Big Data Systems

Abstract

Tristetraprolin (TTP) is a prototypic family member of CCCH-type tandem zinc-finger domain proteins that regu-late mRNA destabilization in eukaryotic cells. TTP binds to AU-rich elements (AREs) in the 3؅-untranslated region of certain mRNAs, including tumor necrosis factor ␣, granulo-cyte macrophage colony-stimulating factor, and immediate early response 3, thereby facilitating their ARE-mediated decay. Expression of TTP is up-regulated by a variety of agents, including inflammatory mediators such as tumor necrosis factor ␣, a prominent activator of the nuclear factor ␬B (NF-␬B) family of transcription factors. Accordingly, TTP is involved in the negative feedback regulation of NF-␬B through promoting mRNA degradation. We describe here a novel, ARE-mediated decay-independent function of TTP on the termination of NF-␬B response: TTP suppresses the tran-scriptional activity of NF-␬B-dependent promoters inde-pendent of its mRNA-destabilizing property. In TTP knock-out mouse embryonic fibroblasts, lack of TTP leads to enhanced nuclear p65 levels, which is associated with the up-regulation of specific, ARE-less NF-␬B target genes. We find that attenuation of NF-␬B activity is at least in part due to an interference of TTP with the nuclear import of the p65 sub-unit of the transcription factor. This novel role of TTP may synergize with its mRNA-degrading function to contribute to the efficient regulation of proinflammatory gene expression. Tristetraprolin (TTP) 4 was first identified in the late 1980s as an immediate early gene rapidly induced by phorbol