Abstract
AU-rich elements (AREs) in the 3' untranslated region (UTR) of unstable mRNAs dictate their degradation. An RNAi-based screen performed in Drosophila S2 cells has revealed that Dicer1, Argonaute1 (Ago1) and Ago2, components involved in microRNA (miRNA) processing and function, are required for the rapid decay of mRNA containing AREs of tumor necrosis factor-alpha. The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells. We further observed that miR16, a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, is required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay is sequence-specific and requires the ARE binding protein tristetraprolin (TTP). TTP does not directly bind to miR16 but interacts through association with Ago/eiF2C family members to complex with miR16 and assists in the targeting of ARE. miRNA targeting of ARE, therefore, appears to be an essential step in ARE-mediated mRNA degradation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3' Untranslated Regions / genetics*
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Animals
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Argonaute Proteins
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Base Sequence / genetics
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Cell Line
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Cell Nucleus / genetics*
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Cell Nucleus / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster
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Eukaryotic Initiation Factors
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Gene Expression Regulation / genetics
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HeLa Cells
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Macromolecular Substances / metabolism
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MicroRNAs / genetics*
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RNA Stability / genetics*
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism*
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RNA-Induced Silencing Complex / genetics
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RNA-Induced Silencing Complex / metabolism
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Ribonuclease III / genetics
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Ribonuclease III / metabolism
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Tristetraprolin
Substances
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3' Untranslated Regions
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AGO1 protein, Drosophila
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AGO2 protein, Drosophila
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Argonaute Proteins
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DNA-Binding Proteins
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Drosophila Proteins
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Eukaryotic Initiation Factors
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Immediate-Early Proteins
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Macromolecular Substances
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MicroRNAs
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RNA, Messenger
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RNA-Induced Silencing Complex
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Tristetraprolin
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ZFP36 protein, human
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Ribonuclease III