Caspase activity is required for stimulated B lymphocytes to enter the cell cycle.
Following activation with proliferative stimuli, including ligation of CD40, dense human tonsillar B cells (>98% cells in G(0)) have increased cleavage and activation of caspase-8 and -6 accompanied by decreased caspase-3 activation and apoptosis. Proliferation was blocked by either a broad specificity caspase inhibitor or inhibitors selective for caspase-6 or caspase-8. In contrast, an inhibitor selective for caspase-3 was without effect. Furthermore, induction of cyclin D and cyclin-dependent kinase 4 mRNA and protein was blocked upon inhibition of caspase-6, but not caspase-3. Thus, caspase-6-like activity is required for quiescent B cells to increase the expression of genes required for entry into G(1). In support of this model, the transcriptional suppressor special AT-rich sequence-binding protein 1, a preferred caspase-6 substrate, was cleaved upon B cell stimulation. Caspase activity was not required for all signaling events, as caspase inhibitors did not affect the phosphorylation of p42/44 mitogen-activated protein kinase, the expression of the survival factor cellular inhibitor of apoptosis 2, or the production of IL-6 by stimulated G(0) B cells. These findings suggest a mechanism by which caspase-6 may selectively allow entry of quiescent B cells into the cell cycle.
Olson
N Eric
NE
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Graves
Jonathan D
JD
Shu
Geraldine L
GL
Ryan
Elizabeth J
EJ
Clark
Edward A
EA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002453:Cell Cycle / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; D019013:CD40 Antigens; D061945:Caspase Inhibitors; D009842:Oligopeptides; C108637:aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505514:CASP6 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505516:Casp6 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases