Destabilization of Interleukin-6 mRNA Requires a Putative RNA Stem-Loop Structure, an AU-Rich Element, and the RNA-Binding Protein AUF1

Paschoud, Serge; Dogar, Afzal M.; Kuntz, Catherine; Grisoni-Neupert, Barbara; Richman, Larry; Kühn, Lukas C.

doi:10.1128/mcb.01155-06

Cited by 136 publications

(150 citation statements)

References 76 publications

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“…In his review, Pestka (2008) summarised the genes with a lower mRNA decay rate upon DON administration, which are COX-2, tumour necrosis factor (TNF)-a and interleukin (IL)-6 in macrophages and IL-2 in EL-4T-cells. It has been reported that all four mRNAs are stabilised by ARE in the 3 0 untranslated region (Chen et al, 2001, Paschoud et al, 2006, Rajasingh et al, 2006. The downregulation of EXOSC9 and XRN1 might be the reason for increased mRNA stability of several ARE-containing genes in DON-challenged cell cultures.…”

Section: Translation Initiationmentioning

confidence: 95%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin-contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P , 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: 21.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: 11.49, DON5), a transporter of D-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 21.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: 21.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: 21.29, DON2.5/5) and DNAJC3 (fc: 21.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed.

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Section: Translation Initiationmentioning

confidence: 95%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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“…The AREs allow rapid mRNA degradation by promoting the recruitment of mRNA-destabilizing proteins to the 3"UTR. The IL-6 3"UTR contains six AREs [8]. In several systems, IL-6 has been described to have a short half life, varying from 30 minutes [8][9][10]] to 50 minutes [11].…”

Section: Introductionmentioning

confidence: 99%

“…The IL-6 3"UTR contains six AREs [8]. In several systems, IL-6 has been described to have a short half life, varying from 30 minutes [8][9][10]] to 50 minutes [11]. Several extracellular stimuli have been described to have a stabilizing effect on IL-6 mRNA, such as IL-1β [9,12]; IL-17 [13,14];…”

Section: Introductionmentioning

confidence: 99%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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“…The structure of an RNA hairpin depends on several parameters, such as loop size, stem length and the number of bulges, among others (Svoboda and di Kara, 2006). It has been reported that RNA hairpins can regulate stability, translation and localization of its target mRNA, as was shown for the ARE-containing interleukin-6 and c-myc transcripts (Chabanon et al, 2005;Paschoud et al, 2006). As a consequence, it is generally accepted that the functionality of AREs depends on different ARE-BPs and additionally on sequence accessibility.…”

Section: Discussionmentioning

confidence: 99%

The human c‐fos and TNFα AU‐rich elements show different effects on mRNA abundance and protein expression depending on the reporter in the yeast Pichia pastoris

Lautz

Ståhl

Lang

2009

Yeast

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AU-rich elements (AREs) are located in the 3 untranslated region (3 UTR) of their host genes and tightly regulate mRNA degradation and expression. Examples for this kind of regulation are the human proto-oncogene c-fos and the cytokine TNFα. Despite large effort in this field, the exact mechanism of ARE-mediated mRNA turnover remains unclear. In this work we analysed the effects of c-fos-and TNFα AREs on mRNA abundance and protein expression of selected human cDNAs in the yeast Pichia pastoris. This yeast is exceedingly well known for its excellent protein production capacity; however, ARE-like mechanisms have not been studied in this yeast to date. Interestingly, we observed both stabilizing and destabilizing effects of the c-fos ARE, whereas the TNFα ARE has a destabilizing or expression-reducing function in all tested cDNAs. Based on this observation, we introduced a number of single-point mutations upstream of the introduced c-fos ARE into the 3 UTR of a single cDNA in order to demonstrate the importance of ARE-flanking sequences for their own regulation. In conclusion, we illustrate that the analysis of ARE-mediated effects on mRNA abundance and protein expression of a reporter depends on the sequence of the reporter itself as well as the ARE-surrounding sequences within the 3 UTR. For this reason, we question whether already established reporter constructs in other cellular systems display the true type of regulation of the tested AREs for its original host gene. Finally, we propose that AREs should be analysed in their native sequence context.

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Destabilization of Interleukin-6 mRNA Requires a Putative RNA Stem-Loop Structure, an AU-Rich Element, and the RNA-Binding Protein AUF1

Cited by 136 publications

References 76 publications

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

The human c‐fos and TNFα AU‐rich elements show different effects on mRNA abundance and protein expression depending on the reporter in the yeast Pichia pastoris

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