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Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene

Published in The Journal of biological chemistry. 2009, vol. 284, no. 39, p. 26261-72
Abstract Myeloid differentiation factor 2 (MD-2) binds Gram-negative bacterial lipopolysaccharide with high affinity and is essential for Toll-like receptor 4-dependent signal transduction. MD-2 has recently been recognized as a type II acute phase protein. Plasma concentrations of the soluble form of MD-2 increase markedly during the course of severe infections. Its production is regulated in hepatocytes and myeloid cells by interleukin-6 (IL-6) but not IL-1beta. In the present work we show that two transcription factors (TF), PU.1 and CAAT/enhancer-binding protein beta (C/EBPbeta), participate in the activation of the human MD-2 gene in hepatocytic cells after stimulation with IL-6. PU.1 TF and proximal PU.1 binding sites in the MD-2 promoter were shown to be critical for the basal activity of the promoter as well as for IL-6-induced soluble MD-2 production. Deletions of proximal portions of the MD-2 promoter containing PU.1 and/or NF-IL-6 consensus binding sites as well as site-directed mutagenesis of these binding sites abrogated IL-6-dependent MD-2 gene activation. We show that the cooperation between C/EBPbeta and PU.1 is critical for the transcriptional activation of the MD-2 gene by IL-6. PU.1 was essentially known as a TF involved in the differentiation of myeloid precursor cells and the expression of surface receptors of the innate immunity. Herein, we show that it also participates in the regulation of an acute phase protein, MD-2, in nonmyeloid cells cooperatively with C/EBPbeta, a classical IL-6-inducible TF.
Keywords Alternative SplicingBase SequenceBinding Sites/geneticsBlotting, WesternCCAAT-Enhancer-Binding Protein-beta/genetics/metabolismCell LineCell Line, TumorChromatin ImmunoprecipitationGene Expression RegulationHL-60 CellsHepatocytes/drug effects/metabolism/pathologyHumansInterleukin-6/pharmacologyLuciferases/genetics/metabolismLymphocyte Antigen 96/genetics/metabolismMolecular Sequence DataMonocytes/cytology/drug effects/metabolismMutationMyeloid Cells/drug effects/metabolism/pathologyPromoter Regions, Genetic/geneticsProtein Binding/drug effectsProto-Oncogene Proteins/genetics/metabolismRNA InterferenceReverse Transcriptase Polymerase Chain ReactionTrans-Activators/genetics/metabolismTransfection
PMID: 19632992
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Other version: http://www.jbc.org/content/284/39/26261.full
Research groups Groupe Pugin Jérôme (Soins intensifs) (587)
Régulation traductionnelle dans les cellules de mammifère (631)
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TISSIÈRES, Pierre et al. Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene. In: The Journal of biological chemistry, 2009, vol. 284, n° 39, p. 26261-72. doi: 10.1074/jbc.M109.042580 https://archive-ouverte.unige.ch/unige:5271

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Deposited on : 2010-02-25

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