Abstract
Epstein-Barr virus (EBV) transforms B lymphocytes into lymphoblastoid cell lines usurping the Notch and tumor necrosis factor receptor pathways to effect transcription including NF-kappaB activation. To determine whether NF-kappaB activity is essential in the growth and survival of EBV-transformed lymphoblastoid cell lines, a nondegradable IkappaBalpha mutant was expressed under tetracycline regulation. Despite continued Bcl-2 and Bcl-x/L expression, NF-kappaB inhibition induced apoptosis as evidenced by poly(ADP-ribose) polymerase cleavage, nuclear condensation and fragmentation, and hypodiploid DNA content. Both caspase 3 and 8 activation and loss of mitochondrial membrane potential were observed in apoptotic cells. However, caspase inhibition failed to block apoptosis. These experiments indicate that NF-kappaB inhibitors may be useful in the therapy of EBV-induced cellular proliferation.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Apoptosis / physiology*
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B-Lymphocytes / cytology*
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B-Lymphocytes / virology
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Caspase 3
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / metabolism
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Cell Cycle / drug effects
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Cell Line, Transformed / cytology
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Cell Transformation, Viral*
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Cysteine Proteinase Inhibitors / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Drug Design
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Flow Cytometry
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Gene Expression Regulation
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Herpesvirus 4, Human / physiology*
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Humans
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I-kappa B Proteins*
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Intracellular Membranes / physiology
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Lymphoproliferative Disorders / drug therapy
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Lymphoproliferative Disorders / virology
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Membrane Potentials
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Microscopy, Confocal
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Minor Histocompatibility Antigens
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Mitochondria / physiology
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / physiology*
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Protein Biosynthesis
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Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2*
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Recombinant Fusion Proteins / physiology
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Transfection
Substances
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Amino Acid Chloromethyl Ketones
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BCL2-related protein A1
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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I-kappa B Proteins
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Minor Histocompatibility Antigens
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NF-kappa B
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NFKBIA protein, human
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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NF-KappaB Inhibitor alpha
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases