title: Prevention of anti-IgM-induced apoptosis accompanying G1 arrest in B lymphoma cells overexpressing dominant-negative mutant form of c-Jun N-terminal kinase 1.
abstract: A family of mitogen-activated protein (MAP) kinases comprising the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAP kinases are involved in proliferation and apoptosis. However, there are some arguments concerning the role of these kinases in Ag-induced B cell apoptosis. Two of the B lymphoma cell lines (CH31 and WEHI-231) susceptible to anti-IgM-induced apoptosis were used as a model. To address these issues, we examined the kinetics of anti-IgM-induced activation of MAP kinases and established cell lines overexpressing a dominant-negative (dn) mutant form of JNK1 (dnJNK1). Anti-IgM induced a sustained JNK1 activation with a peak at 8 h, with a marginal activation of ERK1/ERK2 in CH31 cells. The sustained JNK1 activation was not a secondary event through a caspase activation. The peak point of the JNK1 activation was just before the onset of a decline in mitochondrial membrane potential, which preceded anti-IgM-induced cell death. Following anti-IgM stimulation, dnJNK1 prevented a decline in mitochondrial membrane potential at 24 h, with a prolonged inhibition up to 72 h in WEHI-231, although it did so only partially during a later time period in CH31. The dnJNK1 cells also demonstrated diminished procaspase-3 activation and a decreased rate of apoptosis upon anti-IgM stimulation, with a concomitant increased arrest in G(1) phase, which could be explained by enhanced levels of cyclin-dependent kinase inhibitor p27(Kip1) protein. Thus, anti-IgM-induced JNK activation might be implicated in cell cycle progression as well as in apoptosis regulation, probably involving p27(Kip1) protein.
authors.affiliation: Department of Immunology and Intractable Disease Research Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Takada
authors.forename: H
authors.initials: H
authors.lastname: Toyota
authors.forename: J
authors.initials: J
authors.lastname: Suzuki
authors.forename: J
authors.initials: J
authors.lastname: Mizuguchi
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016193:G1 Phase / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007425:Intracellular Membranes / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008564:Membrane Potentials / Q000276:immunology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000888:Antibodies, Anti-Idiotypic; D061945:Caspase Inhibitors; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D007075:Immunoglobulin M; D008869:Microtubule-Associated Proteins; D011947:Receptors, Antigen, B-Cell; D025521:Tumor Suppressor Proteins; C044203:anti-IgM; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases