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The role of AUF1 in regulated mRNA decay

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Abstract Messenger ribonucleic acid (mRNA) turnover is a major control point in gene expression. In mammals, many mRNAs encoding inflammatory cytokines, oncoproteins, and G‐protein‐coupled receptors are destabilized by the presence of AU‐rich elements (AREs) in their 3′‐untranslated regions. Association of ARE‐binding proteins (AUBPs) with these mRNAs promotes rapid mRNA degradation. ARE/poly(U)‐binding/degradation factor 1 (AUF1), one of the best‐characterized AUBPs, binds to many ARE‐mRNAs and assembles other factors necessary to recruit the mRNA degradation machinery. These factors include translation initiation factor eIF4G, chaperones hsp27 and hsp70, heat‐shock cognate protein hsc70, lactate dehydrogenase, poly(A)‐binding protein, and other unidentified proteins. Numerous signaling pathways alter the composition of this AUF1 complex of proteins to effect changes in ARE‐mRNA degradation rates. This review briefly describes the roles of mRNA decay in gene expression in general and ARE‐mediated decay (AMD) in particular, with a focus on AUF1 and the different modes of regulation that govern AUF1 involvement in AMD. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

Schematic of deadenylation‐dependent, AU‐rich element (ARE)‐mediated messenger ribonucleic acid (mRNA) degradation. The mRNA is depicted with a 5′‐cap structure and 3′‐poly(A) tail. The ARE is shown as the boxed AUUUA. The start and stop codons are highlighted. The sequential pathway involves exoribonucleolytic removal of the poly(A) tail, followed by decapping and subsequent 5′ → 3′ and/or 3′ → 5′ degradation.

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Dynamics of the ARE/poly(U)‐binding/degradation factor 1 (AUF1) complex of proteins and AU‐rich element (ARE)‐mediated mRNA decay. AUF1 interacts with eIF4G and the ARE. During ongoing translation, AUF1 is displaced from the ARE in a complex with poly(A)‐binding protein (PABP), perhaps exposing the poly(A) tail to ribonucleases. This may require destruction of AUF1 by proteasomes. During heat shock, association of hsp70 with AUF1 may disrupt or block the AUF1–PABP interaction, leaving PABP free to remain bound to the poly(A) tail, thus masking it from ribonucleases.

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Three‐step model of ARE/poly(U)‐binding/degradation factor 1 (AUF1)‐dependent, AU‐rich element (ARE)‐mediated decay. The first step, dynamic AUF1 dimer binding and oligomerization, may be sufficient for this phase of assembly. Other association of ARE‐binding proteins, including the Hu family of messenger ribonucleic acid (mRNA)‐stabilizing proteins, may compete for AUF1 binding to the ARE at this stage, thus preventing AUF1 oligomerization and subsequent factor recruitment. The second step, trans‐acting complex assembly, involves association of AUF1 with eIF4G, PABP, hsp/hsc70, hsp27, and additional unidentified proteins. The third step, mRNA catabolism, involves two linked catabolic steps—ubiquitin‐dependent degradation of AUF1 by proteasomes and mRNA destruction by mRNA decay enzymes. (Reprinted with kind permission from Ref. 101 Copyright 2002 Springer Science and Business Media).

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p40AUF1 phosphorylation changes upon PKC: protein kinase c activation. In nonactivated monocytes, Ser 83 and Ser 87 are phosphorylated, concomitant with labile cytokine messenger ribonucleic acids (mRNAs). PKC activation promotes loss of phosphates from Ser 83 and Ser 87, concomitant with cytokine mRNA stabilization.

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ARE/poly(U)‐binding/degradation factor 1 proteins are generated by alternative pre‐messenger ribonucleic acid (mRNA) splicing. The AUF1/HNRPD gene has 10 exons (not shown to scale). The start codon in exon 1 and the stop codon in exon 8 are highlighted. The domain structures are shown in increasing order of apparent molecular weights. The dimerization domain, RRM1, RRM2, and Q‐rich domain common to all isoforms are highlighted. Alternatively spliced exons 2 and 7 are represented by the stripped box and the red box, respectively. (Reprinted with permission from Ref. 44 Copyright 1998 Elsevier).

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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