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Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate

2015-02-20Journal article Open access
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dc.contributor.authorNguyen, Lan K
dc.contributor.authorCavadas, Miguel A S
dc.contributor.authorKholodenko, Boris N
dc.contributor.authorFrank, Till D
dc.contributor.authorCheong, Alex
dc.date.accessioned2017-05-10T14:50:59Z
dc.date.available2017-05-10T14:50:59Z
dc.date.issued2015-02-20
dc.descriptionThere are no funders and sponsors indicated explicitly in the document. The upload is composed by two files: the main article and supplementary materials (both in pdf format).pt_PT
dc.description.abstractCyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFκB)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFα). Here, we report the presence of a molecular logic AND gate composed of two NFκB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFκB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFα, such that a threshold level of NFκB activation is required before the promoter becomes active and initiates transcription. This NFκB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFα. Our data suggest that the NFκB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFα, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation.pt_PT
dc.description.sponsorshipThere are no funders and sponsors indicated explicitly in the document.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNguyen, L.K., Cavadas, M.A.S., Kholodenko, B.N. et al. Cell. Mol. Life Sci. (2015) 72: 2431. doi:10.1007/s00018-015-1850-1pt_PT
dc.identifier.doi10.1007/s00018-015-1850-1pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.7/754
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Verlagpt_PT
dc.relationThere are no funders and sponsors indicated explicitly in the document.pt_PT
dc.relation.publisherversionhttp://link.springer.com/article/10.1007%2Fs00018-015-1850-1pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAnimalspt_PT
dc.subjectBlotting, Westernpt_PT
dc.subjectCells, Culturedpt_PT
dc.subjectChromatin Immunoprecipitationpt_PT
dc.subjectCyclooxygenase 2pt_PT
dc.subjectEmbryo, Mammalianpt_PT
dc.subjectFibroblastspt_PT
dc.subjectHEK293 Cellspt_PT
dc.subjectHT29 Cellspt_PT
dc.subjectHumanspt_PT
dc.subjectMicept_PT
dc.subjectNF-kappa Bpt_PT
dc.subjectPromoter Regions, Geneticpt_PT
dc.subjectResponse Elementspt_PT
dc.subjectSignal Transductionpt_PT
dc.subjectTumor Necrosis Factor-alphapt_PT
dc.subjectGene Expression Regulationpt_PT
dc.subjectModels, Theoreticalpt_PT
dc.titleSpecies differential regulation of COX2 can be described by an NFκB-dependent logic AND gatept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage2443pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage2431pt_PT
oaire.citation.titleCellular and Molecular Life Sciencespt_PT
oaire.citation.volume72pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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