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Perspectives on the ARE as it turns 25 years old

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Abstract The AU‐rich element (ARE) was discovered in 1986 as a conserved mRNA sequence found in the 3′ untranslated region of the TNF‐α transcript and other transcripts encoding cytokines and inflammatory mediators. Shortly thereafter, the ARE was shown to function as a regulator of mRNA degradation, and AREs were later shown to regulate other posttranscriptional mechanisms such as translation and mRNA localization. AREs coordinately regulate networks of chemokine, cytokine, and growth regulatory transcripts involved in cellular activation, proliferation, and inflammation. ARE‐mediated regulation is carried out by a host of ARE‐binding proteins, whose activity is regulated in a cell type and activation‐dependent manner. The last 25 years of ARE research has offered insight into the mechanisms and regulation of ARE‐mediated mRNA decay, and has provided a road map for the discovery of additional mRNA regulatory motifs. The future of ARE research will transition from a discovery phase to a phase focused on translating basic biological findings into novel therapeutic targets. Our understanding of ARE‐mediated gene regulation and posttranscriptional control has implications for many fields of study including developmental biology, neuroscience, immunobiology, and cancer biology. WIREs RNA 2012 doi: 10.1002/wrna.1125 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease

The ARE‐binding proteins TTP and HuR exert opposite effects on ARE‐containing transcripts. (a) HuR binds to the ARE to stabilize the transcript, likely through competitive inhibition of destabilizing ARE‐binding proteins. (b) TTP binds to the ARE and recruits deadenylases as well as proteins involved in both the 5′ → 3′ and 3′ → 5′ decay pathways. The ability of TTP to recruit components of the mRNA decay machinery is blocked by phosphorylation and recruitment of the 14‐3‐3 adaptor protein.

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CELF1 promotes transcript decay by binding to the GRE, followed by the recruitment of deadenylase (i.e., PARN), promoting transcript degradation. CELF1‐mediated mRNA decay is regulated by phosphorylation during T cell stimulation which causes decreased ability of CELF1 to bind to target transcripts.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease

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