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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 Nos. 7,022,487
and 7,238,782. We are seeking an industrial partner who is
interested in the commercialization of this technology. (Ref: J173) |
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«Technology Transfer Office : Sponsored Projects : Dartmouth College |
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11 Rope Ferry Road #6210 |
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Hanover, NH 03755-1404 |
Phone: (603) 646-3027 |
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Fax: (603) 646-3670 |
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