NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells.
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.
Cahir-McFarland
E D
ED
The Channing Laboratory and Department of Infectious Diseases, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02130, USA.
Davidson
D M
DM
Schauer
S L
SL
Duong
J
J
Kieff
E
E
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000821:virology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed / Q000166:cytology; D002472:Cell Transformation, Viral; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015195:Drug Design; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D007425:Intracellular Membranes / Q000502:physiology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000821:virology; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection
D000590:Amino Acid Chloromethyl Ketones; C096816:BCL2-related protein A1; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases