The role of the AU-rich elements of mRNAs in controlling translation

Espel, Enric

doi:10.1016/j.semcdb.2004.11.008

Cited by 113 publications

(90 citation statements)

References 117 publications

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“…Interestingly, about 25% of the p38 MAPK -dependent transcripts (for example, IL8, MMP13, PTGS2, PLAGL2, CSF2, STK3, PTHLH, EREG) contain in the 3 0 untranslated region adenylate/uridylate-rich elements (AREs) (http://rc.kfshrc.edu.sa/ARED/ARED_GENE/ graphics/ARE.html), regulatory sequences in mRNA of genes involved in acute responses, including cytokines, growth factors and proto-oncogenes (Espel, 2005). Thus, the p38 MAPK pathway in PDT-treated T24 cells could rapidly stabilize and increase translation of AREs-containing labile mRNAs, for example, for MMP-13, COX-2 and GM-CSF, involved in tumor promotion (Hashimoto et al, 2000;Hoffmann et al, 2002;Dean et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

et al. 2007

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Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O 2 , cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38 MAPK inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38 MAPK inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

et al. 2007

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“…3A). This sequence was chosen because this or similar sequences found in the 3Ј-UTR of cytokine mRNAs are thought to be responsible for the binding of trans-acting protein factors to the RNA (42,43). When we used this mutated AU2 probe, we did not observe the two distinct complexes that were present when using the nonmutated probe (Fig.…”

Section: Adenosine Regulates Protein Binding To the 3ј-utr Of The Il-mentioning

confidence: 98%

“…The p38 MAPK has been implicated in the posttranscriptional regulation of a number of cytokine genes, including TNF-␣, IL-6, and vascular endothelial growth factor (42,43,45). We recently documented that adenosine activates p38 MAPK in RAW 264.7 macrophages (28).…”

Section: Figurementioning

confidence: 99%

“…These observations suggest that additional regulatory levels of IL-10 biosynthesis are operational in murine macrophages. A growing body of evidence suggests that regulation of gene expression may be accomplished through posttranscriptional mechanisms, which include regulation of mRNA stability, and translational regulation (42,43). The discrepancy between IL-10 mRNA and protein levels was observed when measuring both IL-10 mRNA and protein accumulation at the same relatively late, 5-h time point, indicating that a destabilizing effect is unlikely to have a role in reducing IL-10 protein levels relative to mRNA concentrations.…”

Section: Discusssionmentioning

confidence: 99%

“…AU1, AU2, and AU3 contain related potential regulatory nonamer sequences (40,43) that might be involved in the posttranscriptional regulatory action of adenosine. AUAUUUAUU and CUAUUUAUU are present in AU1, GUAUUUAUU is found in AU2, and UUAUUUAUA is a part of AU3.…”

Section: Discusssionmentioning

confidence: 99%

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Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Németh¹,

Lutz²,

Csóka³

et al. 2005

The Journal of Immunology

239

161

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Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A2B receptor, because the order of potency of selective agonists was 5′-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) > 2-chloro-N6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

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Albumin 3′untranslated region facilitates increased recombinant protein production from Chinese hamster ovary cells

Pearson

Khazaipoul

Optun³

et al. 2012

Biotechnology Journal

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Chinese hamster ovary (CHO) cells are used for recombinant protein production in the pharmaceutical industry but there is a need to improve expression levels. In the present work experiments were carried out to test the effectiveness of different 3'untranslated regions (3'UTRs) in promoting production of a naturally secreted luciferase. Seamless cloning was used to produce expression vectors in which Gaussia princeps luciferase coding sequences were linked to the human albumin, immunoglobulin or chymotrypsinogen 3'UTR. Stably transfected CHO cells expressing these constructs were selected. Luciferase activity in the culture medium was increased 2-3-fold by replacing the endogenous 3'UTR with the albumin 3'UTR and decreased by replacement with immunoglobulin or chymotrypsinogen 3'UTR. Replacement of the native 3'UTR with the albumin 3'UTR led to a 10-fold increase in luciferase mRNA levels. Deletion analysis of the albumin 3'UTR showed that loss of nucleotides 1-50, which removed an AU-rich complex stem loop region, caused significant reductions in both luciferase protein expression and luciferase mRNA levels. The results suggest that recombinant protein expression and yield could be improved by the careful selection of appropriate 3'UTR sequences.

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The role of the AU-rich elements of mRNAs in controlling translation

Cited by 113 publications

References 117 publications

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Albumin 3′untranslated region facilitates increased recombinant protein production from Chinese hamster ovary cells

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