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English Wikipedia
Nephropedia Template TP (
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lüll The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis Carrick DM; Lai WS; Blackshear PJArthritis Res Ther 2004[]; 6 (6): 248-64Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.|Animals[MESH]|Base Sequence[MESH]|Binding Sites[MESH]|Bone Diseases, Developmental/genetics/pathology/physiopathology[MESH]|Crosses, Genetic[MESH]|Epistasis, Genetic[MESH]|Gene Expression Regulation/physiology[MESH]|Granulocyte-Macrophage Colony-Stimulating Factor/*genetics[MESH]|Humans[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Models, Molecular[MESH]|Molecular Sequence Data[MESH]|Phenotype[MESH]|Polymorphism, Genetic[MESH]|Protein Binding[MESH]|Protein Conformation[MESH]|RNA, Messenger/biosynthesis/chemistry[MESH]|Sequence Alignment[MESH]|Structure-Activity Relationship[MESH]|Tumor Necrosis Factor-alpha/*genetics[MESH]|Zinc Fingers/*physiology[MESH] |