Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Outros Autores: | , , , |
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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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 |
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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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1799130574788493312 |