AU-rich element-mediated translational control: complexity and multiple activities of <i>trans</i>-activating factors

Zhang, Tong; Kruys, Véronique; Huez, Georges; Gueydan, Cyril

doi:10.1042/bst0300952

Cited by 201 publications

(163 citation statements)

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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: 83%

“…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: 94%

“…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%

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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

241

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

confidence: 83%

Section: Discusssionmentioning

confidence: 94%

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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

241

161

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“…5 Recently DAZAP1 was identified as a physiological substrate for extracellular signalregulated kinase-1/extracellular signal-regulated kinase-2 26 that interacts specifically with AU-rich elements found in mRNA of a number of pro-inflammatory cytokines (such as tumor necrosis factor a, interleukin-6 and interleukin-8) and immediate-early genes (such as c-fos) affecting their stability/translation. 27 Some reports discuss likely post-transcriptional mechanisms involving shuttling RNA-binding proteins in leukemogenesis. 28 A number of other genes that encode proteins with RNA-binding domains are rearranged in human cancer.…”

Section: Resultsmentioning

confidence: 99%

Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia

Prima

Hunger

2007

Leukemia

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A variant t(1;19)(q23;p13.3) translocation creates reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1 fusion genes that are expressed in acute lymphoblastic leukemia. We used retroviral gene transfer to ectopically express wild-type and chimeric DAZAP1 and MEF2D fusion proteins in NIH 3T3 cells. In soft agar assays, each of the fusion proteins transformed 3T3 cells with a 20-fold increase in colony formation as compared to empty vector or native MEF2D or DAZAP1 proteins. Co-expression of both DAZAP1/MEF2D and MEF2D/DAZAP1 led to a threefold increase in colony formation as compared to either fusion protein alone. Expression of wild-type DAZAP1, MEF2D or DAZAP1/MEF2D allowed 3T3 cells to proliferate under low serum (0.5%) conditions and suppressed apoptosis. In contrast, MEF2D/DAZAP1 expression did not facilitate proliferation in low serum and led to a modest increase in apoptosis. Both MEF2D/DAZAP1 and DAZAP1/MEF2D have oncogenic properties, and co-expression of both fusion proteins is synergistic.

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“…Leptin, like other cytokine mRNAs, includes several adenosine-uridine-rich elements that are known to regulate their half life (90). We may not have seen any variations in our leptin UTR reporter mRNA expression levels in our previous studies because they were not designed to address this issue, i.e., we used a reporter construct that was driven by a strong promoter (SV 40 promoter) (40).…”

Section: Mechanisms Regulating Leptin Translationmentioning

confidence: 99%

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Lee¹,

Fried²

2009

American Journal of Physiology-Endocrinology and Metabolism

112

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Lee M-J, Fried SK. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296: E1230 -E1238, 2009. First published March 24, 2009 doi:10.1152/ajpendo.90927.2008.-This review summarizes recent advances in our understanding of the pre-and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMPactivated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5Ј-and 3Ј-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production. adipose tissue; adrenergic; feeding; insulin; obesity LEPTIN IS A 16-KDA PROTEIN encoded by the obese (lep) gene that is expressed and secreted mainly by adipocytes. When energy stores are low, a fall in leptin decreases thermogenesis, promotes fatty acid (FA) over glucose oxidation, and decreases the activity of the hypothalamic pituitary adrenal and gonadal axes (1). Leptin also modulates the activities of the hematopoietic (5) and immune (52) systems, as well as angiogenesis (7).

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AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors

Cited by 201 publications

References 0 publications

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

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

Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

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