ANALYSIS OF THE BRUTON TYROSINE KINASE GENE PROMOTER REVEALS CRITICALPU1 AND SP1 SITES

The gene defective in X-linked agammaglobulinemia (XLA) encodes a nove l protein kinase termed Bruton's tyrosine kinase (Btk). Whereas the XL A phenotype is confined to abnormalities of B-cell development and fun ction, Btk is expressed not only in B-lymphocyte lineage but also in m yeloid lineage cells. The first 450 basepairs of the Btk promoter fuse d to a luciferase gene displayed a similar cell-type specificity. Crit ical binding sites for the transcription factors PU.1 and Spl were ide ntified in the proximal portion of the Btk promoter upstream of a clus ter of transcriptional start sites, Mutation of either the PU.1 or Sp1 site markedly reduced the activity of a Btk promoter-luciferase repor ter construct in transfection experiments, In addition, PU.1 directly transactivated the Btk promoter, and deletion of the PU.1 binding site abolished this effect, This study implicates PU.1 and Sp1 as major re gulators of Btk expression and provides a foundation for further study of the regulation of this gene in XLA patients that lack Btk mRNA. Th is is a US government work, There are no restrictions on its use.