Translational Blockade Imposed by Cytokine-Derived UA-Rich Sequences

Kruys, Véronique; Marinx, Olivier; Shaw, Gray D.; Deschamps, Jacqueline; Huez, Georges

doi:10.1126/science.2672333

Cited by 337 publications

(212 citation statements)

References 20 publications

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“…The most important region in the regulation of gene expression seems to be the 3Ј untranslated region, which contains a tandem repeat of an octameric sequence, TTATTTAT (39). The corresponding UA-rich sequence in mRNA binds an inducible cytoplasmic factor (40), resulting in mRNA instability and translational blockade (41). It may be that DNA variants in this region are in linkage disequilibrium with HLA-DR4 or -DR2.…”

Section: Discussionmentioning

confidence: 99%

Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation

Wilson

Symons

McDowell

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

2,100

1,393

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Tumor necrosis factor ␣ (TNF␣) is a potent immunomodulator and proinf lammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF␣ are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at ؊308 in the TNF␣ promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF␣ production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at ؊308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF␣ gene regulation and may be responsible for the association of TNF2 with high TNF␣ phenotype and more severe disease in infections such as malaria and leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation

Wilson

Symons

McDowell

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

2,100

1,393

View full text Add to dashboard Cite

show abstract

“…Translational regulation of TNF-␣ mRNA is mediated by a short AU-rich sequence that is conserved among various cytokines and oncogenes and is present within the 3Ј-untranslated regions of such genes (6). This element confers a repression of translation that must be overcome in order for translation to proceed (7)(8)(9)(10)(11).…”

Section: Lipopolysaccharide (Lps)mentioning

confidence: 99%

Lipopolysaccharide-induced Tumor Necrosis Factor-α Promoter Activity Is Inhibitor of Nuclear Factor-κB Kinase-dependent

Swantek

Christerson

Cobb

1999

Journal of Biological Chemistry

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“…The 3Ј untranslated region (UTR) of most cytokine mRNAs including IFN-␥ contains adenosine-uridine (AU)-rich elements (AREs) that target the mRNAs for rapid degradation 33 and inhibit translation. 34 The 3Ј UTR of IFN-␥ contains five AREs. It has been demonstrated 35 that replacement of wild-type AREs by mutated forms (AUGAUA instead of AUUUA for example) is able to induce in vivo an expression level at least 100-fold larger.…”

Section: Figure 6 Residual Colonies Of U-937 After 2 Weeks Of Cocultumentioning

confidence: 99%

Polyethylenimine-mediated transfection of human monocytes with the IFN-γ gene: an approach for cancer adoptive immunotherapy

Ringenbach¹,

Bohbot²,

Tiberghien³

et al. 1998

Gene Ther

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Human monocytes (Mo) and monocyte-derived macroresponse. To overcome this limitation we have developed phages (MdM) are major effectors in host defense systems a gene transfer protocol with IFN-␥ cDNA and polyethyleniagainst cancer. Their antitumoral activity is dependent mine so as to obtain an efficient, long-lasting autocrine upon two processes: recruitment and activation. One of the cytocidal activation in transfected human Mo/MdM. We most powerful activators for these cells is recombinant show, by clonogenic assays, that efficient transfection and human IFN-␥ (rhIFN-␥). However, when the potential of tumoricidal activity can be obtained by this method in activated rhIFN-␥ was evaluated in clinical trials by ex vivo human monocyte populations. Although the proposed adoptive cellular immunotherapy protocols, the major probmodel must be improved before clinical use, IFN-␥ produclem was the short duration of ex vivo activation by rhIFN-␥.ing monocytes have potential for adoptive immunotherapy. Thus repeated injections were required to obtain a clinical

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Translational Blockade Imposed by Cytokine-Derived UA-Rich Sequences

Cited by 337 publications

References 20 publications

Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation

Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation

Lipopolysaccharide-induced Tumor Necrosis Factor-α Promoter Activity Is Inhibitor of Nuclear Factor-κB Kinase-dependent

Polyethylenimine-mediated transfection of human monocytes with the IFN-γ gene: an approach for cancer adoptive immunotherapy

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