Delineation of a Novel Pathway That Regulates Human CD154 (CD40 Ligand) Gene Expression
The expression of CD154 (CD40 ligand) by activated T lymphocytes plays a central role in humoral and cellular immunity. The fundamental importance of this protein in mounting an immune response has made it an attractive target for immunomodulatory strategies. Several studies have demonstrated that CD154 expression is regulated at the level of mRNA turnover in a manner distinct from other cytokine genes. We report characterization of the cis-trans components of this important regulatory pathway. We have purified, sequenced, and characterized the two major proteins that bind the CD154 3'UTR as members of the polypyrimidine tract binding protein (PTB) family. One of these proteins is a previously unreported alternatively spliced PTB isoform, which we call PTB-T. These proteins interact with a polypyrimidine-rich region within the CD154 3'UTR that lacks any known cis-acting instability elements. The 3'UTR of CD154 was shown to reduce reporter gene expression at the level of mRNA accumulation. The polypyrimidine-rich region of the CD154 3'UTR was sufficient to mediate these effects, indicating the presence of a novel cis-acting instability element. The function of this element appears to be dependent on the relative cytoplasmic levels of PTB and PTB-T. Cotransfection of vectors encoding PTB-T consistently decreased the CD154 3'UTR-dependent luciferase expression. In contrast, transfection of plasmids encoding PTB tended to increase CD154 3'UTR-dependent luciferase expression. Thus, the CD154 3'UTR contains a novel cis-acting element whose function is determined by the binding of PTB and PTB-T. These data identify a specific pathway that regulates CD154 expression that can potentially be selectively targeted for the treatment of autoimmune disease and allograft rejection.This technology is claimed in the issued United States Patent No. 7,022,487 and the published United Sates Patent Application No. 11/389,947. We are seeking an industrial partner who is interested in the commercialization of this technology. (Ref: J173)
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