scholarly journals Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8‐Tetrachlorodibenzo‐p‐Dioxin in the Mouse Liver

2021 ◽  
Author(s):  
Yongliang Yang ◽  
David Filipovic ◽  
Sudin Bhattacharya
Keyword(s):  
Transcription Factor ◽  
Negative Feedback ◽  
Mouse Liver ◽  
Feedback Loop ◽  
Gene Induction ◽  
Negative Feedback Loop ◽  
Tetrachlorodibenzo P Dioxin ◽  
Transcription Factor Cooperation

scholarly journals The ZEB1 Transcription Factor Acts in a Negative Feedback Loop with miR200 Downstream of Ras and Rb1 to Regulate Bmi1 Expression

2013 ◽  
Vol 289 (7) ◽  
pp. 4116-4125 ◽  
Author(s):  
Yongqing Liu ◽  
Ester Sánchez-Tilló ◽  
Xiaoqin Lu ◽  
Li Huang ◽  
Brian Clem ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Bmi1 Expression

scholarly journals Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-κB Pathway, Inhibiting Hallmark NF-κB-Induced Proinflammatory Gene Expression

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Nicolás Romero ◽  
Cliff Van Waesberghe ◽  
Herman W. Favoreel
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Pseudorabies Virus ◽  
Negative Feedback Loop ◽  
Tnf Α ◽  
Proinflammatory Gene ◽  
Proinflammatory Gene Expression

ABSTRACT The nuclear factor kappa B (NF-κB) is a potent transcription factor, activation of which typically results in robust proinflammatory signaling and triggering of fast negative feedback modulators to avoid excessive inflammatory responses. Here, we report that infection of epithelial cells, including primary porcine respiratory epithelial cells, with the porcine alphaherpesvirus pseudorabies virus (PRV) results in the gradual and persistent activation of NF-κB, illustrated by proteasome-dependent degradation of the inhibitory NF-κB regulator IκB and nuclear translocation and phosphorylation of the NF-κB subunit p65. PRV-induced persistent activation of NF-κB does not result in expression of negative feedback loop genes, like the gene for IκBα or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-α-induced canonical NF-κB activation. Hence, PRV infection triggers persistent NF-κB activation in an unorthodox way and dramatically modulates the NF-κB signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-κB signaling, which may aid the virus in modulating early proinflammatory responses in the infected host. IMPORTANCE The NF-κB transcription factor is activated via different key inflammatory pathways and typically results in the fast expression of several proinflammatory genes as well as negative feedback loop genes to prevent excessive inflammation. In the current report, we describe that infection of cells with the porcine alphaherpesvirus pseudorabies virus (PRV) triggers a gradual and persistent aberrant activation of NF-κB, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-κB activation shares some mechanistic features with canonical NF-κB activation, it also shows remarkable differences; e.g., it is largely independent of the canonical IκB kinase (IKK) and even renders infected cells resistant to canonical NF-κB activation by the inflammatory cytokine TNF-α. Aberrant PRV-induced NF-κB activation may therefore paradoxically serve as a viral immune evasion strategy and may represent an important tool to unravel currently unknown mechanisms and consequences of NF-κB activation.

scholarly journals Mathematical Analysis of Robustness of Oscillations in Models of the Mammalian Circadian Clock

2020 ◽  
Author(s):  
Benjamin Heidebrecht ◽  
Jing Chen ◽  
John J. Tyson
Keyword(s):  
Transcription Factor ◽  
Protein Binding ◽  
Mathematical Models ◽  
Circadian Clock ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Positive Feedback Loop ◽  
Clock Mechanism

ABSTRACTA wide variety of organisms possess endogenous circadian rhythms (~24 h period), which coordinate many physiological functions with the day-night cycle. These rhythms are mediated by a molecular mechanism based on transcription-translation feedback. A number of mathematical models have been developed to study features of the circadian clock in a variety of organisms. In this paper, we use bifurcation theory to explore properties of mathematical models based on Kim & Forger’s interpretation of the circadian clock in mammals. Their models are based on a simple negative feedback (SNF) loop between a regulatory protein (PER) and its transcriptional activator (BMAL). In their model, PER binds to BMAL to form a stoichiometric complex (PER:BMAL) that is inactive as a transcription factor. However, for oscillations to occur in the SNF model, the dissociation constant of the PER:BMAL complex, Kd, must be smaller than 10−3 nM, orders of magnitude below the limit set by the biophysics of protein binding. We have relaxed this constraint by introducing two modifications to Kim & Forger’s SNF model: (1) replacing the first-order rate law for degradation of PER in the nucleus by a Michaelis-Menten rate law, and (2) introducing a multistep reaction chain for posttranslational modifications of PER. These modifications significantly increase the robustness of oscillations, and increase the maximum allowable Kd to more reasonable values, 1—100 nM. In a third modification, we considered alternative rate laws for gene transcription to resolve an unrealistically large rate of PER transcription at very low levels of BMAL transcription factor. Additionally, we studied Kim & Forger’s extensions of the SNF model to include a second negative feedback loop (involving REV-ERB) and a supplementary positive feedback loop (involving ROR). We found that the supplementary positive feedback loop—but not the supplementary negative feedback loop— provides additional robustness to the clock model.AUTHOR SUMMARYThe circadian rhythm aligns bodily functions to the day/night cycle and is important for our health. The rhythm originates from an intracellular, molecular clock mechanism that mediates rhythmic gene expression. It is long understood that transcriptional negative feedback with sufficient time delay is key to generating circadian oscillations. However, some of the most widely cited mathematical models for the circadian clock suffer from problems of parameter “fragilities”. That is, sustained oscillations are possible only for physically unrealistic parameter values. A recent model by Kim and Forger nicely incorporates the inhibitory binding of PER, a key clock protein, to its transcription activator BMAL, but oscillations in their model require a binding affinity between PER and BMAL that is orders of magnitude lower than the physical limit of protein-protein binding. To rectify this problem, we make several physiologically credible modifications to the Kim-Forger model, which allow oscillations to occur with realistic binding affinity. The modified model is further extended to explore the potential roles of supplementary feedback loops in the mammalian clock mechanism. Ultimately, accurate models of the circadian clock will provide predictive tools for chronotherapy and chrono-pharmacology studies.

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