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The roles of TTP and BRF proteins in regulated mRNA decay

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Abstract Adenylate‐ and uridylate‐rich element (ARE) motifs are cis‐acting elements present in the 3′ untranslated region of mRNA transcripts that encode many inflammation‐ and cancer‐associated genes. The TIS11 family of RNA‐binding proteins, composed of tristetraprolin (TTP) and butyrate response factors 1 and 2 (BRF‐1 and ‐2), plays a critical role in regulating the expression of ARE‐containing mRNAs. Through their ability to bind and target ARE‐containing mRNAs for rapid degradation, this class of RNA‐binding proteins serves a fundamental role in limiting the expression of a number of critical genes, thereby exerting anti‐inflammatory and anti‐cancer effects. Regulation of TIS11 family members occurs on a number of levels through cellular signaling events to control their transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TIS11 members' ability to promote ARE‐mediated mRNA decay along with decay‐independent functions. This review summarizes our current understanding of posttranscriptional regulation of ARE‐containing gene expression by TIS11 family members and discusses their role in maintaining normal physiological processes and the pathological consequences in their absence. WIREs RNA 2011 2 42–57 DOI: 10.1002/wrna.28 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease

TIS11 plays a central role in posttranscriptional regulation of gene expression. Tristetraprolin (TTP) and the other TIS11 family members butyrate response factors 1 and 2 (BRF‐1 and BRF‐2) bind to adenylate‐ and uridylate‐rich elements (ARE) in the 3 untranslated region of mRNA transcripts. Through their direct and indirect association with components of the deadenylase complex such as Ccr4, Caf1, and PARN, TIS11 family members promote rapid mRNA deadenylation. TTP and BRF proteins target the deadenylated mRNA transcript for storage or decay in P‐bodies. Once in P‐bodies, TTP interacts with the mRNA decapping complex and activates mRNA decapping. After decapping, the mRNA body undergoes 5′→3′ exonucleolytic decay. P‐bodies are closely associated with cellular stress granules, and TTP possibly mediates the transport of translationally repressed ARE‐containing mRNAs from stress granules to be decayed in P‐bodies. With regard to 3′→5′ mediated decay, TTP associates with components of the exosome and targets the mRNA for 3′→5′ exosome‐mediated degradation.

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Loss of tristetraprolin (TTP) expression promotes chronic inflammation and progression of tumorigenesis. In normal cells, expression of TTP allows the controlled expression of a variety of cancer‐ and inflammation‐associated genes by selectively targeting these adenylate‐ and uridylate‐rich element (ARE)‐containing mRNA transcripts for rapid decay. Loss of TTP expression promotes chronic inflammation and is observed during tumorigenesis, thereby allowing stabilization of ARE‐containing transcripts. This selective ARE‐mRNA stabilization contributes to overexpression of factors such as COX‐2, tumor necrosis factor‐α, cyclin D1, and vascular endothelial growth factor that promote chronic inflammation, resistance to apoptosis, enhanced cell growth and proliferation, and increased angiogenesis and metastasis.

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RNA in Disease and Development > RNA in Disease
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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