The role of bcl-XL in CD40-mediated rescue from anti-mu-induced apoptosis in WEHI-231 B lymphoma cells.
The phenotypically immature B cell lymphoma WEHI-231 undergoes apoptotic cell death when cultured with anti-immunoglobulin (Ig) antibodies, via a bcl-2-independent mechanism. We have therefore studied the role of the bcl-2-related protein bcl-x in controlling cell death in WEHI-231. We find that overexpression of the long form of bcl-x (bcl-XL) renders these cells refractory to anti-Ig-induced cell death. Stimulation of WEHI-231 via CD40 has similar protective effects. We show here that ligation of CD40 rapidly induces the appearance of the bcl-XL protein in WEHI-231, while stimulation via sIgM, sIgD, CD5 or CD45 receptors, or with phorbol esters plus ionomycin does not. WEHI-231 cells also rapidly undergo massive apoptosis following culture with thapsigargin, a specific inhibitor of the Ca(2+)-ATPase of the endoplasmic reticulum: this is also reversed by anti-CD40, or by overexpression of bcl-XL. We, therefore, conclude that bcl-XL plays a key role in the regulation of antigen receptor-mediated apoptosis via CD40 in WEHI-231. In addition, the fact that this protein is not induced in WEHI-231 in response to phorbol dibutyrate plus ionomycin points to a fundamental signaling defect in these cells, which could conceivably be a reflection of their immature, apoptosis-susceptible phenotype.
Choi
M S
MS
National Institute for Medical Research, Mill Hill, London, GB.
Boise
L H
LH
Gottschalk
A R
AR
Quintans
J
J
Thompson
C B
CB
Klaus
G G
GG
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D019013:CD40 Antigens; D023201:CD40 Ligand; D005786:Gene Expression Regulation; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000888:Antibodies, Anti-Idiotypic; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D013729:Terpenes; C044203:anti-IgM; D051020:bcl-X Protein; D023201:CD40 Ligand; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D019284:Thapsigargin