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John C Reed - One of the best experts on this subject based on the ideXlab platform.
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targeting the bcl 2 Family for cancer therapy
Expert Opinion on Therapeutic Targets, 2013Co-Authors: Shibu Thomas, John C Reed, Bridget A Quinn, Swadesh K Das, Rupesh Dash, Luni Emdad, Santanu Dasgupta, Xiangyang Wang, Paul Dent, Maurizio PellecchiaAbstract:Introduction: Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene Family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation. Areas covered: This review focuses on the resistance induced by the Bcl-2 Family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 Family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 Family proteins, recent approaches use small molecule inhibitors (SMIs) and peptides. Structural similarity of the Bcl-2 Family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics. Expert opinion: Strategies to specifically ident...
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gambogic acid is an antagonist of antiapoptotic bcl 2 Family proteins
Molecular Cancer Therapeutics, 2008Co-Authors: Dayong Zhai, Chungwai Shiau, Shinichi Kitada, Arnold C Satterthwait, John C ReedAbstract:The natural product gambogic acid (GA) has been reported to have cytotoxic activity against tumor cells in culture and was identified as an active compound in a cell-based high-throughput screening assay for activators of caspases, proteases involved in apoptosis. Using the antiapoptotic Bcl-2 Family protein, Bfl-1, as a target for screening of a library of natural products, we identified GA as a competitive inhibitor that displaced BH3 peptides from Bfl-1 in a fluorescence polarization assay. Analysis of competition for BH3 peptide binding revealed that GA inhibits all six human Bcl-2 Family proteins to various extents, with Mcl-1 and Bcl-B the most potently inhibited [concentrations required for 50% inhibition (IC 50 ), in vitro , showing that GA neutralizes their suppressive effects on mitochondria in a concentration-dependent manner. GA killed tumor cell lines via an apoptotic mechanism, whereas analogues of GA with greatly reduced potency at BH3 peptide displacement showed little or no cytotoxic activity. However, GA retained cytotoxic activity against bax −/− bak −/− cells in which antiapoptotic Bcl-2 Family proteins lack a cytoprotective phenotype, implying that GA also has additional targets that contribute to its cytotoxic mechanism. Altogether, the findings suggest that suppression of antiapoptotic Bcl-2 Family proteins may be among the cytotoxic mechanisms by which GA kills tumor cells. [Mol Cancer Ther 2008;7(6):1639–46]
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bcl 2 Family proteins and hematologic malignancies history and future prospects
Blood, 2008Co-Authors: John C ReedAbstract:Bcl-2 was the first antideath gene discovered, a milestone that effectively launched a new era in cell death research. Since its discovery more than 2 decades ago, multiple members of the human Bcl-2 Family of apoptosis-regulating proteins have been identified, including 6 antiapoptotic proteins, 3 structurally similar proapoptotic proteins, and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. Bcl-2-Family proteins regulate all major types of cell death, including apoptosis, necrosis, and autophagy. As such, they operate as nodal points at the convergence of multiple pathways with broad relevance to biology and medicine. Bcl-2 derives its name from its original discovery in the context of B-cell lymphomas, where chromosomal translocations commonly activate the Bcl-2 protooncogene, endowing B cells with a selective survival advantage that promotes their neoplastic expansion. The concept that defective programmed cell death contributes to malignancy was established by studies of Bcl-2, representing a major step forward in current understanding of tumorigenesis. Experimental therapies targeting Bcl-2 Family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may be near.
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vaccinia virus n1l protein resembles a b cell lymphoma 2 bcl 2 Family protein
Protein Science, 2006Co-Authors: Mika Aoyagi, Dayong Zhai, John C Reed, Chaofang Jin, Alexander E Aleshin, Boguslaw Stec, Robert C LiddingtonAbstract:Poxviruses encode immuno-modulatory proteins capable of subverting host defenses. The poxvirus vaccinia expresses a small 14-kDa protein, N1L, that is critical for virulence. We report the crystal structure of N1L, which reveals an unexpected but striking resemblance to host apoptotic regulators of the B cell lymphoma-2 (Bcl-2) Family. Although N1L lacks detectable Bcl-2 homology (BH) motifs at the sequence level, we show that N1L binds with high affinity to the BH3 peptides of pro-apoptotic Bcl-2 Family proteins in vitro, consistent with a role for N1L in modulating host antiviral defenses.
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orphan nuclear receptor tr3 nur77 binds and converts the phenotype of bcl b an anti apoptotic bcl 2 Family protein predominantly expressed in human plasma cells
Blood, 2006Co-Authors: Frederic Luciano, Arnold C Satterthwait, Maryla Krajewska, Xiaokun Zhang, John C ReedAbstract:TR3 (Nur77) is an orphan member of the steroid/retinoid Family of Nuclear Receptors (NRs) that translocates from nucleus to cytosol, where it binds Bcl-2 and converts its phenotype from anti-apoptotic to pro-apoptotic (Li, et al. Science 289: 1159, 2000; Lin, et al CELL 116: 527, 2004). We surveyed TR3 (Nur77) for interactions with all six human anti-apoptotic Bcl-2-Family proteins: Bcl-2, Bcl-XL, Mcl-1, Bcl-W, Bfl-1, and Bcl-B. We observed that Bcl-2, Bfl-1, and Bcl-B interact with TR3 as determined by co-immunoprecipitation assays using lysates from transfected cells and by GST pull down assays using GST-Bcl-2-Family fusion proteins. In contrast, Bcl-XL, Bcl-W, and Mcl-1 displayed little or no binding to TR3 (Nur77). Co-localization experiments using fluorescent protein tagging and confocal microscopy corroborated these findings, showing co-localization of a fragment of TR3 (Nur77) that accumulates in cytosol (rather than nucleus) [TR3 lacking the DNA-binding domain [DDBD]) with Bcl-2, Bfl-1, and Bcl-B on mitochondria and other intracellular organelles in intact cells, but not co-localization with Bcl-XL, Mcl-1 or Bcl-W. Co-expression of Bcl-2, Bfl-1, or Bcl-B with TR3DDBD by transfection resulted in robust apoptosis induction, while co-expression of Bcl-XL, Bcl-W, or Mcl-1 with TR3DDBD did not. In contrast to results obtained in TR3DDBD co-expression studies, expressing any of the anti-apoptotic Bcl-2-Family proteins (Bcl-2, Bfl-1, Bcl-B, Bcl-XL, Mcl-1, Bcl-W) individually resulted in suppression of apoptosis induced by Staurosporine, illustrating the role of TR3 in converting the phenotypes of Bcl-2, Bfl-1 and Bcl-B from protector to killer. Because binding of TR3 (Nur77) to Bcl-B appeared to be strongest among the Bcl-2-Family proteins, we focused on this Bcl-B for additional studies. (Ke, N. et al. J. Biol Chem 276: 12481, 2001. Using monospecific antibodies, the endogenous Bcl-B protein was localized in human tissues, revealing predominant expression in plasma cells. Several myeloma cell lines also expressed Bcl-B protein, as determined by immunoblotting. Stimulating myeloma cell line RPMI8226 with ionomycin and phorbol ester TPA (agents that induce TR3 expression and accumulation in cytosol) resulted in association of endogenous TR3 with endogenous Bcl-B, as determined by co-immunoprecipitation experiments. Reducing endogenous Bcl-B levels using small interfering RNA (siRNA) reduced apoptosis induced by transfected TR3DDBD as well as apoptosis induced by a synthetic peptide that mimics TR3. We conclude that cytosolic TR3 (Nur77) interacts selectively with certain anti-apoptotic members of the Bcl-2-Family (Bcl-2, Bfl-1, Bcl-B), converting them from protectors to killers. The ability of TR3 (Nur77) to convert Bcl-B suggests a possible novel strategy for triggering apoptosis of Bcl-B-expressing cells, which may be of utility for eradicating long-lived autoantibody-producing plasma cells or for killing malignant myeloma cells. (Supported by NIH GM60554 and SASS Foundation).
Yoshihide Tsujimoto - One of the best experts on this subject based on the ideXlab platform.
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role of bcl 2 Family proteins in a non apoptotic programmed cell death dependent on autophagy genes
Nature Cell Biology, 2004Co-Authors: Shigeomi Shimizu, Craig B Thompson, Toku Kanaseki, Noboru Mizushima, Takeshi Mizuta, Satoko Arakawakobayashi, Yoshihide TsujimotoAbstract:Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death). The Bcl-2 Family of proteins are well-characterized regulators of apoptosis, and the multidomain pro-apoptotic members of this Family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis, we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L). These results indicate that the Bcl-2 Family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.
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bcl 2 Family life or death switch
FEBS Letters, 2000Co-Authors: Yoshihide Tsujimoto, Shigeomi ShimizuAbstract:The Bcl-2 Family of proteins that consists of anti-apoptotic and pro-apoptotic members determines life-or-death of a cell by controlling the release of mitochondrial apoptogenic factors, cytochrome c and apoptosis-inducing factor (AIF), that activate downstream executional phases, including the activation of death proteases called caspases. Cytochrome c release is, thus, central to apoptotic signal transduction in mammals, making study of the mechanism for cytochrome c release a major issue. Several models for cytochrome c release have been proposed, including rupture of mitochondrial outer membrane and involvement of a specific channel. Here, we provide an overview of recent findings on the role of Bcl-2 Family members in the life-or-death decision of a cell.
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proapoptotic bh3 only bcl 2 Family members induce cytochrome c release but not mitochondrial membrane potential loss and do not directly modulate voltage dependent anion channel activity
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Shigeomi Shimizu, Yoshihide TsujimotoAbstract:Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic Bcl-2 Family members such as Bax and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential (Δψ) loss in isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 Family, induced cytochrome c release but not Δψ loss. Unlike Bax/Bak, the cytochrome c release induced by Bid/Bik was Ca2+-independent, cyclosporin A-insensitive, and respiration-independent. Furthermore, in contrast to Bax/Bak, Bid/Bik neither interacted with VDAC nor directly affected the VDAC activity in liposomes. Consistently, Bid/Bik induced apoptosis without Δψ loss, whereas Bax induced apoptosis with Δψ loss. These findings indicated the involvement of a different mechanism in BH3-only, protein-induced apoptogenic cytochrome c release.
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bcl 2 Family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel vdac
Nature, 1999Co-Authors: Shigeomi Shimizu, Masashi Narita, Yoshihide TsujimotoAbstract:During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases1,2. The Bcl-2 Family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis3,4,5, but how that is achieved is unclear. Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-xL. In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-xL. Our results indicate that the Bcl-2 Family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.
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role of bcl 2 Family proteins in apoptosis apoptosomes or mitochondria
Genes to Cells, 1998Co-Authors: Yoshihide TsujimotoAbstract:Apoptosis is an essential physiological process for the selective elimination of cells, which is involved in a variety of biological events. The Bcl-2 Family is the best characterized protein Family involved in the regulation of apoptotic cell death, consisting of anti-apoptotic and pro-apoptotic members. The anti-apoptotic members of this Family, such as Bcl-2 and Bcl-XL, prevent apoptosis either by sequestering proforms of death-driving cysteine proteases called caspases (a complex called the apoptosome) or by preventing the release of mitochondrial apoptogenic factors such as cytochrome c and AIF (apoptosis-inducing factor) into the cytoplasm. After entering the cytoplasm, cytochrome c and AIF directly activate caspases that cleave a set of cellular proteins to cause apoptotic changes. In contrast, pro-apoptotic members of this Family, such as Bax and Bak, trigger the release of caspases from death antagonists via heterodimerization and also by inducing the release of mitochondrial apoptogenic factors into the cytoplasm via acting on mitochondrial permeability transition pore, thereby leading to caspase activation. Thus, the Bcl-2 Family of proteins acts as a critical life-death decision point within the common pathway of apoptosis.
Craig B Thompson - One of the best experts on this subject based on the ideXlab platform.
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role of bcl 2 Family proteins in a non apoptotic programmed cell death dependent on autophagy genes
Nature Cell Biology, 2004Co-Authors: Shigeomi Shimizu, Craig B Thompson, Toku Kanaseki, Noboru Mizushima, Takeshi Mizuta, Satoko Arakawakobayashi, Yoshihide TsujimotoAbstract:Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death). The Bcl-2 Family of proteins are well-characterized regulators of apoptosis, and the multidomain pro-apoptotic members of this Family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis, we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L). These results indicate that the Bcl-2 Family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.
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bcl 2 Family members and functional electron transport chain regulate oxygen deprivation induced cell death
Molecular and Cellular Biology, 2002Co-Authors: David S Mcclintock, Matthew T Santore, Vivian Y Lee, Joslyn K Brunelle, G Scott R Budinger, Weixing Zong, Craig B Thompson, Nissim Hay, Navdeep S. ChandelAbstract:The mechanisms underlying cell death during oxygen deprivation are unknown. We report here a model for oxygen deprivation-induced apoptosis. The death observed during oxygen deprivation involves a decrease in the mitochondrial membrane potential, followed by the release of cytochrome c and the activation of caspase-9. Bcl-XL prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-XL to prevent cell death was dependent on allowing the import of glycolytic ATP into the mitochondria to generate an inner mitochondrial membrane potential through the F1F0-ATP synthase. In contrast, although activated Akt has been shown to inhibit apoptosis induced by a variety of apoptotic stimuli, it did not prevent cell death during oxygen deprivation. In addition to Bcl-XL, cells devoid of mitochondrial DNA (ρ° cells) that lack a functional electron transport chain were resistant to oxygen deprivation. Further, murine embryonic fibroblasts from bax−/− bak−/− mice did not die in response to oxygen deprivation. These data suggest that when subjected to oxygen deprivation, cells die as a result of an inability to maintain a mitochondrial membrane potential through the import of glycolytic ATP. Proapoptotic Bcl-2 Family members and a functional electron transport chain are required to initiate cell death in response to oxygen deprivation.
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the role of the bcl 2 Family in the regulation of outer mitochondrial membrane permeability
Cell Death & Differentiation, 2000Co-Authors: Marian H Harris, Craig B ThompsonAbstract:Mitochondria are well known as sites of electron transport and generators of cellular ATP. Mitochondria also appear to be sites of cell survival regulation. In the process of programmed cell death, mediators of apoptosis can be released from mitochondria through disruptions in the outer mitochondrial membrane; these mediators then participate in the activation of caspases and of DNA degradation. Thus the regulation of outer mitochondrial membrane integrity is an important control point for apoptosis. The Bcl-2 Family is made up of outer mitochondrial membrane proteins that can regulate cell survival, but the mechanisms by which Bcl-2 Family proteins act remain controversial. Most metabolites are permeant to the outer membrane through the voltage dependent anion channel (VDAC), and Bcl-2 Family proteins appear to be able to regulate VDAC function. In addition, many Bcl-2 Family proteins can form channels in vitro, and some pro-apoptotic members may form multimeric channels large enough to release apoptosis promoting proteins from the intermembrane space. Alternatively, Bcl-2 Family proteins have been hypothesized to coordinate the permeability of both the outer and inner mitochondrial membranes through the permeability transition (PT) pore. Increasing evidence suggests that alterations in cellular metabolism can lead to pro-apoptotic changes, including changes in intracellular pH, redox potential and ion transport. By regulating mitochondrial membrane physiology, Bcl-2 proteins also affect mitochondrial energy generation, and thus influence cellular bioenergetics. Cell Death and Differentiation (2000) 7, 1182–1191
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bcl 2 Family proteins the role of the bh3 domain in apoptosis
Trends in Cell Biology, 1998Co-Authors: Ameeta Kelekar, Craig B ThompsonAbstract:Bcl-2-related proteins have come to occupy a prominent position in the realm of programmed cell death. Members of this fast-growing Family are highly related in one or more specific regions, commonly referred to as Bcl-2 homology (BH) domains. BH domains contribute at multiple levels to the function of these proteins in cell death and survival. Particularly intriguing is the emergence of the BH3 domain as a potent 'death domain' and of a growing subclass of pro-apoptotic proteins with no similarity to Bcl-2 beyond their BH3 homology. Here, the authors classify proteins of the Bcl-2 Family on the basis of function and domain organization, discuss the importance of the BH3 domain in protein-protein interactions and in cell death and provide possible explanations for the perceived redundancy in the expression of this subclass of death promoters.
Anthony Letai - One of the best experts on this subject based on the ideXlab platform.
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regulation of apoptosis in health and disease the balancing act of bcl 2 Family proteins
Nature Reviews Molecular Cell Biology, 2019Co-Authors: Rumani Singh, Anthony Letai, Kristophe A SarosiekAbstract:The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the Bcl-2 Family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between Bcl-2 Family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.
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proapoptotic bh3 only bcl 2 Family protein bim connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion
Cancer Research, 2007Co-Authors: Jing Deng, Takeshi Shimamura, Samanthi A Perera, Nicole Carlson, Geoffrey I Shapiro, Kwokkin Wong, Anthony LetaiAbstract:A subset of lung cancers expresses mutant forms of epidermal growth factor receptor (EGFR) that are constitutively activated. Cancers bearing activated EGFR can be effectively targeted with EGFR inhibitors such as erlotinib. However, the death-signaling pathways engaged after EGFR inhibition are poorly understood. Here, we show that death after inhibition of EGFR uses the mitochondrial, or intrinsic, pathway of cell death controlled by the Bcl-2 Family of proteins. Bcl-2 inhibits cell death induced by erlotinib, but Bcl-2–protected cells are thus rendered Bcl-2–dependent and sensitive to the Bcl-2 antagonist ABT-737. BH3 profiling reveals that mitochondrial Bcl-2 is primed by death signals after EGFR inhibition in these cells. As this result implies, key death-signaling proteins of the Bcl-2 Family, including BIM, were found to be up-regulated after erlotinib treatment and intercepted by overexpressed Bcl-2. BIM is induced by lung cancer cell lines that are sensitive to erlotinib but not by those resistant. Reduction of BIM by siRNA induces resistance to erlotinib. We show that EGFR activity is inhibited by erlotinib in H1650, a lung cancer cell line that bears a sensitizing EGFR mutation, but that H1650 is not killed. We identify the block in apoptosis in this cell line, and show that a novel form of erlotinib resistance is present, a block in BIM up-regulation downstream of EGFR inhibition. This finding has clear implications for overcoming resistance to erlotinib. Resistance to EGFR inhibition can be modulated by alterations in the intrinsic apoptotic pathway controlled by the Bcl-2 Family of proteins. [Cancer Res 2007;67(24):11867–75]
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proapoptotic bh3 only bcl 2 Family protein bim connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion
Cancer Research, 2007Co-Authors: Jing Deng, Takeshi Shimamura, Samanthi A Perera, Nicole Carlson, Geoffrey I Shapiro, Kwokkin Wong, Dongpo Cai, Anthony LetaiAbstract:A subset of lung cancers expresses mutant forms of epidermal growth factor receptor (EGFR) that are constitutively activated. Cancers bearing activated EGFR can be effectively targeted with EGFR inhibitors such as erlotinib. However, the death-signaling pathways engaged after EGFR inhibition are poorly understood. Here, we show that death after inhibition of EGFR uses the mitochondrial, or intrinsic, pathway of cell death controlled by the Bcl-2 Family of proteins. Bcl-2 inhibits cell death induced by erlotinib, but Bcl-2-protected cells are thus rendered Bcl-2-dependent and sensitive to the Bcl-2 antagonist ABT-737. BH3 profiling reveals that mitochondrial Bcl-2 is primed by death signals after EGFR inhibition in these cells. As this result implies, key death-signaling proteins of the Bcl-2 Family, including BIM, were found to be up-regulated after erlotinib treatment and intercepted by overexpressed Bcl-2. BIM is induced by lung cancer cell lines that are sensitive to erlotinib but not by those resistant. Reduction of BIM by siRNA induces resistance to erlotinib. We show that EGFR activity is inhibited by erlotinib in H1650, a lung cancer cell line that bears a sensitizing EGFR mutation, but that H1650 is not killed. We identify the block in apoptosis in this cell line, and show that a novel form of erlotinib resistance is present, a block in BIM up-regulation downstream of EGFR inhibition. This finding has clear implications for overcoming resistance to erlotinib. Resistance to EGFR inhibition can be modulated by alterations in the intrinsic apoptotic pathway controlled by the Bcl-2 Family of proteins.
Shigeomi Shimizu - One of the best experts on this subject based on the ideXlab platform.
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role of bcl 2 Family proteins in a non apoptotic programmed cell death dependent on autophagy genes
Nature Cell Biology, 2004Co-Authors: Shigeomi Shimizu, Craig B Thompson, Toku Kanaseki, Noboru Mizushima, Takeshi Mizuta, Satoko Arakawakobayashi, Yoshihide TsujimotoAbstract:Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death). The Bcl-2 Family of proteins are well-characterized regulators of apoptosis, and the multidomain pro-apoptotic members of this Family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis, we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L). These results indicate that the Bcl-2 Family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.
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bcl 2 Family life or death switch
FEBS Letters, 2000Co-Authors: Yoshihide Tsujimoto, Shigeomi ShimizuAbstract:The Bcl-2 Family of proteins that consists of anti-apoptotic and pro-apoptotic members determines life-or-death of a cell by controlling the release of mitochondrial apoptogenic factors, cytochrome c and apoptosis-inducing factor (AIF), that activate downstream executional phases, including the activation of death proteases called caspases. Cytochrome c release is, thus, central to apoptotic signal transduction in mammals, making study of the mechanism for cytochrome c release a major issue. Several models for cytochrome c release have been proposed, including rupture of mitochondrial outer membrane and involvement of a specific channel. Here, we provide an overview of recent findings on the role of Bcl-2 Family members in the life-or-death decision of a cell.
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proapoptotic bh3 only bcl 2 Family members induce cytochrome c release but not mitochondrial membrane potential loss and do not directly modulate voltage dependent anion channel activity
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Shigeomi Shimizu, Yoshihide TsujimotoAbstract:Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic Bcl-2 Family members such as Bax and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential (Δψ) loss in isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 Family, induced cytochrome c release but not Δψ loss. Unlike Bax/Bak, the cytochrome c release induced by Bid/Bik was Ca2+-independent, cyclosporin A-insensitive, and respiration-independent. Furthermore, in contrast to Bax/Bak, Bid/Bik neither interacted with VDAC nor directly affected the VDAC activity in liposomes. Consistently, Bid/Bik induced apoptosis without Δψ loss, whereas Bax induced apoptosis with Δψ loss. These findings indicated the involvement of a different mechanism in BH3-only, protein-induced apoptogenic cytochrome c release.
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bcl 2 Family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel vdac
Nature, 1999Co-Authors: Shigeomi Shimizu, Masashi Narita, Yoshihide TsujimotoAbstract:During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases1,2. The Bcl-2 Family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis3,4,5, but how that is achieved is unclear. Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-xL. In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-xL. Our results indicate that the Bcl-2 Family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.