TTP And Related Proteins In Inflammatory Diseases

Environmental Health Sciences

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Abstract

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 found that TTP also controls the secretion of the important cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), again by regulating the stability of its mRNA. We found that TTP, as well as its two known mammalian related proteins, caused instability of TNF and GM-CSF mRNAs by binding directly to their mRNAs, leading in some way to their 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, Crohn's disease, AIDS, cancer and others. We are also interested in using the ability of TTP to modify the expression of GM-CSF; inhibitors of the interaction between TTP and the GM-CSF mRNA may be useful treatments for granulocytopenic diseases. In addition, polymorphisms in the TTP gene and related genes have been determined through the NIEHS Environmental Genome Project, and studies are beginning that will attempt to correlate these changes with human phenotypes.