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Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization.
Chaturvedi R, Cheng Y, Asim M, Bussière FI, Xu H, Gobert AP, Hacker A, Casero RA, Wilson KT
(2004) J Biol Chem 279: 40161-73
MeSH Terms: Acetyltransferases, Animals, Apoptosis, Caspase 3, Caspases, Cell Line, Cytochromes c, Enzyme Induction, Gene Expression Regulation, Enzymologic, Helicobacter Infections, Helicobacter pylori, Hydrogen Peroxide, In Situ Nick-End Labeling, Macrophages, Membrane Potentials, Mice, Mitochondria, Ornithine Decarboxylase, Oxidoreductases Acting on CH-NH Group Donors
Show Abstract · Added March 5, 2014
Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H(2)O(2), which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N(1)-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme (polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N(1)-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H(2)O(2) generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H(2)O(2) was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H(2)O(2) release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection.
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19 MeSH Terms
Mitochondrial calcium uptake regulates cold preservation-induced Bax translocation and early reperfusion apoptosis.
Anderson CD, Belous A, Pierce J, Nicoud IB, Knox C, Wakata A, Pinson CW, Chari RS
(2004) Am J Transplant 4: 352-62
MeSH Terms: Apoptosis, Calcium, Caspase 3, Caspases, Cryopreservation, Cytochromes c, Hepatoblastoma, Humans, Indicators and Reagents, Mitochondria, Protein Transport, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Reperfusion Injury, Ruthenium Red, Tumor Cells, Cultured, bcl-2-Associated X Protein
Show Abstract · Added January 10, 2014
Mitochondrial calcium (mCa + 2) overload occurs during cold preservation and is an integral part of mitochondrial-dependent apoptotic pathways. We investigated the role of mCa + 2 overload in cell death following hypothermic storage using HepG2 cells stored in normoxic-hypothermic (4 degrees C) or hypoxic (< 0.1% O2)-hypothermic Belzer storage solution. Cells were stored for 6 h, with or without 10 microM ruthenium red (mCa + 2 uniporter inhibitor) followed by rewarming in oxygenated media at 37 degrees C. Cytoplasmic cytochrome c levels were studied by Western analysis and by fluorescent microscopy after transfection of cytochrome c-GFP expression plasmid. Immunofluorescence determined the intracellular, spatio-temporal distribution of Bax, and TUNEL staining was used to evaluate cell death after 180 min of rewarming. Caspase activation was evaluated using Western analysis and a caspase 3 activity assay. Bax translocation, cytochrome c release, and early rewarming cell death occurred following hypothermic storage and were exacerbated by hypoxia. Caspase 3 activation did not occur following hypothermic storage. Blockade of mCa + 2 uptake prevented Bax translocation, cytochrome c release, and early rewarming cell death. These studies demonstrate that mCa + 2 uptake during hypothermic storage, both hypoxic and normoxic, contributes to early rewarming apoptosis by triggering Bax translocation to mitochondria and cytochrome c release.
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17 MeSH Terms
Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes.
Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB
(2004) J Biol Chem 279: 8290-9
MeSH Terms: Animals, Anthracyclines, Antibiotics, Antineoplastic, Apoptosis, Calpain, Caspase 3, Caspase Inhibitors, Caspases, Cells, Cultured, Connectin, Doxorubicin, Enzyme Activation, Enzyme Inhibitors, Heart Ventricles, Male, Muscle Cells, Muscle Proteins, Myocardium, Necrosis, Protein Kinases, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 5, 2014
Titin, the largest myofilament protein, serves as a template for sarcomere assembly and acts as a molecular spring to contribute to diastolic function. Titin is known to be extremely susceptible to calcium-dependent protease degradation in vitro. We hypothesized that titin degradation is an early event in doxorubicin-induced cardiac injury and that titin degradation occurs by activation of the calcium-dependent proteases, the calpains. Treatment of cultured adult rat cardiomyocytes with 1 or 3 micromol/liter doxorubicin for 24 h resulted in degradation of titin in myocyte lysates, which was confirmed by a reduction in immunostaining of an antibody to the spring-like (PEVK) domain of titin at the I-band of the sarcomere. The elastic domain of titin appears to be most susceptible to proteolysis because co-immunostaining with an antibody to titin at the M-line was preserved, suggesting targeted proteolysis of the spring-like domain of titin. Doxorubicin treatment for 1 h resulted in approximately 3-fold increase in calpain activity, which remained elevated at 48 h. Co-treatment with calpain inhibitors resulted in preservation of titin, reduction in myofibrillar disarray, and attenuation of cardiomyocyte necrosis but not apoptosis. Co-treatment with a caspase inhibitor did not prevent the degradation of titin, which precludes caspase-3 as an early mechanism of titin proteolysis. We conclude that calpain activation is an early event after doxorubicin treatment in cardiomyocytes and appears to target the degradation of titin. Proteolysis of the spring-like domain of titin may predispose cardiomyocytes to diastolic dysfunction, myofilament instability, and cell death by necrosis.
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22 MeSH Terms
Embryonic fibroblasts from Gpx4+/- mice: a novel model for studying the role of membrane peroxidation in biological processes.
Ran Q, Van Remmen H, Gu M, Qi W, Roberts LJ, Prolla T, Richardson A
(2003) Free Radic Biol Med 35: 1101-9
MeSH Terms: 8-Hydroxy-2'-Deoxyguanosine, Animals, Antioxidants, Caspase 3, Caspases, Catalase, Cell Division, Cell Membrane, Cells, Cultured, Deoxyguanosine, F2-Isoprostanes, Female, Fibroblasts, Gene Deletion, Glutathione Peroxidase, Heterozygote, Lipid Peroxidation, Male, Mice, Mice, Transgenic, Oxidation-Reduction, Oxidative Stress, Oxygen, Phospholipid Hydroperoxide Glutathione Peroxidase, Superoxide Dismutase
Show Abstract · Added December 10, 2013
A previous study using mice null for Gpx4 indicates that PHGPx plays a critical role in antioxidant defense and is essential for the survival of the mouse. In the present study, we further analyzed the stress response of MEFs (murine embryonic fibroblasts) derived from mice heterozygous for the Gpx4 gene (Gpx4(+/-) mice). MEFs from Gpx4(+/-) mice have a 50% reduction in PHGPx expression without any changes in the activities of other major antioxidant defense enzymes. Compared to MEFs from Gpx4(+/+) mice, MEFs from Gpx4(+/-) mice were more sensitive to exposure to the oxidizing agent t-butyl hydroperoxide (t-BuOOH), and t-BuOOH exposure induced increased apoptosis in MEFs from Gpx4(+/-) mice. When cultured at low cell density, MEFs from Gpx4(+/-) mice also showed retarded growth under normal culture conditions (20% oxygen) that was reversed by culturing under low oxygen (2% oxygen). In addition, oxidative damage was increased in the MEFs from the Gpx4(+/-) mice, as indicated by increased levels of F(2)-isoprostanes and 8-oxo-2-deoxyguanosine in these cells. Our data demonstrate that MEFs from Gpx4(+/-) mice are more sensitive to oxidative stress because of reduced expression of PHGPx.
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25 MeSH Terms
COX2 activity promotes organic osmolyte accumulation and adaptation of renal medullary interstitial cells to hypertonic stress.
Moeckel GW, Zhang L, Fogo AB, Hao CM, Pozzi A, Breyer MD
(2003) J Biol Chem 278: 19352-7
MeSH Terms: Adaptation, Physiological, Aldehyde Reductase, Animals, Apoptosis, Betaine, Caspase 3, Caspases, Cell Survival, Cells, Cultured, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, DNA Fragmentation, Dehydration, Gene Expression, Heat-Shock Proteins, Hypertonic Solutions, In Situ Nick-End Labeling, Inositol, Isoenzymes, Kidney Medulla, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Sorbitol, Symporters, Tritium
Show Abstract · Added February 24, 2014
The mechanism by which COX2 inhibition decreases renal cell survival is poorly understood. In the present study we examined the effect of COX2 activity on organic osmolyte accumulation in renal medulla and in cultured mouse renal medullary interstitial cells (MMICs) and its role in facilitating cell survival. Hypertonicity increased accumulation of the organic osmolytes inositol, sorbitol, and betaine in cultured mouse medullary interstitial cells. Pretreatment of MMICs with a COX2-specific inhibitor (SC58236, 10 micromol/liter) dramatically reduced osmolyte accumulation (by 79 +/- 9, 57 +/- 12, and 96 +/- 10% for inositol, sorbitol, and betaine respectively, p < 0.05). Similarly, 24 h of dehydration increased inner medullary inositol, sorbitol, and betaine concentrations in vivo by 85 +/- 10, 197 +/- 28, and 190 +/- 24 pmol/microg of protein, respectively, but this increase was also blunted (by 100 +/- 5, 66 +/- 15, and 81 +/- 9% for inositol, sorbitol, and betaine, respectively, p < 0.05) by pretreatment with an oral COX2 inhibitor. Dehydrated COX2-/- mice also exhibited an impressive defect in sorbitol accumulation (88 +/- 9% less than wild type, p < 0.05) after dehydration. COX2 inhibition (COX2 inhibitor-treated or COX2-/- MMICs) dramatically reduced the expression of organic osmolyte uptake mechanisms including betaine (BGT1) and sodium-myo-inositol transporter and aldose reductase mRNA expression under hypertonic conditions. Importantly, preincubation of COX2 inhibitor-treated MMICs with organic osmolytes restored their ability to survive hypertonic stress. In conclusion, osmolyte accumulation in the kidney inner medulla is dependent on COX2 activity, and providing exogenous osmolytes reverses COX2-induced cell death. These findings may have implications for the pathogenesis of analgesic nephropathy.
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30 MeSH Terms
Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP.
Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC
(2003) J Biol Chem 278: 8091-8
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Caspase 3, Caspase 9, Caspase Inhibitors, Caspases, Cytochrome c Group, Enzyme Activation, Humans, Hydrolysis, Kinetics, Molecular Sequence Data, Proteins, Recombinant Proteins, Sequence Homology, Amino Acid, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The apoptosome is a multiprotein complex comprising Apaf-1, cytochrome c, and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response to apoptotic signals. Binding of cytochrome c and dATP to Apaf-1 in the cytosol leads to the assembly of a heptameric complex in which each Apaf-1 subunit is bound noncovalently to a procaspase-9 subunit via their respective CARD domains. Assembly of the apoptosome results in the proteolytic cleavage of procaspase-9 at the cleavage site PEPD(315) to yield the large (p35) and small (p12) caspase-9 subunits. In addition to the PEPD site, caspase-9 contains a caspase-3 cleavage site (DQLD(330)), which when cleaved, produces a smaller p10 subunit in which the NH(2)-terminal 15 amino acids of p12, including the XIAP BIR3 binding motif, are removed. Using purified proteins in a reconstituted reaction in vitro, we have assessed the relative impact of Asp(315) and Asp(330) cleavage on caspase-9 activity within the apoptosome. In addition, we characterized the effect of caspase-3 feedback cleavage of caspase-9 on the rate of caspase-3 activation, and the potential ramifications of Asp(330) cleavage on XIAP-mediated inhibition of the apoptosome. We have found that cleavage of procaspase-9 at Asp(330) to generate p35, p10 or p37, p10 forms resulted in a significant increase (up to 8-fold) in apoptosome activity compared with p35/p12. The significance of this increase was demonstrated by the near complete loss of apoptosome-mediated caspase-3 activity when a point mutant (D330A) of procaspase-9 was substituted for wild-type procaspase-9 in the apoptosome. In addition, cleavage at Asp(330) exposed a novel p10 NH(2)-terminal peptide motif (AISS) that retained the ability to mediate XIAP inhibition of caspase-9. Thus, whereas feedback cleavage of caspase-9 by caspase-3 significantly increases the activity of the apoptosome, it does little to attenuate its sensitivity to inhibition by XIAP.
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18 MeSH Terms
The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.
Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ
(2002) J Biol Chem 277: 21730-9
MeSH Terms: 3T3 Cells, Animals, Antigens, CD, Apoptosis, Caspase 3, Caspase 8, Caspase 9, Caspases, Cell Death, Cell Survival, Ceramides, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Genes, Reporter, Genes, p53, Humans, Immunoblotting, Mice, Mitomycin, Oncogene Proteins, Viral, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proteins, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Repressor Proteins, Signal Transduction, TNF Receptor-Associated Factor 1, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, U937 Cells
Show Abstract · Added December 10, 2013
High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of p53, although this is not the only function of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that transfection of HPV 16 E6 into the tumor necrosis factor (TNF)-sensitive LM cell line protects expressing cells from TNF-induced apoptosis in a p53-independent manner, and the purpose of this study was to determine the molecular mechanism underlying this protection. Caspase 3 and caspase 8 activation were significantly reduced in E6-expressing cells, indicating that E6 acts early in the TNF apoptotic pathway. In fact, E6 binds directly to TNF R1, as shown both by co-immunoprecipitation and mammalian two-hybrid approaches. E6 requires the same C-terminal portion of TNF R1 for binding as does TNF R1-associated death domain, and TNF R1/TNF R1-associated death domain interactions are decreased in the presence of E6. HA-E6 also blocked cell death triggered by transfection of the death domain of TNF R1. Together, these results provide strong support for a model in which HPV E6 binding to TNF R1 interferes with formation of the death-inducing signaling complex and thus with transduction of proapoptotic signals. They also demonstrate that HPV, like several other viruses, has developed a method for evading the TNF-mediated host immune response.
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37 MeSH Terms
4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release.
Ji C, Amarnath V, Pietenpol JA, Marnett LJ
(2001) Chem Res Toxicol 14: 1090-6
MeSH Terms: Aldehydes, Apoptosis, Caspase 3, Caspases, Colorectal Neoplasms, Cross-Linking Reagents, Cytochrome c Group, DNA Damage, Enzyme Induction, Gene Expression Regulation, Neoplastic, Genes, bcl-2, Humans, Lipid Peroxidation, Mitochondria, Proto-Oncogene Proteins c-bcl-2, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
We investigated the mechanism by which 4-hydroxynonenal (HNE), a major aldehydic product of lipid peroxidation, induces apoptosis in tumor cells. Treatment of human colorectal carcinoma (RKO) cells with HNE-induced poly-ADP-ribose-polymerase (PARP) cleavage and DNA fragmentation in a dose- and time-dependent manner. The induction of PARP cleavage and DNA fragmentation paralleled caspase-2, -3, -8, and -9 activation. Pretreatment of cells with an inhibitor of caspase-3, z-DEVD-fmk, or a broad spectrum caspase inhibitor, z-VAD-fmk, abolished caspase activation and subsequent PARP cleavage. Constitutive expression of high levels of Bcl-2 protected cells from HNE-mediated apoptosis. In addition, Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2, -3, and -9 activation. These findings demonstrate that HNE triggers apoptotic cell death through a mitochondrion-dependent pathway involving cytochrome c release and caspase activation. Bcl-2 overexpression protected cells from HNE-induced apoptosis through inhibition of cytochrome c release.
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16 MeSH Terms
Structural basis for the inhibition of caspase-3 by XIAP.
Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS
(2001) Cell 104: 791-800
MeSH Terms: Carrier Proteins, Caspase 3, Caspases, Catalytic Domain, Crystallography, Mitochondrial Proteins, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, Structure-Activity Relationship, Substrate Specificity, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors.
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13 MeSH Terms
Apoptotic response of HL-60 human leukemia cells to the antitumor drug TAS-103.
Kluza J, Lansiaux A, Wattez N, Mahieu C, Osheroff N, Bailly C
(2000) Cancer Res 60: 4077-84
MeSH Terms: Aminoquinolines, Antineoplastic Agents, Apoptosis, Caspase 3, Caspases, Cell Cycle, DNA Fragmentation, Enzyme Activation, Enzyme Activators, Flow Cytometry, HL-60 Cells, Humans, Hydrogen-Ion Concentration, Indenes, Intercalating Agents, Intracellular Membranes, Membrane Potentials, Mitochondria, Phosphatidylserines, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Show Abstract · Added March 5, 2014
TAS-103 is a DNA intercalating indeno-quinoline derivative that stimulates DNA cleavage by topoisomerases. This synthetic drug has a broad spectrum of antitumor activity against many human solid tumor xenografts and is currently undergoing clinical trials. We investigated the induction of apoptosis in human promyelocytic leukemia cells treated with TAS-103. The treatment of proliferating human leukemia cells for 24 h with various concentrations of the drug induces significant variations in the mitochondrial transmembrane potential (delta(psi)mt) measured by flow cytometry using the fluorochromes 3,3-dihexyloxacarbocyanine iodide, Mitotracker Red, and tetrachloro-tetraethylbenzimidazolcarbocyanine iodide. The collapse of delta(psi)mt is accompanied by a marked decrease of the intracellular pH. Cleavage experiments with the substrates N-acetyl-Asp-Glu-Val-Asp-pNA, poly(ADP-ribose) polymerase, and pro-caspase-3 reveal unambiguously that caspase-3 is a key mediator of the apoptotic pathway induced by TAS-103. Caspase-8 is also cleaved, and the bcl-2 oncoprotein is underexpressed. Drug-induced internucleosomal DNA fragmentation and the externalization of phosphatidylserine residues in the outer leaflet of the plasma membrane were also characterized. The cell cycle perturbations produced by TAS-103 can be connected with the changes in deltapsi(mt). At low concentrations (2-25 nM), the drug induces a marked G2 arrest and concomitantly provokes an increase in the potential of mitochondrial membranes. In contrast, treatment of the HL-60 cells with higher drug concentrations (50 nM to 1 microM) triggers massive apoptosis and a collapse of deltaP(mt) that is a signature for the opening of the mitochondrial permeability transition pores. The discovery of a correlation between the G2 arrest and changes in mitochondrial membrane potential provides an important mechanistic insight into the action of TAS-103.
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21 MeSH Terms