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Physiological networks and disease functions of RNA‐binding protein AUF1

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Regulated messenger RNA (mRNA) decay is an essential mechanism that governs proper control of gene expression. In fact, many of the most physiologically potent proteins are encoded by short‐lived mRNAs, many of which contain AU‐rich elements (AREs) in their 3′‐untranslated region (3′‐UTR). AREs target mRNAs for post‐transcriptional regulation, generally rapid decay, but also stabilization and translation inhibition. AREs control mRNA turnover and translation activities through association with trans‐acting RNA‐binding proteins that display high affinity for these AU‐rich regulatory elements. AU‐rich element RNA‐binding protein (AUF1), also known as heterogeneous nuclear ribonucleoprotein D (HNRNPD), is an extensively studied AU‐rich binding protein (AUBP). AUF1 has been shown to regulate ARE‐mRNA turnover, primarily functioning to promote rapid ARE‐mRNA degradation. In certain cellular contexts, AUF1 has also been shown to regulate gene expression at the translational and even the transcriptional level. AUF1 comprises a family of four related protein isoforms derived from a common pre‐mRNA by differential exon splicing. AUF1 isoforms have been shown to display multiple and distinct functions that include the ability to target ARE‐mRNA stability or decay, and transcriptional activation of certain genes that is controlled by their differential subcellular locations, expression levels, and post‐translational modifications. AUF1 has been implicated in controlling a variety of physiological functions through its ability to regulate the expression of numerous mRNAs containing 3′‐UTR AREs, thereby coordinating functionally related pathways. This review highlights the physiological functions of AUF1‐mediated regulation of mRNA and gene expression, and the consequences of deficient AUF1 levels in different physiological settings. WIREs RNA 2014, 5:549–564. doi: 10.1002/wrna.1230 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease

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Domain organization and subcellular localization of AUF1 family isoforms. (a) The locations of peptide sequences encoded by alternatively spliced exons 2 and 7 are shown, as are the glutamine‐rich (Q‐rich) domain and RNA recognition motifs (RRMs) that are found in all AUF1 isoforms. (b) The smaller p37 and p40 isoforms shuttle more actively between the nucleus and cytoplasm compared with the larger p42 and p45 isoforms.
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Tissue and isoform distribution of AUF1 expression. AUF1 analysis in mouse and human tissue specimens demonstrates tissue‐ and isoform‐specific distribution in a wide range of organs. In mice, AUF1 is highly expressed in the spleen and thymus, moderately expressed in the brain, reproductive organs, heart, liver, kidney, and skeletal muscle, and displays faint expression in the intestine and lung. In the brain, testis, and uterus, p45AUF1, p42AUF1, and p40AUF1 isoforms are predominantly expressed compared with the p37 isoform. In contrast, p37AUF1, p40AUF1, and p42AUF1 isoforms are principally expressed in the lung and ovary where p45AUF1 is undetectable. Similar expression levels of AUF1 are found in human tissue specimens. However, AUF1 expression may be more ubiquitous than in the mouse, as AUF1 can be detected in all human tissues. AUF1‐positive cells were detected in all human tissues, possibly increasing with age in the immune system.
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AUF1 knockout mouse displays multiple physiological abnormalities. The AUF1 knockout mouse was generated by homologous recombination in mouse embryonic stem cells by targeting the RNA‐binding motif containing the third exon of AUF1, allowing for disruption of the remainder of the reading frame. Neo, neomycin‐resistant cassette; TK, thymidine kinase cassette; filled box, coding region; open box, noncoding region. Loss of AUF1 results in dysregulation of multiple mRNA targets and transcription of select genes leading to specific phenotypes observed in the AUF1 knockout mouse.
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease

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