BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program

Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 12/2010; 330(6009):1390-3. DOI: 10.1126/science.1190217
Source: PubMed


Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated
remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating
BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c–mediated activation of caspases in response to
diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of
apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

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Available from: Osamu Takeuchi, Aug 12, 2014
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    • "Deletion of any single BH3-only gene in mice, on the other hand, does not result in obvious developmental defects (Ren et al., 2010; Villunger et al., 2011), although Bid deletion inhibits Fas-induced apoptosis in certain cell types (Yin et al., 1999). Intriguingly, mice with Bid, Bim, and Puma triple knockout showed embryonic lethality, and a subset of the viable triple null mice displayed similar developmental defects to those of Bax-/-Bak-/-mice with persistent interdigital webs of skin on their feet and imperforate vaginas, indicating these three BH3-only proteins in combination are essential for Bak/Bax activation (Ren et al., 2010; Villunger et al., 2011). "
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    ABSTRACT: The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, maintenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehensively studied, yet a great deal of new evidence indicates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the targeted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.
    Protein & Cell 07/2014; 5(10). DOI:10.1007/s13238-014-0089-1 · 3.25 Impact Factor
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    • "In our study, we investigated expression levels for three apoptosis-related genes and found significant changes in RARA and BBC3. In general, BBC3 is involved in BAX-dependent cell death related to developing retina and brain [59] but in the adult nervous system the cell death process is mediated by BIM. BBC3 expression can be altered in response to various insults and is involved in adult retinal cell degeneration [60]–[62]. "
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    ABSTRACT: Background It has been recognized that cells do not respond equally to ultraviolet (UV) radiation but it is not clear whether this is due to genetic, biochemical or structural differences of the cells. We have a novel cybrid (cytoplasmic hybrids) model that allows us to analyze the contribution of mitochondrial DNA (mtDNA) to cellular response after exposure to sub-lethal dose of UV. mtDNA can be classified into haplogroups as defined by accumulations of specific single nucleotide polymorphisms (SNPs). Recent studies have shown that J haplogroup is high risk for age-related macular degeneration while the H haplogroup is protective. This study investigates gene expression responses in J cybrids versus H cybrids after exposure to sub-lethal doses of UV-radiation. Methodology/Principal Findings Cybrids were created by fusing platelets isolated from subjects with either H (n = 3) or J (n = 3) haplogroups with mitochondria-free (Rho0) ARPE-19 cells. The H and J cybrids were cultured for 24 hours, treated with 10 mJ of UV-radiation and cultured for an additional 120 hours. Untreated and treated cybrids were analyzed for growth rates and gene expression profiles. The UV-treated and untreated J cybrids had higher growth rates compared to H cybrids. Before treatment, J cybrids showed lower expression levels for CFH, CD55, IL-33, TGF-A, EFEMP-1, RARA, BCL2L13 and BBC3. At 120 hours after UV-treatment, the J cybrids had decreased CFH, RARA and BBC3 levels but increased CD55, IL-33 and EFEMP-1 compared to UV-treated H cybrids. Conclusion/Significance In cells with identical nuclei, the cellular response to sub-lethal UV-radiation is mediated in part by the mtDNA haplogroup. This supports the hypothesis that differences in growth rates and expression levels of complement, inflammation and apoptosis genes may result from population-specific, hereditary SNP variations in mtDNA. Therefore, when analyzing UV-induced damage in tissues, the mtDNA haplogroup background may be important to consider.
    PLoS ONE 06/2014; 9(6):e99003. DOI:10.1371/journal.pone.0099003 · 3.23 Impact Factor
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    • "Thus, upregulation of anti-apoptotic Bcl-2 proteins and/or down-regulation of pro-apoptotic proteins can confer resistance to apoptotic stimuli on tumor cells [3], [4]. Indeed, one or more of these anti-apoptotic Bcl-2 proteins is overexpressed in human cancers, resulting in resistance to chemotherapy and radiation [4], [5], [6], [7], [8], [9], [10]. Therefore, pharmacological inhibition of one or more of these anti-apoptotic Bcl-2 family proteins has been pursued as a novel cancer therapeutic strategy with the goal of overcoming apoptosis resistance of tumor cells. "
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    ABSTRACT: Bcl-2 and Bcl-xL are critical regulators of apoptosis that are overexpressed in a variety of human cancers and pharmacological inhibition of Bcl-2 and Bcl-xL represents a promising strategy for cancer treatment. Using a structure-based design approach, we have designed BM-1197 as a potent and efficacious dual inhibitor of Bcl-2 and Bcl-xL. BM-1197 binds to Bcl-2 and Bcl-xL proteins with Ki values less than 1 nM and shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed in the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed that BM-1197 potently disassociates the heterodimeric interactions between anti-apoptotic and pro-apoptotic Bcl-2 family proteins, concomitant with conformational changes in Bax protein, loss of mitochondrial membrane potential and subsequent cytochrome c release to the cytosol, leading to activation of the caspase cascade and apoptosis. BM-1197 exerts potent growth-inhibitory activity in 7 of 12 small cell lung cancer cell lines tested and induces mechanism-based apoptotic cell death. When intravenously administered at daily or weekly in H146 and H1963 small-cell lung cancer xenograft models, it achieves complete and long-term tumor regression. Consistent with its targeting of Bcl-xL, BM-1197 causes transit platelet reduction in mice. Collectively, our data indicate that BM-1197 is a promising dual Bcl-2/Bcl-xL inhibitor which warrants further investigation as a new anticancer drug.
    PLoS ONE 06/2014; 9(6):e99404. DOI:10.1371/journal.pone.0099404 · 3.23 Impact Factor
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