Tristetraprolin, or TTP, is the prototype of a small family of three known CCCH tandem zinc finger proteins;other known human members of this class are ZFP36L1 and ZFP36L2, while rodents express an additional protein, ZFP36L3. TTP is the best studied member of this family. It is rapidly induced, translocated from the nucleus to the cytosol, and is phosphorylated on serine residues in response to a variety of growth factors and inflammatory stimuli. 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 cell-free 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, Crohns 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 underway that will attempt to correlate these changes with human phenotypes. Finally, within the past several years knockout mice have been generated for the other two TTP-related genes common to mice and humans, as well as the third, rodent specific gene, and ongoing evaluation of their phenotypes should provide new insights into the physiological importance of this interesting gene family. Other ongoing studies in organisms that express only a single TTP family member, such as Drosophila melanogaster, S. pombe, and C. albicans, may help to determine the physiological importance of these proteins in these and econonomically and medically related species, as well as to unravel the mechanisms of action of these important proteins in the regulation of gene expression.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2012
Total Cost
$3,553,073
Indirect Cost
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State
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