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Nguyen2016 - Feedback regulation in cell signalling: Lessons for cancer therapeutics

ABSTRACT: Feedback regulation in cell signalling: Lessons for cancer therapeutics This model is described in the article: Feedback regulation in cell signalling: Lessons for cancer therapeutics. Nguyen LK, Kholodenko BN. Semin. Cell Dev. Biol. 2016 Feb; 50: 85-94 Abstract: The notion of feedback is fundamental for understanding signal transduction networks. Feedback loops attenuate or amplify signals, change the network dynamics and modify the input-output relationships between the signal and the target. Negative feedback provides robustness to noise and adaptation to perturbations, but as a double-edged sword can prevent effective pathway inhibition by a drug. Positive feedback brings about switch-like network responses and can convert analog input signals into digital outputs, triggering cell fate decisions and phenotypic changes. We show how a multitude of protein-protein interactions creates hidden feedback loops in signal transduction cascades. Drug treatments that interfere with feedback regulation can cause unexpected adverse effects. Combinatorial molecular interactions generated by pathway crosstalk and feedback loops often bypass the block caused by targeted therapies against oncogenic mutated kinases. We discuss mechanisms of drug resistance caused by network adaptations and suggest that development of effective drug combinations requires understanding of how feedback loops modulate drug responses. This model is hosted on BioModels Database and identified by: MODEL1708250003. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Emma Fairbanks

PROVIDER: BIOMD0000000651 | BioModels | 2019-03-21

REPOSITORIES: BioModels

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Feedback regulation in cell signalling: Lessons for cancer therapeutics.

Nguyen Lan K LK Kholodenko Boris N BN

Seminars in cell & developmental biology 20151019

The notion of feedback is fundamental for understanding signal transduction networks. Feedback loops attenuate or amplify signals, change the network dynamics and modify the input-output relationships between the signal and the target. Negative feedback provides robustness to noise and adaptation to perturbations, but as a double-edged sword can prevent effective pathway inhibition by a drug. Positive feedback brings about switch-like network responses and can convert analog input signals into d ...[more]

PMID: 26481970

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Project description:This model is from the article: Mathematical modeling elucidates the role of transcriptional feedback in gibberellin signaling. Middleton AM , Úbeda-Tomás S , Griffiths J , Holman T , Hedden P , Thomas SG , Phillips AL , Holdsworth MJ , Bennett MJ , King JR, Owen MR Proc. Natl. Acad. Sci. U.S.A. 2012 May; 109(19): 7571-6 22523240 , Abstract: The hormone gibberellin (GA) is a key regulator of plant growth. Many of the components of the gibberellin signal transduction [e.g., GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and DELLA], biosynthesis [e.g., GA 20-oxidase (GA20ox) and GA3ox], and deactivation pathways have been identified. Gibberellin binds its receptor, GID1, to form a complex that mediates the degradation of DELLA proteins. In this way, gibberellin relieves DELLA-dependent growth repression. However, gibberellin regulates expression of GID1, GA20ox, and GA3ox, and there is also evidence that it regulates DELLA expression. In this paper, we use integrated mathematical modeling and experiments to understand how these feedback loops interact to control gibberellin signaling. Model simulations are in good agreement with in vitro data on the signal transduction and biosynthesis pathways and in vivo data on the expression levels of gibberellin-responsive genes. We find that GA-GID1 interactions are characterized by two timescales (because of a lid on GID1 that can open and close slowly relative to GA-GID1 binding and dissociation). Furthermore, the model accurately predicts the response to exogenous gibberellin after a number of chemical and genetic perturbations. Finally, we investigate the role of the various feedback loops in gibberellin signaling. We find that regulation of GA20ox transcription plays a significant role in both modulating the level of endogenous gibberellin and generating overshoots after the removal of exogenous gibberellin. Moreover, although the contribution of other individual feedback loops seems relatively small, GID1 and DELLA transcriptional regulation acts synergistically with GA20ox feedback.

Dataset Information

Nguyen2016 - Feedback regulation in cell signalling: Lessons for cancer therapeutics

Publications

Feedback regulation in cell signalling: Lessons for cancer therapeutics.

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