Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/754
Título: Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate
Autor: Nguyen, Lan K
Cavadas, Miguel A S
Kholodenko, Boris N
Frank, Till D
Cheong, Alex
Palavras-chave: Animals
Blotting, Western
Cells, Cultured
Chromatin Immunoprecipitation
Cyclooxygenase 2
Embryo, Mammalian
HEK293 Cells
HT29 Cells
NF-kappa B
Promoter Regions, Genetic
Response Elements
Signal Transduction
Tumor Necrosis Factor-alpha
Gene Expression Regulation
Models, Theoretical
Data: 20-Fev-2015
Editora: Springer Verlag
Citação: 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
Resumo: 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.
Descrição: 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).
Peer review: yes
URI: http://hdl.handle.net/10400.7/754
DOI: 10.1007/s00018-015-1850-1
Versão do Editor: http://link.springer.com/article/10.1007%2Fs00018-015-1850-1
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Cell.Mol.Life.Sci.(2015)_72-2431.2443_SM.pdfsupplementary material2,37 MBAdobe PDFVer/Abrir
Cell.Mol.Life.Sci.(2015)_72-2431.2443.pdfmain article1,34 MBAdobe PDFVer/Abrir

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