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

Detalhes bibliográficos
Autor(a) principal: Nguyen, Lan K
Data de Publicação: 2015
Outros Autores: Cavadas, Miguel A S, Kholodenko, Boris N, Frank, Till D, Cheong, Alex
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.7/754
Resumo: There 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).
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spelling Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gateAnimalsBlotting, WesternCells, CulturedChromatin ImmunoprecipitationCyclooxygenase 2Embryo, MammalianFibroblastsHEK293 CellsHT29 CellsHumansMiceNF-kappa BPromoter Regions, GeneticResponse ElementsSignal TransductionTumor Necrosis Factor-alphaGene Expression RegulationModels, TheoreticalThere 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).Cyclooxygenase 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.There are no funders and sponsors indicated explicitly in the document.Springer VerlagARCANguyen, Lan KCavadas, Miguel A SKholodenko, Boris NFrank, Till DCheong, Alex2017-05-10T14:50:59Z2015-02-202015-02-20T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/10400.7/754engNguyen, L.K., Cavadas, M.A.S., Kholodenko, B.N. et al. Cell. Mol. Life Sci. (2015) 72: 2431. doi:10.1007/s00018-015-1850-110.1007/s00018-015-1850-1info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-11-29T14:35:09Zoai:arca.igc.gulbenkian.pt:10400.7/754Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:11:58.874601Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
title Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
spellingShingle Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
Nguyen, Lan K
Animals
Blotting, Western
Cells, Cultured
Chromatin Immunoprecipitation
Cyclooxygenase 2
Embryo, Mammalian
Fibroblasts
HEK293 Cells
HT29 Cells
Humans
Mice
NF-kappa B
Promoter Regions, Genetic
Response Elements
Signal Transduction
Tumor Necrosis Factor-alpha
Gene Expression Regulation
Models, Theoretical
title_short Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
title_full Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
title_fullStr Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
title_full_unstemmed Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
title_sort Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
author Nguyen, Lan K
author_facet Nguyen, Lan K
Cavadas, Miguel A S
Kholodenko, Boris N
Frank, Till D
Cheong, Alex
author_role author
author2 Cavadas, Miguel A S
Kholodenko, Boris N
Frank, Till D
Cheong, Alex
author2_role author
author
author
author
dc.contributor.none.fl_str_mv ARCA
dc.contributor.author.fl_str_mv Nguyen, Lan K
Cavadas, Miguel A S
Kholodenko, Boris N
Frank, Till D
Cheong, Alex
dc.subject.por.fl_str_mv Animals
Blotting, Western
Cells, Cultured
Chromatin Immunoprecipitation
Cyclooxygenase 2
Embryo, Mammalian
Fibroblasts
HEK293 Cells
HT29 Cells
Humans
Mice
NF-kappa B
Promoter Regions, Genetic
Response Elements
Signal Transduction
Tumor Necrosis Factor-alpha
Gene Expression Regulation
Models, Theoretical
topic Animals
Blotting, Western
Cells, Cultured
Chromatin Immunoprecipitation
Cyclooxygenase 2
Embryo, Mammalian
Fibroblasts
HEK293 Cells
HT29 Cells
Humans
Mice
NF-kappa B
Promoter Regions, Genetic
Response Elements
Signal Transduction
Tumor Necrosis Factor-alpha
Gene Expression Regulation
Models, Theoretical
description There 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).
publishDate 2015
dc.date.none.fl_str_mv 2015-02-20
2015-02-20T00:00:00Z
2017-05-10T14:50:59Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.7/754
url http://hdl.handle.net/10400.7/754
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Nguyen, L.K., Cavadas, M.A.S., Kholodenko, B.N. et al. Cell. Mol. Life Sci. (2015) 72: 2431. doi:10.1007/s00018-015-1850-1
10.1007/s00018-015-1850-1
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer Verlag
publisher.none.fl_str_mv Springer Verlag
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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