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Regulation of genes in the arachidonic acid metabolic pathway by RNA processing and RNA‐mediated mechanisms

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Arachidonic acid (AA) is converted by enzymes in an important metabolic pathway to produce molecules known collectively as eicosanoids, 20 carbon molecules with significant physiological and pathological functions in the human body. Cyclooxygenase (COX) enzymes work in one arm of the pathway to produce prostaglandins (PGs) and thromboxanes (TXs), while the actions of 5‐lipoxygenase (ALOX5 or 5LO) and its associated protein (ALOX5AP or FLAP) work in the other arm of the metabolic pathway to produce leukotrienes (LTs). The expression of the COX and ALOX5 enzymes that convert AA to eicosanoids is highly regulated at the post‐ or co‐transcriptional level by alternative mRNA splicing, alternative mRNA polyadenylation, mRNA stability, and microRNA (miRNA) regulation. This review article will highlight these mechanisms of mRNA modulation. WIREs RNA 2013, 4:593–605. doi: 10.1002/wrna.1177 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3' End Processing Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease

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Schematic of arachidonic acid (AA) metabolism. This diagram depicts the pathways responsible for conversion of AA to molecules that are mediators of physiological and inflammatory processes. First, membrane phospholipids are released by the actions of phospholipase A2. AA then serves as a substrate for two arms of metabolic reactions. Cyclooxygenase enzymes, COX‐1 and COX‐2, convert AA to prostaglandin H2 (PGH2), the intermediate molecule that can be further processed into various prostaglandins and thromboxanes. The other arm of the pathway is carried out by lipoxygenase‐5 (ALOX5 or 5LO). With the aid of 5LO Activating Protein (ALOX5AP or FLAP), ALOX5 converts AA into leukotrienes.
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Multiple mechanisms of post‐transcriptional regulation of COX‐1, COX‐2, ALOX5, and ALOX5AP mRNAs are possible. This schematic highlights the various means of regulation that likely work in concert to regulate COX‐1, ‐2 ALOX5, and ALOX5AP mRNAs at the post‐transcriptional level. Poly(A) signals are depicted by vertical red lines; AU‐rich elements (AREs) are depicted by vertical blue lines; putative miRNA binding sites are depicted by vertical green lines. 3′ UTRs are shown as horizontal black lines. Since some of the blue lines are close together, they may appear as thicker lines. The translational stop codons are marked by a ‘stop sign.’
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Putative microRNAs (miRNAs). Based on Target Scan and miRanda databases, miRNAs were selected based on conservation and microRNA support vector regression (mirSVR) score. mirSVR is a regression method used for quantifiable predictions of miRNA/mRNA target duplexes; mirSVR scores rank miRNAs by the extent of potential downregulation associated with each target gene. This method allows the identification of non‐canonical and non‐conserved sites. Highly conserved and miRNAs with high mirSVR scores are shown. miRNAs that have been experimentally investigated and are known to specifically regulate the target mRNA are described in the text, are listed under the ‘Validated miRNA’ heading, and references for each are listed in superscript.
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Alternative polyadenylation of COX mRNAs. (a) COX‐1 possesses three poly(A) signals in its 3′most exon. These poly(A) signals when utilized could result in mRNA molecules varying only in length of their 3′ UTRs. Use of the COX‐1 proximal polyadenylation signal would result in an mRNA ∼2.6 kb in length; use of the far distal signal would result in a message ∼5.0 kb in length; use of the intermediate non‐canonical polyadenylation signal (AAGAAA) would result in a message ∼4.9 kb in length. (b) COX‐2 possesses two poly(A) signals with expression sequence tag (EST) data to support usage of both. Use of the COX‐2 proximal polyadenylation signal would yield an mRNA molecule ∼2.8 kb in length, while use of the distal signal would yield a ∼4.5 kb long mRNA. Poly(A) signals are shown by vertical red lines. The relative size of each mature polyadenylated mRNA molecule is depicted as a pink box with associated poly(A) tail. The translational stop codons are marked by a ‘stop sign.’
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Schematic of cyclooxgenase‐1 (PTGS‐1) alternatively spliced variants. Based on the NCBI database, COX‐1 has seven alternatively spliced transcripts. 5′ and 3′ untranslated regions (UTRs) are depicted as blue boxes. Exonic regions are depicted as red boxes. Introns are shown as black lines. Alternative exonic regions or alternative 5′ UTRs (promoters) are depicted by a lighter shade of blue or red, respectively. (a) All variants are described in comparison to Variant 1. Variant 2 uses an alternate in‐frame splice site in the coding region in exon 9. Variant 3 lacks an alternate exon (exon 5) in the coding region. Variant 4 differs in the 5′ UTR, lacks a portion of the 5′ coding region, and initiates translation at an alternate downstream in‐frame start site. The encoded isoform 4 has a shorter N‐terminus. Variant 5 differs in the 5′ UTR and contains differences in the 5′ coding region. This results in initiation of translation at an alternate downstream in‐frame start site. Variant 6 uses two alternate splice sites at two exons. These differences result in translation initiation at an alternate downstream in‐frame start site. The primary ORF can be translated due to a combination of reinitiation and leaky scanning. Variant 7 differs in the 5′ UTR and initiates translation at an alternate start site. The primary ORF can be translated due to a combination of reinitiation and leaky scanning. The encoded isoform 7 has a distinct N‐terminus. (b) This diagram depicts the coding regions responsible for COX‐1 prostaglandin endoperoxide synthase activity and the calcium‐binding EGF‐like domain. COX‐1 Variants 4, 5, and 6 lack the calcium‐binding EGF‐like domain. The active site of COX‐1 is found in exon 11, and contains isoleucine at position 523 (marked by an asterisk), as well as a serine residue at position 516, which is the acetylation site of aspirin. The equivalent exon in COX‐2 also contains an N‐glycosylation site not found in COX‐1; it has an unknown function but is glycosylated in vivo. In COX‐1, amino acid 523 is isoleucine; in COX‐2 amino acid 523 is valine. (C) COX‐3 is a special alternative spliced variant of COX‐1. In mice and dogs, COX‐3 is the result of a retained intron of 93 bases in length, resulting in the loss of 31 amino acids in the COX‐3 sequence, and does not impair its functionality. In humans, however, the intron is 94 bases long, causing a frame shift when alternative splicing occurs, resulting in a non‐functional protein with a completely different amino acid sequence from those of COX‐1 or COX‐2. Arrow denotes the location of the retained intron (flanks exon 1 and exon 2). The schematics are not necessarily representative of relative scale. The translational stop codons are marked by a ‘stop sign.’
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ALOX5 and ALOX5AP alternatively spliced variants. Based on the NCBI database, ALOX5, and ALOX5AP have three and two alternatively spliced transcripts, respectively. 5′ and 3′ untranslated regions (UTRs) are depicted as blue boxes. Exonic regions are depicted as red boxes. Introns are shown as black lines. Alternative exonic regions or alternative 5′ UTRs (promoters) are depicted by a lighter shade of blue or red, respectively. (A) All ALOX5 variants are described with respect to ALOX5 Variant 1. ALOX5 Variant 1 contains 14 exons separated by 13 intronic regions. ALOX5 Variant 2 lacks a segment of exon 10. The resulting Variant 2 is 96 nucleotides shorter than Variant 1. Variant 3 lacks exon 13 in the 3′ coding region, compared to variant 1. The resulting Variant 3 is 171 nucleotides shorter than variant 1. (B) All ALOX5AP variants are described with respect to ALOX5AP Variant 1. ALOX5AP Variant 1 contains 5 exons and 4 intronic regions. ALOX5AP Variant 2 contains a different 5′ UTR region and a new exon 1. Variant 2 also contains an extremely large intronic region between exons 1 and 2. Variant 1 Exon 1 encodes 23 amino acids. Variant 2 Exon 2 encodes 41 amino acids. Variant 2 Exon 2 is a 5′ extension of Variant 1 Exon 1 by 18 amino acids. These alternatively spliced forms were identified and listed in the NCBI Database in January 2012. The schematics are not necessarily representative of relative scale. The translational stop codons are marked by a ‘stop sign.’
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease
RNA Processing > 3′ End Processing

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