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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

TRIP-Br3 expression levels in cancer and normal cell lines under the stressful condition of nutrient deficiency(A) TRIP-Br3 expression levels in breast cancer and normal cell lines under the stressful conditions of nutrient deficiency (overcrowded environment and depletion of glucose or amino acid). Cells were cultured in complete medium until cells reached ~70% confluence (CM) or overcrowded with high levels of cell confluence by culturing in a complete medium for long time (OC). Each cell line was grown in high (HG) or low (LG) levels of glucose containing medium. Cells were also cultured in sufficient amino acid containing normal medium (AANM) or amino acid starved EBSS minimal medium (AASM). (B) Cancer and normal cell lines were grown in serum containing complete medium (CM) or serum starved medium (SS). (C) Expression levels of TRIP-Br3 in response to serum depletion were measured in time- or concentration-dependent manner.
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Figure 1: TRIP-Br3 expression levels in cancer and normal cell lines under the stressful condition of nutrient deficiency(A) TRIP-Br3 expression levels in breast cancer and normal cell lines under the stressful conditions of nutrient deficiency (overcrowded environment and depletion of glucose or amino acid). Cells were cultured in complete medium until cells reached ~70% confluence (CM) or overcrowded with high levels of cell confluence by culturing in a complete medium for long time (OC). Each cell line was grown in high (HG) or low (LG) levels of glucose containing medium. Cells were also cultured in sufficient amino acid containing normal medium (AANM) or amino acid starved EBSS minimal medium (AASM). (B) Cancer and normal cell lines were grown in serum containing complete medium (CM) or serum starved medium (SS). (C) Expression levels of TRIP-Br3 in response to serum depletion were measured in time- or concentration-dependent manner.

Mentions: Low nutrient condition is one of characteristics in cancer cells under overcrowded conditions with high cell density. In particular, highly aggressive and rapidly growing tumors are easily exposed to nutrient deficiency due to uncontrolled growth and proliferation. In the process of finding genes responsible for the resistance to nutrient depletion derived cell death, TRIP-Br3 expression was found to be more decreased in normal cells compared to cancer cells under overcrowded conditions (Figure 1A). To examine what kind of nutrient deficiency is especially responsible for the decreased TRIP-Br1 expression, cells were placed under conditions deprived of representative nutrients, glucose and amino acids, in which TRIP-Br3 expression was decreased significantly in normal cells and slightly in cancer cells (Figure 1A). In particular, serum deficiency, the main stress in this study, markedly decreased TRIP-Br3 protein level in all tested cancer and normal cells (Figure 1B). It was confirmed in time- and dose-dependent ways, in which TRIP-Br3 expression level was more rapidly and greatly decreased in normal cells compared to cancer cells (Figure 1C).


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)

TRIP-Br3 expression levels in cancer and normal cell lines under the stressful condition of nutrient deficiency(A) TRIP-Br3 expression levels in breast cancer and normal cell lines under the stressful conditions of nutrient deficiency (overcrowded environment and depletion of glucose or amino acid). Cells were cultured in complete medium until cells reached ~70% confluence (CM) or overcrowded with high levels of cell confluence by culturing in a complete medium for long time (OC). Each cell line was grown in high (HG) or low (LG) levels of glucose containing medium. Cells were also cultured in sufficient amino acid containing normal medium (AANM) or amino acid starved EBSS minimal medium (AASM). (B) Cancer and normal cell lines were grown in serum containing complete medium (CM) or serum starved medium (SS). (C) Expression levels of TRIP-Br3 in response to serum depletion were measured in time- or concentration-dependent manner.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: TRIP-Br3 expression levels in cancer and normal cell lines under the stressful condition of nutrient deficiency(A) TRIP-Br3 expression levels in breast cancer and normal cell lines under the stressful conditions of nutrient deficiency (overcrowded environment and depletion of glucose or amino acid). Cells were cultured in complete medium until cells reached ~70% confluence (CM) or overcrowded with high levels of cell confluence by culturing in a complete medium for long time (OC). Each cell line was grown in high (HG) or low (LG) levels of glucose containing medium. Cells were also cultured in sufficient amino acid containing normal medium (AANM) or amino acid starved EBSS minimal medium (AASM). (B) Cancer and normal cell lines were grown in serum containing complete medium (CM) or serum starved medium (SS). (C) Expression levels of TRIP-Br3 in response to serum depletion were measured in time- or concentration-dependent manner.
Mentions: Low nutrient condition is one of characteristics in cancer cells under overcrowded conditions with high cell density. In particular, highly aggressive and rapidly growing tumors are easily exposed to nutrient deficiency due to uncontrolled growth and proliferation. In the process of finding genes responsible for the resistance to nutrient depletion derived cell death, TRIP-Br3 expression was found to be more decreased in normal cells compared to cancer cells under overcrowded conditions (Figure 1A). To examine what kind of nutrient deficiency is especially responsible for the decreased TRIP-Br1 expression, cells were placed under conditions deprived of representative nutrients, glucose and amino acids, in which TRIP-Br3 expression was decreased significantly in normal cells and slightly in cancer cells (Figure 1A). In particular, serum deficiency, the main stress in this study, markedly decreased TRIP-Br3 protein level in all tested cancer and normal cells (Figure 1B). It was confirmed in time- and dose-dependent ways, in which TRIP-Br3 expression level was more rapidly and greatly decreased in normal cells compared to cancer cells (Figure 1C).

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