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.

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Andrianne, Mathieu; Assabban, Assiya; La, Caroline et al. (2017) Tristetraprolin expression by keratinocytes controls local and systemic inflammation. JCI Insight 2:
Wells, Melissa L; Perera, Lalith; Blackshear, Perry J (2017) An Ancient Family of RNA-Binding Proteins: Still Important! Trends Biochem Sci 42:285-296
Shukla, Smita; Elson, Genie; Blackshear, Perry J et al. (2017) 3'UTR AU-Rich Elements (AREs) and the RNA-Binding Protein Tristetraprolin (TTP) Are Not Required for the LPS-Mediated Destabilization of Phospholipase-C?-2 mRNA in Murine Macrophages. Inflammation 40:645-656
Fu, Mingui; Blackshear, Perry J (2017) RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. Nat Rev Immunol 17:130-143
Gingerich, Timothy J; Stumpo, Deborah J; Lai, Wi S et al. (2016) Emergence and evolution of Zfp36l3. Mol Phylogenet Evol 94:518-530
Patial, Sonika; Blackshear, Perry J (2016) Tristetraprolin as a Therapeutic Target in Inflammatory Disease. Trends Pharmacol Sci 37:811-21
Stumpo, Deborah J; Trempus, Carol S; Tucker, Charles J et al. (2016) Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism. Development 143:1424-33
Patial, Sonika; Stumpo, Deborah J; Young 3rd, W Scott et al. (2016) Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome. Mol Cell Biol 36:1395-411
Tiedje, Christopher; Diaz-Muñoz, Manuel D; Trulley, Philipp et al. (2016) The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation. Nucleic Acids Res 44:7418-40
Qiu, Lian-Qun; Lai, Wi S; Stumpo, Deborah J et al. (2016) Mouse Embryonic Fibroblast Cell Culture and Stimulation. Bio Protoc 6:

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