THE B-CELL-SPECIFIC TRANSCRIPTION FACTOR BSAP REGULATES B-CELL PROLIFERATION

The B cell-specific activator protein (BSAP) is a DNA-binding transcri ption factor expressed in pro-B, pre-B, and mature B cells, but not in plasma cells. In this study, we explored the role of BSAP in B cell f unction by assessing how the content of this protein varies in cells d riven by proliferative stimuli and, conversely, how artificial manipul ation of BSAP activity affects cell proliferation. We found that BSAP activity of nuclear extracts increased when B cells were activated by mitogen (lipopolysaccharide [LPS]), antigen receptor-mediated signalin g (surface immunoglobulin D [IgD] cross-linking) or T cell-dependent s timulation (CD40 cross-linking). We could suppress BSAP activity by ex posure of B cells to phosphorothioate oligonucleotides antisense to th e BSAP translation initiation start site, whereas control oligonucleot ides were virtually inactive. Antisense-induced BSAP suppression was a ssociated with a striking reduction in LPS-induced proliferation of sp lenic B cells and in the spontaneous proliferation of B lymphoma cells (CH12.LX), but the antisense oligonucleotide had virtually no effect on proliferation of two cell lines lacking BSAP: the T lymphoma line E L-4 and the plasma cell line MOPC-315. Overexpression of BS.AP in sple nic B cells or de novo expression in MOPC-315 plasma cells induced by transfection of a BSAP expression plasmid stimulated cell proliferatio n. Taken together, these results suggest that BSAP activity is a rate- limiting regulator of B cell proliferation. We also found that treatme nt with the antisense BSAP oligonucleotide downregulated Ig class swit ching induced by interleukin 4 plus LPS. This effect may be secondary to reduced proliferation or could be mediated through BSAP binding sit es in the IgH locus.