The p54 cleaved form of the tyrosine kinase Lyn generated by caspases during BCR-induced cell death in B lymphoma acts as a negative regulator of apoptosis.
Engagement of the B cell receptor antigen (BCR) triggers apoptosis on immature B cell lines. We report here that BCR triggering leads to caspase activation followed by Lyn cleavage and induction of apoptosis. The cleavage process is mitochondrion-dependent and involves caspases 9 and 7. Stable expression of the cleaved form of Lyn (Lyn-Delta-N) in Ramos B cells impairs BCR-mediated apoptosis as judged by loss of Delta(psi)m, caspase activation and PARP cleavage. Activation of the main survival pathways upon BCR-triggering was unaltered in both cell variants. However, the PI3-K inhibitor Ly294002 resensitizes Lyn-Delta-N cells to apoptosis. Selected cDNA expression arrays revealed that anti-IgM modulates the expression of approximately 20 genes in both cell variants. Among them, only c-Myc was found to be differentially regulated, which suggests a role for c-Myc in the B cell apoptotic response. Interestingly, c-Myc expression decreased more rapidly in Lyn-Delta-N compared with Lyn-WT cells during the first hours of anti-IgM stimulation. Nevertheless, rapid down-regulation of c-Myc following BCR engagement seems to correlate with the resistance of B cells to apoptosis. Thus, the soluble form of Lyn generated by caspases following BCR triggering acts as an inhibitor of B lymphocyte death likely through the modulation of c-Myc expression.
Luciano
Frederic
F
INSERM U526 Activation des Cellules Hematopoietiques, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, Equipe Labellisée Ligue Nationale contre le Cancer, IFR50, Faculté de Médecine, 06107 Nice-Cédex 2, France.
Herrant
Magali
M
Jacquel
Arnaud
A
Ricci
Jean-Ehrland
JE
Auberger
Patrick
P
D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C505520:CASP7 protein, human; C506433:CASP9 protein, human; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases