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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

Immunohistochemical expression of TRIP-Br3 in breast tissuesImmunohistochemical assay was performed on the normal breast epithelial cells (A), ductal hyperplastic epithelial cells (B), ductal carcinoma in situ(C) or invasive ductal carcinoma (D) as indicated in Materials and Methods. Representative images are shown, in which weak or strong immune-reactivity against TRIP-Br3 are shown in brown color. Forty cases of normal breast tissue, thirty cases of ductal hyperplasia, thirty cases of ductal carcinoma in situ, and thirty five cases of invasive ductal carcinoma were tested for the TRIP-Br3 expression. The TRIP-Br3 expression was found in 85% (34/40) of normal breast tissue, 60% (18/30) of ductal hyperplasia, 53% (16/30) of ductal carcinoma in situ, and 51% (18/35) of invasive ductal carcinoma. The TRIP-Br3 expression was decreased in the invasive ductal carcinoma compared to the normal breast tissue with statistical significance by student t-test (p = 0.002).
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Figure 6: Immunohistochemical expression of TRIP-Br3 in breast tissuesImmunohistochemical assay was performed on the normal breast epithelial cells (A), ductal hyperplastic epithelial cells (B), ductal carcinoma in situ(C) or invasive ductal carcinoma (D) as indicated in Materials and Methods. Representative images are shown, in which weak or strong immune-reactivity against TRIP-Br3 are shown in brown color. Forty cases of normal breast tissue, thirty cases of ductal hyperplasia, thirty cases of ductal carcinoma in situ, and thirty five cases of invasive ductal carcinoma were tested for the TRIP-Br3 expression. The TRIP-Br3 expression was found in 85% (34/40) of normal breast tissue, 60% (18/30) of ductal hyperplasia, 53% (16/30) of ductal carcinoma in situ, and 51% (18/35) of invasive ductal carcinoma. The TRIP-Br3 expression was decreased in the invasive ductal carcinoma compared to the normal breast tissue with statistical significance by student t-test (p = 0.002).

Mentions: Our previous data showed that TRIP-Br1 is highly expressed in human breast cancer but weakly in normal tissues, suggesting the role of TRIP-Br1 as an oncoprotein [12]. However, our previous and current data showed that both TRIP-Br3 and TRIP-Br1 have an anti-apoptotic function. Therefore, we further tested whether TRIP-Br3 have a potential to function as a tumor suppressor by employing Immunohistochemistry analysis. Our data revealed that TRIP-Br3 protein was detected to be relatively high in normal tissue samples compared to cancer tissues. Normal epithelial cells have strong positive reaction for TRIP-Br3 in the cytoplasm. Ductal hyperplastic epithelial cells and ductal carcinoma in situ also exhibited relatively high level of TRIP-Br3. (Figure 6). However, TRIP-Br3 was not expressed in the invasive ductal carcinoma cells (Figure 6). This data show that TRIP-Br3 protein level might be significantly decreased during breast cancer cell development, implying the role of TRIP-Br3 as a tumor suppressor.


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)

Immunohistochemical expression of TRIP-Br3 in breast tissuesImmunohistochemical assay was performed on the normal breast epithelial cells (A), ductal hyperplastic epithelial cells (B), ductal carcinoma in situ(C) or invasive ductal carcinoma (D) as indicated in Materials and Methods. Representative images are shown, in which weak or strong immune-reactivity against TRIP-Br3 are shown in brown color. Forty cases of normal breast tissue, thirty cases of ductal hyperplasia, thirty cases of ductal carcinoma in situ, and thirty five cases of invasive ductal carcinoma were tested for the TRIP-Br3 expression. The TRIP-Br3 expression was found in 85% (34/40) of normal breast tissue, 60% (18/30) of ductal hyperplasia, 53% (16/30) of ductal carcinoma in situ, and 51% (18/35) of invasive ductal carcinoma. The TRIP-Br3 expression was decreased in the invasive ductal carcinoma compared to the normal breast tissue with statistical significance by student t-test (p = 0.002).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Immunohistochemical expression of TRIP-Br3 in breast tissuesImmunohistochemical assay was performed on the normal breast epithelial cells (A), ductal hyperplastic epithelial cells (B), ductal carcinoma in situ(C) or invasive ductal carcinoma (D) as indicated in Materials and Methods. Representative images are shown, in which weak or strong immune-reactivity against TRIP-Br3 are shown in brown color. Forty cases of normal breast tissue, thirty cases of ductal hyperplasia, thirty cases of ductal carcinoma in situ, and thirty five cases of invasive ductal carcinoma were tested for the TRIP-Br3 expression. The TRIP-Br3 expression was found in 85% (34/40) of normal breast tissue, 60% (18/30) of ductal hyperplasia, 53% (16/30) of ductal carcinoma in situ, and 51% (18/35) of invasive ductal carcinoma. The TRIP-Br3 expression was decreased in the invasive ductal carcinoma compared to the normal breast tissue with statistical significance by student t-test (p = 0.002).
Mentions: Our previous data showed that TRIP-Br1 is highly expressed in human breast cancer but weakly in normal tissues, suggesting the role of TRIP-Br1 as an oncoprotein [12]. However, our previous and current data showed that both TRIP-Br3 and TRIP-Br1 have an anti-apoptotic function. Therefore, we further tested whether TRIP-Br3 have a potential to function as a tumor suppressor by employing Immunohistochemistry analysis. Our data revealed that TRIP-Br3 protein was detected to be relatively high in normal tissue samples compared to cancer tissues. Normal epithelial cells have strong positive reaction for TRIP-Br3 in the cytoplasm. Ductal hyperplastic epithelial cells and ductal carcinoma in situ also exhibited relatively high level of TRIP-Br3. (Figure 6). However, TRIP-Br3 was not expressed in the invasive ductal carcinoma cells (Figure 6). This data show that TRIP-Br3 protein level might be significantly decreased during breast cancer cell development, implying the role of TRIP-Br3 as a tumor suppressor.

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