title: Differential roles for extracellularly regulated kinase-mitogen-activated protein kinase in B cell antigen receptor-induced apoptosis and CD40-mediated rescue of WEHI-231 immature B cells.
abstract: One of the major unresolved questions in B cell biology is how the B cell Ag receptor (BCR) differentially signals to transduce anergy, apoptosis, proliferation, or differentiation during B cell maturation. We now report that extracellularly regulated kinase-mitogen-activated protein kinase (Erk-MAP kinase) can play dual roles in the regulation of the cell fate of the immature B cell lymphoma, WEHI-231, depending on the kinetics and context of Erk-MAP kinase activation. First, we show that the BCR couples to an early (< or =2 h) Erk-MAP kinase signal which activates a phospholipase A(2) pathway that we have previously shown to mediate collapse of mitochondrial membrane potential, resulting in depletion of cellular ATP and cathepsin B execution of apoptosis. Rescue of BCR-driven apoptosis by CD40 signaling desensitizes such early extracellularly regulated kinase (Erk) signaling and hence uncouples the BCR from the apoptotic mitochondrial phospholipase A(2) pathway. A second role for Erk-MAP kinase in promoting the growth and proliferation of WEHI-231 immature B cells is evidenced by data showing that proliferating and CD40-stimulated WEHI-231 B cells exhibit a sustained cycling pattern (8-48 h) of Erk activation that correlates with cell growth and proliferation. This growth-promoting role for Erk signaling is supported by three key pieces of evidence: 1) signaling via the BCR, under conditions that induce growth arrest, completely abrogates sustained Erk activation; 2) CD40-mediated rescue from growth arrest correlates with restoration of cycling Erk activation; and 3) sustained inhibition of Erk prevents CD40-mediated rescue of BCR-driven growth arrest of WEHI-231 immature B cells. Erk-MAP kinase can therefore induce diverse biological responses in WEHI-231 cells depending on the context and kinetics of activation.
authors.affiliation: Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gauld
authors.forename: Derek
authors.initials: D
authors.lastname: Blair
authors.forename: Catriona A
authors.initials: CA
authors.lastname: Moss
authors.forename: Steven D
authors.initials: SD
authors.lastname: Reid
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D019013:CD40 Antigens / Q000502:physiology*; D002453:Cell Cycle / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000888:Antibodies, Anti-Idiotypic; D002070:Butadienes; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D009570:Nitriles; D011947:Receptors, Antigen, B-Cell; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one