BSAP has been identified previously as a transcription factor that is expressed at early, but not late, stages of B-cell differentiation. Biochemical purification and cDNA cloning has now revealed that BSAP belongs to the family of paired domain proteins. BSAP is encoded by the Pax-5 gene and has been highly conserved between human and mouse. An intact paired domain was shown to be both necessary and sufficient for DNA binding of BSAP. Binding studies with several BSAP recognition sequences demonstrated that the sequence specificity of BSAP differs from that of the distantly related paired domain protein Pax-1. During embryogenesis, the BSAP gene is transiently expressed in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other Pax genes in the developing central nervous system (CNS). Later, the expression of the BSAP gene shifts to the fetal liver where it correlates with the onset of B lymphopoiesis. BSAP expression persists in B lymphocytes and is also seen in the testis of the adult mouse. All of this evidence indicates that the transcription factor BSAP may not only play an important role in B-cell differentiation but also in neural development and spermatogenesis.
The CD19 protein is expressed on the surface of all B-lymphoid cells with the exception of terminally differentiated plasma cells and has been implicated as a signal-transducing receptor in the control of proliferation and differentiation. Here we demonstrate complete correlation between the expression pattern of the CD19 gene and the B-cell-specific transcription factor BSAP in a large panel of B-lymphoid cell lines. The human CD19 gene has been cloned, and several BSAP-binding sites have been mapped by in vitro protein-DNA binding studies. In particular, a high-affinity BSAP-binding site instead of a TATA sequence is located in the -30 promoter region upstream of a cluster of heterogeneous transcription start sites. Moreover, this site is occupied by BSAP in vivo in a CD19-expressing B-cell line but not in plasma or HeLa cells. This high-affinity site has been conserved in the promoters of both human and mouse CD19 genes and was furthermore shown to confer B-cell specificity to a f-globin reporter gene in transient transfection experiments. In addition, BSAP was found to be the only abundant DNA-binding activity of B-cell nuclear extracts that interacts with the CD19 promoter. Together, this evidence strongly implicates BSAP in the regulation of the CD19 gene.The differentiation of B lymphocytes from progenitor cells to immunoglobulin-secreting plasma cells is a multistep process which is characterized by the sequential expression of specific cell surface markers involved in cell-cell interaction and signal transduction (29). Among them is the B-cellspecific antigen CD19. This protein is expressed throughout B-cell ontogeny from the early progenitor cell up to the mature B-cell stage and is lost from the cell surface only at the terminal stages of B-cell differentiation. The CD19 molecule is present on both normal and malignant B-lymphoid cells and hence is the most reliable diagnostic surface marker of the human B-cell lineage (23, 35). The CD19 gene codes for a 95-kDa protein with two extracellular immunoglobulinlike domains, a short transmembrane region, and a large cytoplasmic tail (33,34,38). These features suggest that the CD19 protein is a membrane receptor involved in signal transduction of B lymphocytes. No natural ligand for CD19 is as yet known; instead, monoclonal anti-CD19 antibodies have been used to study the physiological function of the CD19 molecule. In agreement with the receptor hypothesis, antibody binding leads to rapid internalization of CD19 (7,35) and to mobilization of free intracellular calcium ions (17,27,35). CD19 antibodies strongly inhibit proliferation of resting mature B cells in response to stimulation with antiimmunoglobulin M (IgM) antibodies (11,27,35 (14).Regulation of B-cell-specific gene expression is brought about by several distinct transcription factors (reference 3 and references therein). One of them is the B-cell lineagespecific activator protein (BSAP). We have identified this transcription factor as a mammalian homolog of the sea urchin protein TSAP, which is res...
The CD19 protein is expressed on the surface of all B-lymphoid cells with the exception of terminally differentiated plasma cells and has been implicated as a signal-transducing receptor in the control of proliferation and differentiation. Here we demonstrate complete correlation between the expression pattern of the CD19 gene and the B-cell-specific transcription factor BSAP in a large panel of B-lymphoid cell lines. The human CD19 gene has been cloned, and several BSAP-binding sites have been mapped by in vitro protein-DNA binding studies. In particular, a high-affinity BSAP-binding site instead of a TATA sequence is located in the -30 promoter region upstream of a cluster of heterogeneous transcription start sites. Moreover, this site is occupied by BSAP in vivo in a CD19-expressing B-cell line but not in plasma or HeLa cells. This high-affinity site has been conserved in the promoters of both human and mouse CD19 genes and was furthermore shown to confer B-cell specificity to a beta-globin reporter gene in transient transfection experiments. In addition, BSAP was found to be the only abundant DNA-binding activity of B-cell nuclear extracts that interacts with the CD19 promoter. Together, this evidence strongly implicates BSAP in the regulation of the CD19 gene.
The paired domain is a DNA binding domain initially described as a 128 amino acid region of homology shared by a group of transcription factors coded for by the paired-box containing genes (pax genes) [ l -
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