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

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• 作者：Lan K. Nguyen ; Miguel A. S. Cavadas…
• 关键词：NFκB signaling ; COX2 ; Switch ; like gene regulation ; Logic AND gate ; Kinetic modeling
• 刊名：Cellular and Molecular Life Sciences (CMLS)
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：72
• 期：12
• 页码：2431-2443
• 全文大小：1,343 KB
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  24.Shimizu H, Mitomo K, Watanabe
• 作者单位：Lan K. Nguyen (1)
  Miguel A. S. Cavadas (1) (2)
  Boris N. Kholodenko (1)
  Till D. Frank (3)
  Alex Cheong (1) (4)
  
  1. Systems Biology Ireland, University College Dublin, Dublin 4, Ireland
  2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
  3. Center for the Ecological Study of Perception and Action, University of Connecticut, Storrs, CT, 06269, USA
  4. School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Biomedicine
  Life Sciences
  Biochemistry
  
• 出版者：Birkh盲user Basel
• ISSN：1420-9071

文摘

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.