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Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice.
Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS
(2019) Blood 133: 107-120
MeSH Terms: Animals, BH3 Interacting Domain Death Agonist Protein, Bone Marrow, Bone Marrow Diseases, Cells, Cultured, Cytokines, Hematopoietic Stem Cells, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelodysplastic Syndromes, Necrosis, Receptor-Interacting Protein Serine-Threonine Kinases, bcl-2 Homologous Antagonist-Killer Protein
Show Abstract · Added December 11, 2018
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
© 2019 by The American Society of Hematology.
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15 MeSH Terms
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
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
A role for proapoptotic Bax and Bak in T-cell differentiation and transformation.
Biswas S, Shi Q, Matise L, Cleveland S, Dave U, Zinkel S
(2010) Blood 116: 5237-46
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Cell Differentiation, Cell Transformation, Neoplastic, Coculture Techniques, Lymphoma, B-Cell, Mice, Mice, Knockout, Stem Cells, Stromal Cells, T-Lymphocytes, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added September 7, 2011
Proapoptotic Bax and Bak are the key B-cell lymphoma-2 family members mediating apoptosis through the intrinsic pathway. Cells doubly deficient for Bax and Bak are profoundly resistant to apoptotic stimuli originating from multiple stimuli. Here we describe mice in which Bax and Bak have been deleted specifically in T-cells using Lck-Cre. In these T cell-specific BaxBak-deficient mice, early T-cell progenitors accumulate in the thymus, with relative depletion of more mature T cells. In addition, bone marrow progenitor cells fail to progress to the double positive stage when cultured on OP9 stromal cells expressing the Notch ligand Delta-like 1, consistent with a critical role for Bax and Bak in early T-cell development. Over time, T cell-specific BaxBak-deficient mice progress to an aggressive T-cell lymphoblastic leukemia/lymphoma. Interestingly, quantitative real-time polymerase chain reaction analysis of BaxBak-deficient T-cell lymphomas does not display amplification of the Notch signal transduction pathway, commonly activated in T-cell leukemia in both mouse and man. Bax and Bak, key regulators of the intrinsic pathway of apoptosis, are thus required to prevent T-cell malignancy, and for normal T-cell differentiation, regulating early T-cell development at the stage of early T-lineage progenitor cells.
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13 MeSH Terms
Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells.
Li Y, He K, Huang Y, Zheng D, Gao C, Cui L, Jin YH
(2010) Mol Carcinog 49: 630-40
MeSH Terms: Antineoplastic Agents, Phytogenic, Apoptosis, Caspase 3, Caspase 7, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, HeLa Cells, Hep G2 Cells, Humans, Intracellular Signaling Peptides and Proteins, K562 Cells, Mitochondria, Mitochondrial Proteins, Neoplasms, Triterpenes, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
We examined whether betulin, a naturally abundant compound, has anticancer functions in human cancer cells. The results showed that betulin significantly inhibited cell viability in cervix carcinoma HeLa cells, hepatoma HepG2 cells, lung adenocarcinoma A549 cells, and breast cancer MCF-7 cells with IC(50) values ranging from 10 to 15 microg/mL. While betulin exhibited only moderate anticancer activity in other human cancer cells such as hepatoma SK-HEP-1 cells, prostate carcinoma PC-3, and lung carcinoma NCI-H460, with IC(50) values ranging from 20 to 60 microg/mL, it showed minor growth inhibition in human erythroleukemia K562 cells (IC(50) > 100 microg/mL). We further investigated the mechanism of anticancer activity by betulin, using HeLa cells as an experimental model. Betulin (10 microg/mL) induces apoptotic cell death, as evidenced by morphological characteristics such as membrane phosphatidylserine translocation, nuclear condensation/fragmentation, and apoptotic body formation. A kinetics analysis showed that the depolarization of mitochondrial membrane potential and the release of mitochondrial cytochrome c occurred as early as 30 min after treatment with betulin. Betulin, unlike its chemical derivative betulinic acid, did not directly trigger mitochondrial cytochrome c release in isolated mitochondria. Importantly, Bax and Bak were rapidly translocated to the mitochondria 30 min after betulin treatment. The sequential activation of caspase-9 and caspase-3/-7 and the cleavage of poly(ADP-ribose) polymerase (PARP) were observed behind those mitochondrial events. Furthermore, specific downregulation of either caspase-9, Bax, or Bak by siRNA effectively reduced PARP cleavage and caspase-3 activation. Taken together, the lines of evidence demonstrate that betulin triggers apoptosis of human cancer cells through the intrinsic apoptotic pathway.
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19 MeSH Terms
Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells.
Kaddour-Djebbar I, Choudhary V, Brooks C, Ghazaly T, Lakshmikanthan V, Dong Z, Kumar MV
(2010) Int J Oncol 36: 1437-44
MeSH Terms: Apoptosis, Blotting, Western, Calcium, Cell Line, Tumor, Clonazepam, GTP Phosphohydrolases, Humans, Immunohistochemistry, Immunoprecipitation, Male, Membrane Proteins, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Proteins, Prostatic Neoplasms, Sodium-Calcium Exchanger, TNF-Related Apoptosis-Inducing Ligand, Thiazepines, Transfection, bcl-2 Homologous Antagonist-Killer Protein
Show Abstract · Added September 12, 2016
Mitochondria are structurally complex organelles that undergo fragmentation or fission in apoptotic cells. Mitochondrial fission requires the cytoplasmic dynamin-related protein, Drp1, which translocates to the mitochondria during apoptosis and interacts with the mitochondrial protein, Fis1. Finely tuned changes in cellular calcium modulate a variety of intracellular functions; in resting cells, the level of mitochondrial calcium is low, while it is higher during apoptosis. Mitochondria take up Ca(2+) via the Uniporter and extrude it to the cytoplasm through the mitochondrial Na+/Ca(2+) exchanger. Overload of Ca(2+) in the mitochondria leads to their damage, affecting cellular function and survival. The mitochondrial Na+/Ca2+ exchanger was blocked by benzodiazepine, CGP37157 (CGP) leading to increased mitochondrial calcium and enhancing the apoptotic effects of TRAIL, TNFalpha related apoptosis inducing ligand. In the present study, we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp1 at the mitochondria in CGP treated cells. Under these conditions, we observed interactions between Drp1 and Fis1. The importance of Drp1 in fragmentation was confirmed by transfection of dominant negative Drp1 construct. However, fragmentation of the mitochondria was not sufficient to induce apoptosis, although it enhanced TRAIL-induced apoptosis. Furthermore, oligomerization of Bak was partially responsible for the increased apoptosis in cells treated with both CGP and TRAIL. Thus, our results show that combination of an apoptogenic agent and an appropriate calcium channel blocker provide therapeutic advantages.
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21 MeSH Terms
The C-terminus of interferon gamma receptor beta chain (IFNgammaR2) has antiapoptotic activity as a Bax inhibitor.
Gomez JA, Sun W, Gama V, Hajkova D, Yoshida T, Wu Z, Miyagi M, Pink JJ, Jackson MW, Danielpour D, Matsuyama S
(2009) Cancer Biol Ther 8: 1771-86
MeSH Terms: Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, Binding Sites, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Membrane, Cytosol, Green Fluorescent Proteins, HeLa Cells, Humans, Immunoprecipitation, Janus Kinase 2, Mass Spectrometry, Membrane Proteins, Microscopy, Fluorescence, Mitochondria, Protein Binding, Proto-Oncogene Proteins, RNA Interference, Receptors, Interferon, STAT1 Transcription Factor, Signal Transduction, Transfection, Yeasts, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Bax is a pro-apoptotic protein that mediates intrinsic cell-death signaling. Using a yeast-based functional screening approach, we identified interferon gamma receptor beta chain (IFNgammaR2) as a new Bax suppressor. IFNgammaR2 is a component of the IFNgamma receptor complex along with the IFNgammaR alpha chain (IFNgammaR1). Upon IFNgamma binding, a conformational change in the receptor complex occurs that activates the Jak2/STAT1 signaling cascade. We found that the C-terminal region (amino acids 296-337) of IFNgammaR2 (IFNgammaR2(296-337)) contains a novel Bax inhibitory domain. This portion does not contain the Jak2-binding domain; therefore, the antiapoptotic function of IFNgammaR2 is independent of JAK/STAT signaling. IFNgammaR2(296-337) rescued human cells from apoptosis induced by overexpression of Bax but not Bak. Overexpression of IFNgammaR2 (wild type and IFNgammaR2(296-337)) rescued cells from etoposide and staurosporine, which are known to induce Bax-mediated cell death. Interestingly, IFNgammaR2 inhibited apoptosis induced by the BH3-only protein Bim-EL, suggesting that IFNgammaR2 inhibits Bax activation through a BH3-only protein. Bax and IFNgammaR2 were co-immunoprecipitated from cell lysates prepared from HEK293 and DAMI cells. Furthermore, direct binding of purified recombinant proteins of Bax and IFNgammaR2 was also confirmed. Addition of recombinant Bcl-2 protein to cell lysates significantly reduced the interaction of IFNgammaR2 and Bax, suggesting that Bcl-2 and IFNgammaR2 bind a similar domain of Bax. We found that the C-terminal fragment (cytoplasmic domain) of IFNgammaR2 is expressed in human cancer cell lines of megakaryocytic cancer (DAMI), breast cancer (MDA-MD-468), and prostate cancer (PC3 cells). The presence of the C-terminal fragment of IFNgammaR2 may confer on cancer cells resistance to apoptotic stresses. Our discovery of the anti-Bax activity of the cytoplasmic domain of IFNgammaR2 may shed new light on the mechanism of how cell death is controlled by IFNgamma and Bax.
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28 MeSH Terms
Selective roles for antiapoptotic MCL-1 during granulocyte development and macrophage effector function.
Steimer DA, Boyd K, Takeuchi O, Fisher JK, Zambetti GP, Opferman JT
(2009) Blood 113: 2805-15
MeSH Terms: Animals, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, Bone Marrow Cells, Escherichia coli, Filgrastim, Gene Deletion, Granulocyte Colony-Stimulating Factor, Granulocytes, Macrophage Activation, Macrophages, Peritoneal, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cell Leukemia Sequence 1 Protein, Myelopoiesis, Organ Specificity, Phagocytosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Recombinant Proteins, Specific Pathogen-Free Organisms, Tumor Suppressor Proteins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added March 5, 2014
During hematopoiesis, myeloid cell leukemia-1 (MCL-1) mediates the survival of bone marrow progenitors and lymphocytes. However, its requirement during myeloid cell differentiation, development, and effector function is less clear. Lineage-specific deletion of MCL-1 in myeloid precursors results in neutropenia due to death during differentiation. The loss of mature neutrophils induced by Mcl-1 deletion was not rescued by genetic deletion of proapoptotic Bim and Puma or by exogenous cytokine treatment. However, blockade of intrinsic apoptosis by lineage-specific deletion of both multidomain proapoptotics Bax and Bak was capable of rescuing the neutropenia associated with Mcl-1 deletion. In the monocytic lineage, despite efficient Mcl-1 deletion, monocytes and macrophages undergo normal development. During the phagocytosis of extracellular bacteria, macrophages concomitantly increase the expression of both MCL-1 and BIM. However, Mcl-1-deficient macrophages exhibit increased sensitivity to death during bacterial phagocytosis that can be abolished by codeletion of Bim. These data suggest that MCL-1 may be necessary to antagonize BIM during macrophage effector responses. Thus, MCL-1 plays selective roles in myeloid development, being required for neutrophil development and setting the threshold for apoptosis during a macrophage effector response.
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27 MeSH Terms
Regulation of mitochondrial morphological dynamics during apoptosis by Bcl-2 family proteins: a key in Bak?
Brooks C, Dong Z
(2007) Cell Cycle 6: 3043-7
MeSH Terms: Animals, Apoptosis, Humans, Membrane Fusion, Mitochondria, Mitochondrial Membranes, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added September 12, 2016
Early during apoptosis, the mitochondrial network collapses into short punctuate fragments. The seemingly morphological change, called mitochondrial fragmentation, contributes to mitochondrial injury. Mitochondrial morphology is dictated by two opposing processes, fission and fusion. It is unclear how the fission-fusion balance is tilted during apoptosis, resulting in mitochondrial fragmentation. Emerging evidence has now suggested a regulation of mitochondrial morphological dynamics by Bcl-2 family proteins. In this regulation, Bak appears to be a key. Through interaction with mitofusins, Bak may block mitochondrial fusion to induce fragmentation. By this function, Bak may collaborate with Bax to permeabilize mitochondrial outer membrane, leading to the release of apoptogenic factors.
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8 MeSH Terms
Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins.
Brooks C, Wei Q, Feng L, Dong G, Tao Y, Mei L, Xie ZJ, Dong Z
(2007) Proc Natl Acad Sci U S A 104: 11649-54
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Cells, Cultured, GTP Phosphohydrolases, HeLa Cells, Humans, Intracellular Membranes, Mice, Mitochondria, Permeability, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added September 12, 2016
Mitochondrial injury, characterized by outer membrane permeabilization and consequent release of apoptogenic factors, is a key to apoptosis of mammalian cells. Bax and Bak, two multidomain Bcl-2 family proteins, provide a requisite gateway to mitochondrial injury. However it is unclear how Bax and Bak cooperate to provoke mitochondrial injury and whether their roles are redundant. Here, we have identified a unique role of Bak in mitochondrial fragmentation, a seemingly morphological event that contributes to mitochondrial injury during apoptosis. We show that mitochondrial fragmentation is attenuated in Bak-deficient mouse embryonic fibroblasts, baby mouse kidney cells, and, importantly, also in primary neurons isolated from brain cortex of Bak-deficient mice. In sharp contrast, Bax deficiency does not prevent mitochondrial fragmentation during apoptosis. Bcl-2 and Bcl-XL inhibit mitochondrial fragmentation, and their inhibitory effects depend on the presence of Bak. Reconstitution of Bak into Bax/Bak double-knockout cells restores mitochondrial fragmentation, whereas reconstitution of Bax is much less effective. Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins. During apoptosis, Bak dissociates from Mfn2 and enhances the association with Mfn1. Mutation of Bak in the BH3 domain prevents its dissociation from Mfn2 and diminishes its mitochondrial fragmentation activity. This study has uncovered a previously unrecognized function of Bak in the regulation of mitochondrial morphological dynamics during apoptosis. By this function, Bak may collaborate with Bax to permeabilize the outer membrane of mitochondria, unleashing the apoptotic cascade.
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13 MeSH Terms