to serum deprived condition

Mentions: Considering all our data, we propose a plausible model, in which TRIP-Br3 and TRIP-Br1 regulate the apoptosis coordinately in normal and cancer cells during serum starvation (Figure 7). In nutrient sufficient environment, TRIP-Br3 contributes the cell survival by stabilizing XIAP. However, this situation can be changed in nutrient deficient stressful environment. In normal cells, cytosolic TRIP-Br3 proteins are rapidly degraded at much earlier times compared to cancer cells. Rapid decrease of TRIP-Br3 triggers XIAP protein to be unstable and eventually lead to cell death. In cancer cells, TRIP-Br3 expression is slightly down-regulated compared to normal cells. Moreover, TRIP-Br3 down-regulation derived XIAP degradation seems to be alleviated by the TRIP-Br1 overexpression.


Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP.

Li C, Jung S, Lee S, Jeong D, Yang Y, Kim KI, Lim JS, Cheon CI, Kim C, Kang YS, Lee MS - Oncotarget (2015)

Summary model showing the coordinated regulation by TRIP-Br3 and TRIP-Br1 with anti-apoptotic functions in normal and cancer cells in response to serum deprived condition
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480697&req=5

Figure 7: Summary model showing the coordinated regulation by TRIP-Br3 and TRIP-Br1 with anti-apoptotic functions in normal and cancer cells in response to serum deprived condition
Mentions: Considering all our data, we propose a plausible model, in which TRIP-Br3 and TRIP-Br1 regulate the apoptosis coordinately in normal and cancer cells during serum starvation (Figure 7). In nutrient sufficient environment, TRIP-Br3 contributes the cell survival by stabilizing XIAP. However, this situation can be changed in nutrient deficient stressful environment. In normal cells, cytosolic TRIP-Br3 proteins are rapidly degraded at much earlier times compared to cancer cells. Rapid decrease of TRIP-Br3 triggers XIAP protein to be unstable and eventually lead to cell death. In cancer cells, TRIP-Br3 expression is slightly down-regulated compared to normal cells. Moreover, TRIP-Br3 down-regulation derived XIAP degradation seems to be alleviated by the TRIP-Br1 overexpression.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, 140-742, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus