Tristetraprolin impairs NF-kappaB/p65 nuclear translocation.
Tristetraprolin (TTP) is a prototypic family member of CCCH-type tandem zinc-finger domain proteins that regulate mRNA destabilization in eukaryotic cells. TTP binds to AU-rich elements (AREs) in the 3'-untranslated region of certain mRNAs, including tumor necrosis factor alpha, granulocyte 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 alpha, a prominent activator of the nuclear factor kappaB (NF-kappaB) family of transcription factors. Accordingly, TTP is involved in the negative feedback regulation of NF-kappaB through promoting mRNA degradation. We describe here a novel, ARE-mediated decay-independent function of TTP on the termination of NF-kappaB response: TTP suppresses the transcriptional activity of NF-kappaB-dependent promoters independent 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-kappaB target genes. We find that attenuation of NF-kappaB activity is at least in part due to an interference of TTP with the nuclear import of the p65 subunit 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.
Schichl
Yvonne M
YM
Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, A-1090 Vienna, Austria. yvonne.schichl@gmx.net
Resch
Ulrike
U
Hofer-Warbinek
Renate
R
de Martin
Rainer
R
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020871:RNA Stability / Q000502:physiology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C099815:IER3 protein, human; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor