scholarly journals Dichotomous Feedback: A Signal Sequestration-based Feedback Mechanism for Biocontroller Design

2021 ◽  
Author(s):  
Aivar Sootla ◽  
Nicolas Delalez ◽  
Emmanouil Alexis ◽  
Arthur Norman ◽  
Harrison Steel ◽  
...  
Keyword(s):  
Response Regulator ◽  
Feedback Regulation ◽  
Intrinsic Noise ◽  
Feedback Mechanism ◽  
Control Law ◽  
Regulation Mechanism ◽  
Negative Feedback Regulation ◽  
Process Output ◽  
Natural Response ◽  
Signalling Systems

We introduce a new design framework for implementing negative feedback regulation in Synthetic Biology, which we term "dichotomous feedback". Our approach is different from current methods, in that it sequesters existing fluxes in the process to be controlled, and in this way takes advantage of the process's architecture to design the control law. This signal sequestration mechanism appears in many natural biological systems and can potentially be easier to realise than 'molecular sequestration' and other comparison motifs that are nowadays common in biomolecular feedback control design. The loop is closed by linking the strength of signal sequestration to the process output. Our feedback regulation mechanism is motivated by two-component signalling systems, where we introduce a second response regulator competing with the natural response regulator thus sequestering kinase activity. Here, dichotomous feedback is established by increasing the concentration of the second response regulator as the level of the output of the natural process increases. Extensive analysis demonstrates how this type of feedback shapes the signal response, attenuates intrinsic noise while increasing robustness and reducing crosstalk.

scholarly journals β-catenin/LEF-1 Transcription Complex is Responsible for the Transcriptional Activation of LINC01278

2020 ◽  
Author(s):  
Shaojian Lin ◽  
Weiwei Zhang ◽  
Ziwen Shi ◽  
Langping Tan ◽  
Yue Zhu ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Feedback Regulation ◽  
Luciferase Reporter ◽  
Regulation Mechanism ◽  
Putative Promoter ◽  
Negative Feedback Regulation ◽  
Pathway Activation ◽  
Rna Immunoprecipitation

Abstract Background: Our previous study shows that LINC01278 inhibits the development of papillary thyroid carcinoma (PTC) by regulating miR-376c-3p/DNM3 axis. However, the regulation mechanism of LINC01278 expression in PTC cells is still unclear. Methods: The luciferase reporter and ChIP assays were used to confirme the binding of LEF-1 to the putative promoter site of LINC01278. The RNA immunoprecipitation was used the enrichment of LINC01278 in β-catenin protein. Western blot was used to detected the expression of target proteins. Results: Firstly, the online PROMO algorithm determined a putative LEF-1 binding site on LINC01278 promoter. Then, the luciferase reporter and ChIP assays confirmed the binding of LEF-1 to the putative promoter site of LINC01278. Furthermore, the overexpression of β-catenin increased the binding of LEF-1 to the LINC01278 promoter, and the knockdown or overexpression of LEF-1 or β-catenin can affect the expression level of LINC01278. In addition, RNA immunoprecipitation showed that LINC01278 was enriched in β-catenin protein. RNA pulldown and western blot also confirmed that LINC01278 precipitated β-catenin in TPC-1 and BCPAP cells. Furthermore, the knockdown or overexpression of LINC01278 significantly affected the expression of β-catenin and targets of Wnt/β-catenin signaling pathway (CCND2, CyclinD1, MYC, and SOX4). Conclusion: In summary, we found the transcriptional activation of LINC01278 by the β-catenin/LEF-1 transcription factor, and the negative feedback regulation of LINC01278 on Wnt/β-catenin signaling pathway activation.

Negative feedback regulation of activated macrophages via Fas-mediated apoptosis

2000 ◽  
Vol 279 (2) ◽  
pp. C504-C509 ◽  
Author(s):  
Tadaaki Niinobu ◽  
Keisuke Fukuo ◽  
Osamu Yasuda ◽  
Maki Tsubakimoto ◽  
Masaki Mogi ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Fas Ligand ◽  
Feedback Regulation ◽  
Feedback Mechanism ◽  
Soluble Form ◽  
Critical Event ◽  
Activated Macrophages ◽  
Negative Feedback Regulation ◽  
Macrophage Apoptosis ◽  
Induced Apoptosis

Apoptosis is a critical event for eliminating activated macrophages. Here we show that Fas-mediated apoptosis may participate in the mechanism of negative feedback regulation of activated macrophages. Cytokine-activated macrophages released high levels of nitric oxide (NO) that induced apoptosis in macrophages themselves. This NO-induced macrophage apoptosis was inhibited by a Fas-Fc chimeric molecule that binds to Fas ligand (FasL) and prevents its interaction with endogenous cell surface Fas. High levels of NO stimulated the release of the soluble form of FasL that was inhibited by a matrix metalloproteinase inhibitor KB-8301. High levels of NO also upregulated the expression of Fas mRNA in macrophages. In addition, macrophages isolated from Fas-lacking mice were resistant to NO-induced apoptosis. Finally, inhibition of apoptosis by a caspase inhibitor augmented peroxide production from activated macrophages. These findings suggest that high levels of NO released from activated macrophages may promote the Fas-mediated macrophage apoptosis that may be a negative feedback mechanism for elimination and the downregulation of activated macrophages in the vessel wall.

scholarly journals Limitation of immune tolerance–inducing thymic epithelial cell development by Spi-B–mediated negative feedback regulation

2014 ◽  
Vol 211 (12) ◽  
pp. 2425-2438 ◽  
Author(s):  
Nobuko Akiyama ◽  
Miho Shinzawa ◽  
Maki Miyauchi ◽  
Hiromi Yanai ◽  
Ryosuke Tateishi ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Feedback Regulation ◽  
Feedback Mechanism ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Cytokine Signaling ◽  
Negative Feedback Regulation

Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B–mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage–specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL–Spi-B–OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.

scholarly journals β-Catenin/LEF-1 transcription complex is responsible for the transcriptional activation of LINC01278

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shaojian Lin ◽  
Weiwei Zhang ◽  
Ziwen Shi ◽  
Langping Tan ◽  
Yue Zhu ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Feedback Regulation ◽  
Luciferase Reporter ◽  
Protein Accumulation ◽  
Regulation Mechanism ◽  
Putative Promoter ◽  
Negative Feedback Regulation ◽  
Proteasome Degradation ◽  
Rna Immunoprecipitation

Abstract Background Our previous study shows that LINC01278 inhibits the malignant proliferation and invasion of papillary thyroid carcinoma (PTC) cells by regulating the miR-376c-3p/DNM3 axis. However, the regulation mechanism of LINC01278 expression in PTC cells is still unclear. Methods The luciferase reporter and ChIP assays were used to confirm the binding of LEF-1 to the putative promoter site of LINC01278 gene. The RNA immunoprecipitation and RNA pulldown were used to determine the enrichment of LINC01278 in β-catenin protein. The proteasome inhibitors (MG132) was used for detecting the β-catenin ubiquitination-proteasome degradation. Wnt/β-catenin specific agonists (LiCI), inhibitors (WiKI4) and TOP/FOP-flash reporter assay were used for detecting the activation of Wnt/β-catenin signal. Western blot was used to detected the expression of target proteins. Results The online PROMO algorithm determines a putative LEF-1 binding site on LINC01278 promoter, the LEF-1 binds to the putative promoter site of LINC01278 gene, and β-catenin enhances the binding of LEF-1 to the LINC01278 gene promoter. Furthermore, LINC01278 negatively regulated the protein accumulation of β-catenin in the cytoplasm, into nucleus, and ultimately inhibited the transcription of downstream target genes activated by Wnt/β-catenin signal. The results of RNA immunoprecipitation and RNA pulldown proved the direct binding of LINC01278 to β-catenin protein. In addition, the combination of LINC01278 and β-catenin promotes the β-catenin ubiquitination-proteasome degradation. Conclusion In summary, we found the transcriptional activation of LINC01278 by the β-catenin/LEF-1 transcription factor, and the negative feedback regulation of LINC01278 onβ-catenin signal.

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