title: A comparison of signaling requirements for apoptosis of human B lymphocytes induced by the B cell receptor and CD95/Fas.
abstract: To define how the signaling pathways that mediate the B cell receptor (BCR) death pathway differ from those responsible for CD95/Fas-mediated death, we compared the BCR and Fas death pathways in two human B cell lines, B104 and BJAB. Both BCR- and Fas-induced apoptosis are blocked by the peptide cysteine protease inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (ZVAD (mlz)), demonstrating a common requirement caspase activity. Despite this common characteristic, the ability of actinomycin D and cycloheximide to block BCR-induced apoptosis, but not apoptosis induced by Fas cross-linking, suggests that a major difference between these two pathways is their differential requirements for new gene and protein synthesis. BCR- and Fas-mediated apoptosis are both accompanied by activation of stress-activated protein kinase and p38 mitogen-activated protein kinase (MAPK). Activation of both stress-activated protein kinase and p38 MAPK was inhibited by ZVAD (mlz), suggesting the involvement of caspases. To determine the role of p38 MAPK activation in BCR- and Fas-induced apoptosis, we employed SB203580, a specific inhibitor of p38 MAPK. SB203580 inhibited BCR-induced apoptosis, but not apoptosis induced by cross-linking Fas. Furthermore, both actinomycin D and SB203580 inhibited BCR-induced, but not Fas-induced, activation of caspase. Collectively, these findings establish a role for p38 MAPK in BCR-induced apoptosis both upstream and downstream of caspase activity. The p38 MAPK pathway may function to regulate transcriptional or translational events that are critical for BCR-induced apoptosis.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle 98195, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Graves
authors.forename: K E
authors.initials: KE
authors.lastname: Draves
authors.forename: A
authors.initials: A
authors.lastname: Craxton
authors.forename: E G
authors.initials: EG
authors.lastname: Krebs
authors.forename: E A
authors.initials: EA
authors.lastname: Clark
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D016393:Lymphoma, B-Cell; D020928:Mitogen-Activated Protein Kinases; D011485:Protein Binding / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D017304:Annexin A5; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015853:Cysteine Proteinase Inhibitors; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D019014:fas Receptor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases