Abstract
TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-beta receptor (LTbetaR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTbetaR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma-associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-DeltaEx3 could inhibit LTbetaR-mediated caspase-3 activation. However, only survivin-DeltaEx3 could protect cells from LTbetaR-mediated cell death. The differential protective effects of survivin-DeltaEx3 and KSHV-K7 can be attributed to the fact that survivin-DeltaEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-DeltaEx3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTbetaR. Furthermore, survivin-DeltaEx3 protects LTbetaR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-DeltaEx3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTbetaR-mediated cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Carcinoma, Hepatocellular
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Caspase 3
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Caspase Inhibitors
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Cyclin D1 / antagonists & inhibitors
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Cyclin D1 / metabolism
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HeLa Cells
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Humans
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Inhibitor of Apoptosis Proteins
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Interferon-gamma / pharmacology
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Intracellular Signaling Peptides and Proteins / metabolism
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Lymphotoxin beta Receptor
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Microtubule-Associated Proteins / physiology*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitochondrial Proteins / physiology*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Receptors, Tumor Necrosis Factor / agonists
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Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor / physiology
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Recombinant Proteins
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Signal Transduction
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Survivin
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Transfection
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / physiology
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Viral Proteins / genetics
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Viral Proteins / metabolism
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Viral Proteins / physiology*
Substances
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Antibodies, Monoclonal
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Apoptosis Regulatory Proteins
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BIRC5 protein, human
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Caspase Inhibitors
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DIABLO protein, human
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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K7 protein, Human herpesvirus 8
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LTBR protein, human
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Lymphotoxin beta Receptor
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Membrane Proteins
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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Neoplasm Proteins
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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Survivin
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TNFSF14 protein, human
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha
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Viral Proteins
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Cyclin D1
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Interferon-gamma
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MAP Kinase Kinase Kinase 5
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MAP3K5 protein, human
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CASP3 protein, human
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Caspase 3