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Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics.
Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, Cantlon A, Fisch S, Golomb-Mello G, Ryan JA, Deng J, Jian B, Corbett C, Goldenberg M, Madsen JR, Liao R, Walsh D, Sedivy J, Murphy DJ, Carrasco DR, Robinson S, Moslehi J, Letai A
(2017) Cancer Cell 31: 142-156
MeSH Terms: Age Factors, Animals, Apoptosis, Doxorubicin, Humans, Mice, Mitochondria, Neoplasms, Organ Specificity, Proto-Oncogene Proteins c-myc, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added March 26, 2017
It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.
Copyright © 2017 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX.
Fischer AW, Bordignon E, Bleicken S, García-Sáez AJ, Jeschke G, Meiler J
(2016) J Struct Biol 195: 62-71
MeSH Terms: Algorithms, Amino Acid Sequence, Animals, Electron Spin Resonance Spectroscopy, Humans, Models, Molecular, Molecular Structure, Protein Conformation, Protein Folding, Protein Multimerization, bcl-2-Associated X Protein
Show Abstract · Added April 8, 2017
Structure determination remains a challenge for many biologically important proteins. In particular, proteins that adopt multiple conformations often evade crystallization in all biologically relevant states. Although computational de novo protein folding approaches often sample biologically relevant conformations, the selection of the most accurate model for different functional states remains a formidable challenge, in particular, for proteins with more than about 150 residues. Electron paramagnetic resonance (EPR) spectroscopy can obtain limited structural information for proteins in well-defined biological states and thereby assist in selecting biologically relevant conformations. The present study demonstrates that de novo folding methods are able to accurately sample the folds of 192-residue long soluble monomeric Bcl-2-associated X protein (BAX). The tertiary structures of the monomeric and homodimeric forms of BAX were predicted using the primary structure as well as 25 and 11 EPR distance restraints, respectively. The predicted models were subsequently compared to respective NMR/X-ray structures of BAX. EPR restraints improve the protein-size normalized root-mean-square-deviation (RMSD100) of the most accurate models with respect to the NMR/crystal structure from 5.9Å to 3.9Å and from 5.7Å to 3.3Å, respectively. Additionally, the model discrimination is improved, which is demonstrated by an improvement of the enrichment from 5% to 15% and from 13% to 21%, respectively.
Copyright © 2016 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma.
Crowther AJ, Gama V, Bevilacqua A, Chang SX, Yuan H, Deshmukh M, Gershon TR
(2013) J Neurosci 33: 18098-108
MeSH Terms: Animals, Apoptosis, Cells, Cultured, Female, Male, Medulloblastoma, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Neural Stem Cells, Protein Binding, Time Factors, bcl-2-Associated X Protein, bcl-X Protein
Show Abstract · Added October 26, 2015
Commitment to survival or apoptosis within expanding progenitor populations poses distinct risks and benefits to the organism. We investigated whether specialized mechanisms regulate apoptosis in mouse neural progenitors and in the progenitor-derived brain tumor medulloblastoma. Here, we identified constitutive activation of proapoptotic Bax, maintained in check by Bcl-xL, as a mechanism for rapid cell death, common to postnatal neural progenitors and medulloblastoma. We found that tonic activation of Bax in cerebellar progenitors, along with sensitivity to DNA damage, was linked to differentiation state. In cerebellar progenitors, active Bax localized to mitochondria, where it was bound to Bcl-xL. Disruption of Bax:Bcl-xL binding by BH3-mimetic ABT 737 caused rapid apoptosis of cerebellar progenitors and primary murine medulloblastoma cells. Conditional deletion of Mcl-1, in contrast, did not cause death of cerebellar progenitors. Our findings identify a mechanism for the sensitivity of brain progenitors to typical anticancer therapies and reveal that this mechanism persists in medulloblastoma, a malignant brain tumor markedly sensitive to radiation and chemotherapy.
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15 MeSH Terms
Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax.
He K, Zheng X, Zhang L, Yu J
(2013) Mol Cancer Ther 12: 2559-68
MeSH Terms: Animals, Apoptosis, Apoptosis Regulatory Proteins, Benzoquinones, Cell Line, Tumor, Colorectal Neoplasms, DNA Damage, HCT116 Cells, HSP90 Heat-Shock Proteins, Humans, Isoxazoles, Lactams, Macrocyclic, Mice, Mice, Nude, Mitochondria, Proto-Oncogene Proteins, Resorcinols, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
Hsp90 is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promise in solid and hematologic malignancies, which likely involves degradation of client oncoproteins in a cell-type-specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53, at lesser extent, abrogated 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17-AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17-AAG analog 17-DMAG in xenografts. These results show an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 wild-type cells, and have important implications for their clinical applications.
©2013 AACR.
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20 MeSH Terms
Human embryonic stem cells: living on the edge.
Gama V, Deshmukh M
(2012) Cell Cycle 11: 3905-6
MeSH Terms: Apoptosis, Caspases, Cell Differentiation, Cytochromes c, DNA Damage, Embryonic Stem Cells, Golgi Apparatus, Humans, Mitochondria, bcl-2-Associated X Protein
Added October 26, 2015
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10 MeSH Terms
Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
Garcia I, Crowther AJ, Gama V, Miller CR, Miller CR, Deshmukh M, Gershon TR
(2013) Oncogene 32: 2304-14
MeSH Terms: Animals, Apoptosis, Cell Differentiation, Cell Movement, Cerebellar Neoplasms, Cerebellum, Down-Regulation, Medulloblastoma, Mice, Mice, Transgenic, Neurogenesis, Proto-Oncogene Proteins c-bcl-2, Receptors, G-Protein-Coupled, Smoothened Receptor, Stem Cells, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
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16 MeSH Terms
Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis.
Dumitru R, Gama V, Fagan BM, Bower JJ, Swahari V, Pevny LH, Deshmukh M
(2012) Mol Cell 46: 573-83
MeSH Terms: Acetylation, Antigens, Nuclear, Apoptosis, Biological Transport, DNA Damage, DNA-Binding Proteins, Embryonic Stem Cells, Gene Silencing, Genes, bcl-2, Golgi Apparatus, Humans, Ku Autoantigen, Mitochondria, Tumor Suppressor Protein p53, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Human embryonic stem (hES) cells activate a rapid apoptotic response after DNA damage but the underlying mechanisms are unknown. A critical mediator of apoptosis is Bax, which is reported to become active and translocate to the mitochondria only after apoptotic stimuli. Here we show that undifferentiated hES cells constitutively maintain Bax in its active conformation. Surprisingly, active Bax was maintained at the Golgi rather than at the mitochondria, thus allowing hES cells to effectively minimize the risks associated with having preactivated Bax. After DNA damage, active Bax rapidly translocated to the mitochondria by a p53-dependent mechanism. Interestingly, upon differentiation, Bax was no longer active, and cells were not acutely sensitive to DNA damage. Thus, maintenance of Bax in its active form is a unique mechanism that can prime hES cells for rapid death, likely to prevent the propagation of mutations during the early critical stages of embryonic development.
Copyright © 2012 Elsevier Inc. All rights reserved.
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15 MeSH Terms
CRM1 protein-mediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor.
Leskov KS, Araki S, Lavik JP, Gomez JA, Gama V, Gonos ES, Trougakos IP, Matsuyama S, Boothman DA
(2011) J Biol Chem 286: 40083-90
MeSH Terms: Active Transport, Cell Nucleus, Animals, Antibiotics, Antineoplastic, Apoptosis, Cell Nucleus, Clusterin, Fatty Acids, Unsaturated, Gamma Rays, Humans, Karyopherins, Mice, Mice, Knockout, Protein Isoforms, Radiation Tolerance, Receptors, Cytoplasmic and Nuclear, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Expression of the clusterin (CLU) gene results in the synthesis of a conventional secretory isoform set (pre- and mature secretory clusterin proteins, psCLU/sCLU), as well as another set of intracellular isoforms, appearing in the cytoplasm (pre-nuclear CLU, pnCLU) and in the nucleus as an ∼55-kDa mature nuclear clusterin (nCLU) form. These two isoform sets have opposing cell functions: pro-survival and pro-death, respectively. Although much is known about the regulation and function of sCLU as a pro-survival factor, the regulation and function of endogenous nCLU in cell death are relatively unexplored. Here, we show that depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells. nCLU-mediated apoptosis was Bax-dependent, and lethality correlated with accumulation of mature nCLU protein. nCLU accumulation was regulated by CRM1 because binding between CRM1 and nCLU proteins was significantly diminished by leptomycin B (LMB), and nuclear levels of nCLU protein were significantly enhanced by LMB and IR co-treatment. Moreover, LMB treatment significantly enhanced IR-induced nCLU-mediated cell death responses. Importantly, bax(-/-) and bax(-/-)/bak(-/-) double knock-out cells were resistant to nCLU-mediated cell death, whereas bak(-/-) or wild-type bax(+/+)/bak(+/+) cells were hypersensitive. The regulation of nCLU by CRM1 nuclear export/import may explain recent clinical results showing that highly malignant tumors have lost the ability to accumulate nCLU levels, thereby avoiding growth inhibition and cell death.
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17 MeSH Terms
Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release.
Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C, Jin YH
(2011) Mol Carcinog 50: 760-9
MeSH Terms: Antineoplastic Agents, Phytogenic, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Blotting, Western, Caspase 3, Caspase 8, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Activation, Flow Cytometry, Ginsenosides, HeLa Cells, Hep G2 Cells, Humans, Molecular Structure, Neoplasms, Poly(ADP-ribose) Polymerases, Protein Transport, RNA Interference, Triterpenes, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
We provide evidence for the first time, that two natural compounds ginsenoside Rh2 (G-Rh2) and betulinic acid (Bet A) synergistically induce apoptosis in human cervical adenocarcinoma (HeLa), human lung cancer A549, and human hepatoma HepG2 cells. G-Rh2 and Bet A cooperated to induce Bax traslocation to mitochondria and cytochrome c release. Co-treatment of G-Rh2 and Bet A resulted in enhanced cleavage of caspase-8 and Bid. Moreover, specific inhibition of caspase-8 by siRNA technology effectively reduced caspase-9 processing, poly (ADP-ribose) polymerase (PARP) cleavage, caspase-3 activation, and apoptosis in co-treated cells, which indicated that the caspase-8 feedback amplification pathway may have been involved in the apoptosis process. A previous study has shown that G-Rh2 induces cancer cell apoptosis via a Bcl-2 and/or Bcl-xL-independent mechanism, and Bet A induces apoptosis mainly through a mitochondrial pathway with tumor specificity. Since the antiapoptotic Bcl-2 and Bcl-xL are frequently overexpressed in human cancer cells, combined treatment with G-Rh2 and Bet A may be a novel strategy to enhance efficacy of anticancer therapy. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
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25 MeSH Terms
Induction of podocyte-derived VEGF ameliorates podocyte injury and subsequent abnormal glomerular development caused by puromycin aminonucleoside.
Ma J, Matsusaka T, Yang HC, Zhong J, Takagi N, Fogo AB, Kon V, Ichikawa I
(2011) Pediatr Res 70: 83-9
MeSH Terms: Actinin, Animals, Animals, Newborn, Apoptosis, Autocrine Communication, Caspase 3, Cells, Cultured, Desmin, Disease Models, Animal, Doxycycline, Glomerulonephritis, Humans, Intracellular Signaling Peptides and Proteins, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Podocytes, Puromycin Aminonucleoside, Response Elements, Vascular Endothelial Growth Factor A, bcl-2-Associated X Protein, bcl-X Protein
Show Abstract · Added January 25, 2012
Our previous studies using puromycin aminonucleoside (PAN) established that podocyte damage leads to glomerular growth arrest during development and glomerulosclerosis later in life. This study examined the potential benefit of maintaining podocyte-derived VEGF in podocyte defense and survival after PAN injury using conditional transgenic podocytes and mice, in which human VEGF-A (hVEGF) transgene expression is controlled by tetracycline responsive element (TRE) promoter and reverse tetracycline transactivator (rtTA) in podocytes. In vitro experiments used primary cultured podocytes harvested from mice carrying podocin-rtTA and TRE-hVEGF transgenes, in which hVEGF can be induced selectively. Induction of VEGF in PAN-exposed podocytes resulted in preservation of intrinsic VEGF, α-actinin-4 and synaptopodin, antiapoptotic marker Bcl-xL/Bax, as well as attenuation in apoptotic marker cleaved/total caspase-3. In vivo, compared with genotype controls, PAN-sensitive neonatal mice with physiologically relevant levels of podocyte-derived VEGF showed significantly larger glomeruli. Furthermore, PAN-induced up-regulation of desmin, down-regulation of synaptopodin and nephrin, and disruption of glomerular morphology were significantly attenuated in VEGF-induced transgenic mice. Our data indicate that podocyte-derived VEGF provides self-preservation functions, which can rescue the cell after injury and preempt subsequent deterioration of the glomerulus in developing mice.
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25 MeSH Terms