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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

Positive effect of TRIP-Br1 on XIAP expression under serum depletion(A) Expression levels of TRIP-Br1, 2, 3 and SERTAD3 proteins were checked in breast cancer and normal cells under the condition of serum deficiency. (B) Indicated cells were grown in complete or serum starved media for 24 h or 48 h and the protein levels of TRIP-Br1 were measured by using Western blot. Expression levels of TRIP-Br1 in response to serum depletion were measured in time- or concentration-dependent manner. (C) and (D). TRIP-Br1 genes were suppressed by transiently transfecting with TRIP-Br1 silencing RNAs (siTRIP-Br1) with scRNA control as detailed in Methods and Materials. Transfected cells were then incubated in the complete (CM) or serum starved (SS) medium for the indicated times.
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Figure 4: Positive effect of TRIP-Br1 on XIAP expression under serum depletion(A) Expression levels of TRIP-Br1, 2, 3 and SERTAD3 proteins were checked in breast cancer and normal cells under the condition of serum deficiency. (B) Indicated cells were grown in complete or serum starved media for 24 h or 48 h and the protein levels of TRIP-Br1 were measured by using Western blot. Expression levels of TRIP-Br1 in response to serum depletion were measured in time- or concentration-dependent manner. (C) and (D). TRIP-Br1 genes were suppressed by transiently transfecting with TRIP-Br1 silencing RNAs (siTRIP-Br1) with scRNA control as detailed in Methods and Materials. Transfected cells were then incubated in the complete (CM) or serum starved (SS) medium for the indicated times.

Mentions: In an extended study, the effect of serum deficiency was also tested in other TRIP-Br family members. Very interestingly, the expression levels of other members were found to be increased in cancer and/or normal cells (Figure 4A). Among them, TRIP-Br1 was especially chosen for further study because its protein level was greatly increased in cancer cells but not in normal cells (Figure 4A). It was confirmed in time- and concentration-dependent ways (Figure 4B). Importantly, TRIP-Br1 also stabilized the XIAP in MCF7 and MDA-MB-231 cells such as the case of TRIP-Br3. As shown in Figure 4C, XIAP down-regulation was enhanced by the suppression of TRIP-Br1. Interestingly, conversion of LC3-I to LC3-II was accelerated by the TRIP-Br1 suppression, suggesting the inhibitory role of TRIP-Br1 in serum starvation–induced autophagy. Effect of TRIP-Br3 and TRIP-Br1 on XIAP expression was further tested in MCF7 cells that both genes were knock-downed, in which XIAP protein level was significantly decreased (Figure 4D). This data suggest that both TRIP-Br3 and TRIP-Br1 exert a positive effect on XIAP expression.


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)

Positive effect of TRIP-Br1 on XIAP expression under serum depletion(A) Expression levels of TRIP-Br1, 2, 3 and SERTAD3 proteins were checked in breast cancer and normal cells under the condition of serum deficiency. (B) Indicated cells were grown in complete or serum starved media for 24 h or 48 h and the protein levels of TRIP-Br1 were measured by using Western blot. Expression levels of TRIP-Br1 in response to serum depletion were measured in time- or concentration-dependent manner. (C) and (D). TRIP-Br1 genes were suppressed by transiently transfecting with TRIP-Br1 silencing RNAs (siTRIP-Br1) with scRNA control as detailed in Methods and Materials. Transfected cells were then incubated in the complete (CM) or serum starved (SS) medium for the indicated times.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Positive effect of TRIP-Br1 on XIAP expression under serum depletion(A) Expression levels of TRIP-Br1, 2, 3 and SERTAD3 proteins were checked in breast cancer and normal cells under the condition of serum deficiency. (B) Indicated cells were grown in complete or serum starved media for 24 h or 48 h and the protein levels of TRIP-Br1 were measured by using Western blot. Expression levels of TRIP-Br1 in response to serum depletion were measured in time- or concentration-dependent manner. (C) and (D). TRIP-Br1 genes were suppressed by transiently transfecting with TRIP-Br1 silencing RNAs (siTRIP-Br1) with scRNA control as detailed in Methods and Materials. Transfected cells were then incubated in the complete (CM) or serum starved (SS) medium for the indicated times.
Mentions: In an extended study, the effect of serum deficiency was also tested in other TRIP-Br family members. Very interestingly, the expression levels of other members were found to be increased in cancer and/or normal cells (Figure 4A). Among them, TRIP-Br1 was especially chosen for further study because its protein level was greatly increased in cancer cells but not in normal cells (Figure 4A). It was confirmed in time- and concentration-dependent ways (Figure 4B). Importantly, TRIP-Br1 also stabilized the XIAP in MCF7 and MDA-MB-231 cells such as the case of TRIP-Br3. As shown in Figure 4C, XIAP down-regulation was enhanced by the suppression of TRIP-Br1. Interestingly, conversion of LC3-I to LC3-II was accelerated by the TRIP-Br1 suppression, suggesting the inhibitory role of TRIP-Br1 in serum starvation–induced autophagy. Effect of TRIP-Br3 and TRIP-Br1 on XIAP expression was further tested in MCF7 cells that both genes were knock-downed, in which XIAP protein level was significantly decreased (Figure 4D). This data suggest that both TRIP-Br3 and TRIP-Br1 exert a positive effect on XIAP expression.

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