One major area of study in the laboratory began with the cloning of a gene that was rapidly induced by insulin. The protein encoded by this gene, known as TTP, is the prototype of a novel class of CCCH zinc finger proteins. TTP is rapidly induced, translocated from the nucleus to the cytosol, and phosphorylated on serine residues by insulin and by many other mitogens and growth factors. Mice deficient in this protein develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death; more recent work has identified an excess of tumor necrosis factor (TNF)as the cause of most if not all aspects of the syndrome. TNF is over-produced by macrophages derived from these knockout mice, due to an increase in the stability of its mRNA. We recently determined that TTP caused instability of TNF by binding directly to its mRNA, leading in some way to its rapid degradation. Current studies are attempting to determine the mechanisms of this effect, as well as attempts to utilize this novel pathway regulating TNF expression as a target for new drugs for the treatment of TNF excess diseases, such as rheumatoid arthritis, Crohns disease, AIDS, cancer and others. - tumor necrosis factor; rheumatoid arthritis; cancer; AIDS; Crohn's disease; mRNA stability; knockout mice; zinc finger proteins
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