|
|
||||
|
|
|
|
|
|
|
|
|
|
||
|
|
|
|
|
|
|
|
|
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) |
||
|
|
|
|
|
|
|
|
|
«Technology Transfer Office : Sponsored Projects : Dartmouth College |
||
|
|
||||
|
11 Rope Ferry Road #6210 |
||||
|
Hanover, NH 03755-1404 |
Phone: (603) 646-3027 |
|||
|
|
|
|
Fax: (603) 646-3670 |
|
