Posttranscriptional Regulation of Human ADH5/FDH and Myf6 Gene Expression by Upstream AUG Codons

Kwon, Hye Sook; Lee, Dong Kee; Lee, Jae Jung; Edenberg, Howard J.; Ahn, Young Soo; Hur, Man‐Wook

doi:10.1006/abbi.2000.2205

Cited by 26 publications

(20 citation statements)

References 25 publications

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“…3), indicating that uATG Ϫ105 was recognized by the ribosome and inhibited the translation of the downstream ORF. These findings are consistent with most other findings that uATGs inhibit downstream ORF translation (Meijer et al, 2000;Diba et al, 2001;Kwon et al, 2001;Blaschke et al, 2003;Mihailovich et al, 2007;Song et al, 2007). Further studies showed that the amino acid sequence of the peptide encoded by uORF-105 was not important in regulating translation and that uORF-105 acted only as a cis element to inhibit downstream ORF translation.…”

Section: Translational Regulation Of Human Mrp2 243supporting

confidence: 91%

“…Alternatively, there may be internal ribosomal entry sites located in the 5ЈUTR, such that the translation machinery skips the uATGs and instead uses the internal ribosomal entry sites to initiate translation of the downstream ORF (Le and Maizel, 1997). Whereas some upstream start codons (uATGs) inhibit downstream ORF translation (Meijer et al, 2000;Diba et al, 2001;Kwon et al, 2001;Blaschke et al, 2003;Mihailovich et al, 2007;Song et al, 2007), other uATGs have no such effect (Diba et al, 2001). uORFs can also influence the stability of mRNA by a process termed nonsense-mediated mRNA decay (Hood et al, 2009).…”

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confidence: 99%

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The 5′-Untranslated Region of Multidrug Resistance Associated Protein 2 (MRP2; ABCC2) Regulates Downstream Open Reading Frame Expression through Translational Regulation

Zhang

Zhao²,

Li³

et al. 2009

Mol Pharmacol

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MRP2 (ABCC2), a member of the ATP binding cassette superfamily of efflux transporters that mediates the apical efflux of organic anions from hepatocytes, enterocytes, and renal epithelial cells, is postulated to undergo post-transcriptional regulation. The MRP2 5Ј-untranslated region (5ЈUTR) contains seven upstream start codons and six upstream open reading frames (uORFs). Ribonuclease protection assays in human liver, placenta, kidney, small intestine, and HepG2 cells identified multiple MRP2 transcription initiation sites. We investigated MRP2 5ЈUTRs [Ϫ247 (Ϫ247 to Ϫ1), Ϫ204 (Ϫ204 to Ϫ1), or Ϫ99 (Ϫ99 to Ϫ1)] for their effects on regulation of gene expression with the use of transient gene expression in HepG2 cells and in vitro translation assays. In HepG2 cells transfected with SV40-MRP2-5ЈUTR-Luciferase cassettes, luciferase activities of constructs Ϫ247 and Ϫ204 were significantly lower than that of Ϫ99. Disruption of the uORFs at Ϫ105 and Ϫ74 nucleotides by mutation of ATGs to AAG enhanced luciferase activity significantly without affecting luciferase mRNA expression. The translation efficiencies of T7-5ЈUTR-Luciferase cassettes determined in vitro were consistent with transfected HepG2 cells and showed that inhibition of translation by the Ϫ105 uORF occurred only in the cis configuration and not in the trans configuration and that inhibition of translation by the Ϫ105 uORF was independent of the encoded peptide sequence. Characterization of an MRP2 polymorphism, Ϫ24CϾT, in the MRP2 5ЈUTR, demonstrated no effect on mRNA expression or downstream ORF translation. These data indicate for the first time that the 5ЈUTR of MRP2 mRNA transcripts and the uORF at Ϫ105 markedly influence MRP2 translation.

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Section: Translational Regulation Of Human Mrp2 243supporting

confidence: 91%

mentioning

confidence: 99%

The 5′-Untranslated Region of Multidrug Resistance Associated Protein 2 (MRP2; ABCC2) Regulates Downstream Open Reading Frame Expression through Translational Regulation

Zhang

Zhao²,

Li³

et al. 2009

Mol Pharmacol

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“…Kwon et al [7] have carried out experimental work to investigate the regulatory role of uORFs and secondary structures in 5 UTRs. They carried out site-directed mutagenesis studies of human ADH5/FDH and Myf6 genes, measuring the RNA transcripts, investigating the interactions between mRNA and proteins involved in translation, and analysing the RNA secondary structures of the 5 UTRs.…”

Section: Discussionmentioning

confidence: 99%

A First Step towards Learning which uORFs Regulate Gene Expression

Bryant

Kemp

Cvijović

2006

Journal of Integrative Bioinformatics

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SummaryWe have taken a first step towards learning which upstream Open Reading Frames (uORFs) regulate gene expression (i.e., which uORFs are functional) in the yeast Saccharomyces cerevisiae. We do this by integrating data from several resources and combining a bioinformatics tool, ORF Finder, with a machine learning technique, inductive logic programming (ILP). Here, we report the challenge of using ILP as part of this integrative system, in order to automatically generate a model that identifies functional uORFs. Our method makes searching for novel functional uORFs more efficient than random sampling. An attempt has been made to predict novel functional uORFs using our method. Some preliminary evidence that our model may be biologically meaningful is presented.

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“…The 5Ј-untranslated region of human ADH3 shares little homology with other human ADH classes, and unlike other ADH family members, the 5Ј region of both human and rodent ADH3 lacks a TATA box and contains many CpG doublets (Hur and Edenberg, 1992). Although these are typical characteristics of housekeeping genes, human ADH3 mRNA also contains two weak 5Ј translation start sites upstream of the ADH3 open reading frame; this structure is more characteristic of genes with regulatory function such as growth factors, transcription factors, and genes involved in signal transduction (Hur and Edenberg, 1992;Kwon et al, 2001). Site-directed mutations to silence these 5Ј start codons significantly increase ADH3 expression in human cell lines (Table 4), suggesting that these upstream open reading frames (uORFs) may play a role in the regulation of ADH3 (Kwon et al, 2001).…”

mentioning

confidence: 99%

“…Although these are typical characteristics of housekeeping genes, human ADH3 mRNA also contains two weak 5Ј translation start sites upstream of the ADH3 open reading frame; this structure is more characteristic of genes with regulatory function such as growth factors, transcription factors, and genes involved in signal transduction (Hur and Edenberg, 1992;Kwon et al, 2001). Site-directed mutations to silence these 5Ј start codons significantly increase ADH3 expression in human cell lines (Table 4), suggesting that these upstream open reading frames (uORFs) may play a role in the regulation of ADH3 (Kwon et al, 2001). In this regard, uORFS are known to regulate protein translation, and mutations that create or delete such sites are associated with certain diseases (Chatterjee and Pal, 2009 …”

mentioning

confidence: 99%

The Ontogeny, Distribution, and Regulation of Alcohol Dehydrogenase 3: Implications for Pulmonary Physiology

Thompson

Sonawane²,

Grafström³

2009

Drug Metab Dispos

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ABSTRACT:Class III alcohol dehydrogenase (ADH3), also termed formaldehyde dehydrogenase or S-nitrosoglutathione reductase, plays a critical role in the enzymatic oxidation of formaldehyde and reduction of nitrosothiols that regulate bronchial tone. Considering reported associations between formaldehyde vapor exposure and childhood asthma risk, and thus potential involvement of ADH3, we reviewed the ontogeny, distribution, and regulation of mammalian ADH3. Recent studies indicate that multiple biological and chemical stimuli influence expression and activity of ADH3, including the feedback regulation of nitrosothiol metabolism. The levels of ADH3 correlate with, and potentially influence, bronchial tone; however, data gaps remain with respect to the expression of ADH3 during postnatal and early childhood development. Consideration of ADH3 function relative to the respiratory effects of formaldehyde, as well as to other chemical and biological exposures that might act in an additive or synergistic manner with formaldehyde, might be critical to gain better insight into the association between formaldehyde exposure and childhood asthma.

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Posttranscriptional Regulation of Human ADH5/FDH and Myf6 Gene Expression by Upstream AUG Codons

Cited by 26 publications

References 25 publications

The 5′-Untranslated Region of Multidrug Resistance Associated Protein 2 (MRP2; ABCC2) Regulates Downstream Open Reading Frame Expression through Translational Regulation

The 5′-Untranslated Region of Multidrug Resistance Associated Protein 2 (MRP2; ABCC2) Regulates Downstream Open Reading Frame Expression through Translational Regulation

A First Step towards Learning which uORFs Regulate Gene Expression

The Ontogeny, Distribution, and Regulation of Alcohol Dehydrogenase 3: Implications for Pulmonary Physiology

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