title: CD38 induces apoptosis of a murine pro-B leukemic cell line by a tyrosine kinase-dependent but ADP-ribosyl cyclase- and NAD glycohydrolase-independent mechanism.
abstract: Cross-linking of CD38 on hematopoietic cells induces activation, proliferation and differentiation of mature T and B cells and mediates apoptosis of myeloid and lymphoid progenitor cells. In addition to acting as a signaling receptor, CD38 is also an enzyme capable of producing several calcium-mobilizing metabolites, including cyclic adenosine diphosphate ribose (cADPR). It has been previously postulated that the calcium-mobilizing metabolites produced by CD38 may regulate its receptor-based activities. To test this hypothesis, we examined whether the enzyme activity of CD38 controls the apoptosis of an anti-CD38-stimulated leukemic B cell. We show that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B cell line, is not affected by blocking the calcium-mobilizing activity of cADPR or by inhibiting intracellular or extracellular calcium mobilization. In addition, we demonstrate that blocking CD38 enzyme activity with 2'-deoxy-2'-fluoro-nicotinamide arabinoside adenine dinucleotide has no effect on apoptosis and that Ba/F3 cells expressing catalytically inactive mutant forms of CD38 still undergo apoptosis upon CD38 cross-linking. Instead, we find that anti-CD38-induced apoptosis is dependent on tyrosine kinase and caspase activation, and that this process appears to be potentiated by the presence of membrane microdomains. Thus, the receptor-mediated functions of CD38 can be separated from its enzyme activity in a murine leukemic cell line, suggesting that CD38 plays multiple, but independent, biologic roles.
authors.affiliation: Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA. flund@trudeainstitute.org
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.forename: Hélène
authors.initials: H
authors.lastname: Muller-Steffner
authors.forename: Héctor
authors.initials: H
authors.lastname: Romero-Ramirez
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Moreno-García
authors.forename: Santiago
authors.initials: S
authors.lastname: Partida-Sánchez
authors.forename: Melissa
authors.initials: M
authors.lastname: Makris
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Oppenheimer
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Santos-Argumedo
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D007152:Immunologic Capping / Q000187:drug effects / Q000276:immunology; D015448:Leukemia, B-Cell / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D021962:Membrane Microdomains / Q000201:enzymology / Q000276:immunology; D051379:Mice; D009243:NAD / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009243:NAD; C053851:nicotinamide arabinoside adenine dinucleotide; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium