Role for CD40-mediated activation of c-Rel and maintenance of c-myc RNA levels in mitigating anti-IgM-induced growth arrest.
CD40 crosslinking on B cells activates NF-kappaB and stress-activated protein kinase (SAPK) pathways. Since CD40 crosslinking rescues WEHI 231 B cells from anti-IgM-induced apoptosis, those pathways were likely candidates to be involved. Indeed, both signaling cascades predominated in anti-IgM-treated WEHI 231 cells, treated concurrently with anti-CD40 to rescue them from apoptosis. Crosslinking of CD40 activated the NF-kappaB proteins c-Rel and p50, but had no influence on their cytoplasmic steady state level. However, in contrast to-and even in the presence of-anti-IgM-mediated signals, engagement of CD40 resulted in a prolonged nuclear translocation of c-Rel, thereby allowing the formation of active NF-kappaB complexes. Consistent with this, the upstream regulatory element of the c-myc promoter, known to be regulated by NF-kappaB, was differently regulated after BCR ligation vs BCR plus CD40 crosslinking. The level of c-myc RNA was rapidly downregulated after BCR engagement, but persistent in the presence of CD40 signaling.
Siebelt
F
F
Department of Microbiology and Regional Primate Research Center, University of Washington, Seattle, Washington, 98195, USA.
Berberich
I
I
Shu
G
G
Serfling
E
E
Clark
E A
EA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D008213:Lymphocyte Activation; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology*; D020569:Proto-Oncogene Proteins c-rel; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D019013:CD40 Antigens; D007075:Immunoglobulin M; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; D011947:Receptors, Antigen, B-Cell