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
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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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    • " promotes mitochondrial apoptosis and also regulates mitochondrial dynamics ( Xiang et al . , 1998 ; Karbowski et al . , 2002 , 2004a ; Steckley et al . , 2007 ) , and Bif - 1 has been shown to bind and activate Bax upon apoptosis in - duction in non - neuronal cells while also promoting mito - chondrial fragmentation ( Karbowski et al . , 2004b ; Takahashi et al . , 2005 ) . Here , we sought to determine whether Bif - 1 also plays a role in mediating a p53 - Bax apoptotic pathway in neurons . CPT is a topoisomerase I inhibitor that causes DNA dam - age and activates p53 to induce apoptosis in a number of cell types , including neurons ( Xiang et al . , 1996 , 1998 ; Uo et al . , 2007 ; Wang et al . , 20"
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    ABSTRACT: Bax-interacting factor 1 (Bif-1, also known as endophilin B1) is a multifunctional protein involved in the regulation of apoptosis, mitochondrial morphology, and autophagy. Previous studies in non-neuronal cells have shown that Bif-1 is proapoptotic and promotes mitochondrial fragmentation. However, the role of Bif-1 in postmitotic neurons has not been investigated. In contrast to non-neuronal cells, we now report that in neurons Bif-1 promotes viability and mitochondrial elongation. In mouse primary cortical neurons, Bif-1 knockdown exacerbated apoptosis induced by the DNA-damaging agent camptothecin. Neurons from Bif-1-deficient mice contained fragmented mitochondria and Bif-1 knockdown in wild-type neurons also resulted in fragmented mitochondria which were more depolarized, suggesting mitochondrial dysfunction. During ischemic stroke, Bif-1 expression was downregulated in the penumbra of wild-type mice. Consistent with Bif-1 being required for neuronal viability, Bif-1-deficient mice developed larger infarcts and an exaggerated astrogliosis response following ischemic stroke. Together, these data suggest that, in contrast to non-neuronal cells, Bif-1 is essential for the maintenance of mitochondrial morphology and function in neurons, and that loss of Bif-1 renders neurons more susceptible to apoptotic stress. These unique actions may relate to the presence of longer, neuron-specific Bif-1 isoforms, because only these forms of Bif-1 were able to rescue deficiencies caused by Bif-1 suppression. This finding not only demonstrates an unexpected role for Bif-1 in the nervous system but this work also establishes Bif-1 as a potential therapeutic target for the treatment of neurological diseases, especially degenerative disorders characterized by alterations in mitochondrial dynamics.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2014; 34(7):2674-83. DOI:10.1523/JNEUROSCI.4074-13.2014 · 6.34 Impact Factor
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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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