Tristetraprolin, or TTP, is the prototype of a recently discovered class of CCCH tandem zinc finger proteins; other known mammalian members of this class are ZFP36L1 and ZFP36L2. TTP is rapidly induced, translocated from the nucleus to the cytosol, and phosphorylated on serine residues by insulin, other mitogens and growth factors, and activators of innate immunity such as LPS. Mice deficient in TTP develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death; most aspects of the syndrome are due to an excess of circulating tumor necrosis factor (TNF). TNF is over-produced by macrophages derived from these knockout mice, due to an increase in the stability of its mRNA. Conversely, TTP has been found to bind to and promote the degradation of this mRNA as well as that encoding granulocyte-macrophage colony-stimulating factor (GM-CSF). More recent studies have identified the initial process regulated by TTP as the deadenylation of the mRNA, or removal of its poly(A) tail, thought to be the rate limiting step in mammalian mRNA turnover. Current studies are using a recently developed TTP-dependent deadenylation assay to try to determine the mechanism of this effect. In addition, attempts are underway 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. Similarly, inhibitors of the interaction between TTP and GM-CSF mRNA may be useful treatments for granulocytopenic diseases. A number of 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. Finally, within the past year knockout mice have been generated for both TTP-related genes, and ongoing evaluation of their phenotypes should provide new insights into the physiological importance of this interesting gene family.
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