scholarly journals Anatomy of a negative feedback loop: the case of I κ B α

2015 ◽  
Vol 12 (110) ◽  
pp. 20150262 ◽  
Author(s):  
Riku Fagerlund ◽  
Marcelo Behar ◽  
Karen T. Fortmann ◽  
Y. Eason Lin ◽  
Jesse D. Vargas ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Nuclear Import ◽  
Nuclear Export ◽  
Feedback Loop ◽  
Signalling Pathway ◽  
Imaging Studies ◽  
Negative Feedback Loops ◽  
Emergent Systems ◽  
Negative Feedback Control ◽  
Feedback Regulator

The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an ‘activator-induced inhibitor’ regulatory motif. Within the NF κ B signalling pathway, a key negative feedback regulator is I κ B α . We show here that, contrary to current understanding, NF κ B-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NF κ B signalling to identify I κ B α molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of I κ B α and the I κ B α –NF κ B complex, as well as the free I κ B α half-life, as key determinants of post-induction repression of NF κ B and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required ‘activator-induced inhibitor’ relationship.

scholarly journals miR-146a controls the resolution of T cell responses in mice

2012 ◽  
Vol 209 (9) ◽  
pp. 1655-1670 ◽  
Author(s):  
Lili Yang ◽  
Mark P. Boldin ◽  
Yang Yu ◽  
Claret Siyuan Liu ◽  
Chee-Kwee Ea ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Inflammatory Diseases ◽  
T Cell Responses ◽  
Cell Receptor ◽  
Immune Protection ◽  
Tcr Signaling ◽  
Cell Responses ◽  
Negative Feedback Control

T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell–mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.

scholarly journals Stability and Hopf Bifurcation Analysis in a Delayed Myc/E2F/miR-17-92 Network Involving Interlinked Positive and Negative Feedback Loops

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Guiyuan Wang ◽  
Zhuoqin Yang
Keyword(s):  
Hopf Bifurcation ◽  
Time Delay ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Sufficient Conditions ◽  
Center Manifold Theorem ◽  
Negative Feedback Loops ◽  
Feedback Strength ◽  
Normal Form Method ◽  
Delay Differential

MiR-17-92 plays an important role in regulating the levels of the Myc/E2F protein. In this paper, we consider a coupling network between Myc/E2F/miR-17-92 delayed negative feedback loop and Myc/E2F positive feedback loop described by a two-dimensional delay differential equation. Based on linear stability analysis and bifurcation theory, sufficient conditions for stability of equilibria and oscillatory behaviors via Hopf bifurcation are derived when choosing time delay as well as negative feedback strength associated with oscillations as bifurcation parameters, respectively. Furthermore, direction and stability of Hopf bifurcation of time delay are studied by using the normal form method and center manifold theorem. Finally, several numerical simulations are performed to verify the results we obtained.

scholarly journals A synthetic gene circuit for measuring autoregulatory feedback control.

2015 ◽  
Author(s):  
Miquel Angel Schikora-Tamarit ◽  
Carlos Toscano-Ochoa ◽  
Julia Domingo Espinos ◽  
Lorena Espinar ◽  
Lucas Carey
Keyword(s):  
High Throughput ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Feedback Regulation ◽  
Feedback Loops ◽  
Expression Noise ◽  
Negative Feedback Loops

Auto regulatory feedback loops occur in the regulation of molecules ranging from ATP to MAP kinases to zinc. Negative feedback loops can increase a system′s robustness, while positive feedback loops can mediate transitions between cell states. Recent genome-wide experimental and computational studies predict hundreds of novel feedback loops. However, not all physical interactions are regulatory, and many experimental methods cannot detect self-interactions. Our understanding of regulatory feedback loops is therefore hampered by the lack of high-throughput methods to experimentally quantify the presence, strength, and temporal dynamics of auto regulatory feedback loops. Here we present a mathematical and experimental framework for high-throughput quantification of feedback regulation, and apply it to RNA binding proteins (RBPs) in yeast. Our method is able to determine the existence of both direct and indirect positive and negative feedback loops, and to quantify the strength of these loops. We experimentally validate our model using two RBPs which lack native feedback loops, and by the introduction of synthetic feedback loops. We find that the the RBP Puf3 does not natively participate in any direct or indirect feedback regulation, but that replacing the native 3′UTR with that of COX17 generates an auto-regulatory negative feedback loop which reduces gene expression noise. Likewise, the RBP Pub1 does not natively participate in any feedback loops, but a synthetic positive feedback loop involving Pub1 results in increased expression noise. Our results demonstrate a synthetic experimental system for quantifying the existence and strength of feedback loops using a combination of high-throughput experiments and mathematical modeling. This system will be of great use in measuring auto-regulatory feedback by RNA binding proteins, a regulatory motif that is difficult to quantify using existing high-throughput methods.

scholarly journals WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

2017 ◽  
Vol 114 (50) ◽  
pp. E10772-E10781 ◽  
Author(s):  
Rachel E. Bosserman ◽  
Tiffany T. Nguyen ◽  
Kevin G. Sanchez ◽  
Alexandra E. Chirakos ◽  
Micah J. Ferrell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Feedback Control ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Protein Substrates ◽  
Membrane Complex ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Negative Feedback Control ◽  
Membrane Components

ESX (ESAT-6 system) export systems play diverse roles across mycobacterial species. Interestingly, genetic disruption of ESX systems in different species does not result in an accumulation of protein substrates in the mycobacterial cell. However, the mechanisms underlying this observation are elusive. We hypothesized that the levels of ESX substrates were regulated by a feedback-control mechanism, linking the levels of substrates to the secretory status of ESX systems. To test this hypothesis, we used a combination of genetic, transcriptomic, and proteomic approaches to define export-dependent mechanisms regulating the levels of ESX-1 substrates inMycobacterium marinum. WhiB6 is a transcription factor that regulates expression of genes encoding ESX-1 substrates. We found that, in the absence of the genes encoding conserved membrane components of the ESX-1 system, the expression of thewhiB6gene and genes encoding ESX-1 substrates were reduced. Accordingly, the levels of ESX-1 substrates were decreased, and WhiB6 was not detected inM. marinumstrains lacking genes encoding ESX-1 components. We demonstrated that, in the absence of EccCb1, a conserved ESX-1 component, substrate gene expression was restored by constitutive, but not native, expression of thewhiB6gene. Finally, we found that the loss of WhiB6 resulted in a virulentM. marinumstrain with reduced ESX-1 secretion. Together, our findings demonstrate that the levels of ESX-1 substrates inM. marinumare fine-tuned by negative feedback control, linking the expression of thewhiB6gene to the presence, not the functionality, of the ESX-1 membrane complex.

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