title: The role of CaMKII in calcium-activated death pathways in bone marrow B cells.
abstract: Calcium is an essential signaling molecule in developing B cells, thus altering calcium dynamics represents a potential target for toxicant effects. GW7845, a tyrosine analog and potent peroxisome proliferator-activated receptor γ agonist, induces rapid mitogen-activated protein kinase (MAPK)-dependent apoptosis in bone marrow B cells. Changes in calcium dynamics are capable of mediating rapid initiation of cell death; therefore, we investigated the contribution of calcium to GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre-B cell line (BU-11) with GW7845 (40 μM) resulted in intracellular calcium release. Multiple features of GW7845-induced cell death were suppressed by the calcium chelator BAPTA, including MAPK activation, loss of mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation. A likely mechanism for the calcium-mediated effects is activation of CaMKII, a calcium-dependent MAP4K. We observed that three CaMKII isoforms (β, γ, and δ) are expressed in lymphoid tissues and bone marrow B cells. Treatment with GW7845 increased CaMKII activity. All features of GW7845-induced cell death, except loss of mitochondrial membrane potential, were suppressed by CaMKII inhibitors (KN93 and AIP-II), suggesting the activation of multiple calcium-driven pathways. To determine if CaMKII activation is a common feature of early B cell death following perturbation of Ca(2+) flux, we dissected tributyltin (TBT)-induced death signaling. High-dose TBT (1 μM) is known to activate calcium-dependent death. TBT induced rapid apoptosis that was associated with intracellular calcium release, CaMKII activation and MAPK activation, and was inhibited by AIP-II. Thus, we show that early B cells are susceptible to calcium-triggered cell death through a CaMKII/MAPK-dependent pathway.
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bissonnette
authors.forename: Amelia
authors.initials: A
authors.lastname: Haas
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schlezinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008024:Ligands; D010080:Oxazoles; D014220:Trialkyltin Compounds; C401311:GW 7845; D014443:Tyrosine; C011559:tributyltin; D004533:Egtazic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048670:MAP Kinase Kinase 4; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
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