Loss of Bif-1 Suppresses Bax/Bak Conformational Change and Mitochondrial Apoptosis

Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 12/2005; 25(21):9369-82. DOI: 10.1128/MCB.25.21.9369-9382.2005
Source: PubMed


Bif-1, a member of the endophilin B protein family, interacts with Bax and promotes interleukin-3 withdrawal-induced Bax conformational change and apoptosis when overexpressed in FL5.12 cells. Here, we provide evidence that Bif-1 plays a regulatory role in apoptotic activation of not only Bax but also Bak and appears to be involved in suppression of tumorigenesis. Inhibition of endogenous Bif-1 expression in HeLa cells by RNA interference abrogated the conformational change of Bax and Bak, cytochrome c release, and caspase 3 activation induced by various intrinsic death signals. Similar results were obtained in Bif-1 knockout mouse embryonic fibroblasts. While Bif-1 did not directly interact with Bak, it heterodimerized with Bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the Bax conformational change. Moreover, suppression of Bif-1 expression was associated with an enhanced ability of HeLa cells to form colonies in soft agar and tumors in nude mice. Taken together, these findings support the notion that Bif-1 is an important component of the mitochondrial pathway for apoptosis as a novel Bax/Bak activator, and loss of this proapoptotic molecule may contribute to tumorigenesis.

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Available from: Jie Wu, Oct 09, 2015
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    • "Bax-interacting factor-1 (Bif-1, also known as endophilin B1 and SH3GLB1), a member of the membrane curvaturedriving endophilin family of proteins, associates with the proapoptotic Bcl-2 family protein Bax [5] [6] and promotes Bax conformational changes to induce apoptosis [7]. Inhibition of Bif-1 expression in vitro abrogates cytochrome í µí± release and caspase-3 activation induced by various intrinsic apoptosis signals, and Bif-1 knockout mouse shows delayed mitochondrial apoptosis [7]. These findings support an important role for Bif-1 in apoptotic activation, as loss of this molecule is involved in tumorigenesis. "
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    ABSTRACT: Background/aim: Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). Methods: We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. Results: Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P = 0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285-0.739; P = 0.001). Conclusion: Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC.
    09/2013; 2013:329839. DOI:10.1155/2013/329839
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    • "Bif-1, a member of the endophilin B protein family, activates the conformational change of proapoptotic proteins BAX and BAK and subsequent cytochrome c release and caspase 3 activation during apoptosis [103]. More recently, it was shown that Bif-1 binds via its SH3 domain to the N-terminal polyproregion of UVRAG, while the Bif-1 BAR domain associates with membranes, facilitating autophagosome formation [96]. "
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    ABSTRACT: Autophagy and apoptosis are catabolic pathways essential for organismal homeostasis. Autophagy is normally a cell-survival pathway involving the degradation and recycling of obsolete, damaged, or harmful macromolecular assemblies; however, excess autophagy has been implicated in type II cell death. Apoptosis is the canonical programmed cell death pathway. Autophagy and apoptosis have now been shown to be interconnected by several molecular nodes of crosstalk, enabling the coordinate regulation of degradation by these pathways. Normally, autophagy and apoptosis are both tumor suppressor pathways. Autophagy fulfils this role as it facilitates the degradation of oncogenic molecules, preventing development of cancers, while apoptosis prevents the survival of cancer cells. Consequently, defective or inadequate levels of either autophagy or apoptosis can lead to cancer. However, autophagy appears to have a dual role in cancer, as it has now been shown that autophagy also facilitates the survival of tumor cells in stress conditions such as hypoxic or low-nutrition environments. Here we review the multiple molecular mechanisms of coordination of autophagy and apoptosis and the role of the proteins involved in this crosstalk in cancer. A comprehensive understanding of the interconnectivity of autophagy and apoptosis is essential for the development of effective cancer therapeutics.
    Journal of Oncology 06/2013; 2013:102735. DOI:10.1155/2013/102735
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    • "EndoB1 binds Bax to promote division of the mitochondrial membrane. EndoB1 knockout mice show increased rate of spontaneous tumor development [129] and downregulation of EndoB1 blocks Bax translocation and cytochrome c release induced by apoptotic stimuli [130]. Manipulation of these fission players greatly impacts the onset of apoptosis. "
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    ABSTRACT: The influence of mitochondria in human health and disease is a rapidly expanding topic in the scientific literature due to their integral roles in cellular death and survival. Mitochondrial biology and alterations in function were first linked to cancer in the 1920s with the discovery of the Warburg effect. The utilization of aerobic glycolysis in ATP synthesis was the first of many observations of metabolic reprogramming in cancer. Mitochondrial dysfunction in cancer has expanded to include defects in mitochondrial genomics and biogenesis, apoptotic signaling and mitochondrial dynamics. This review will focus on the role of mitochondria and their influence on cancer initiation, progression and treatment in the lung.
    Computational and Structural Biotechnology Journal 03/2013; 6(7):e201303019. DOI:10.5936/csbj.201303019
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