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Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis
Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056434/ https://www.ncbi.nlm.nih.gov/pubmed/27687249 http://dx.doi.org/10.1038/ncomms12428 |
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author | Vogel, Robert M. Erez, Amir Altan-Bonnet, Grégoire |
author_facet | Vogel, Robert M. Erez, Amir Altan-Bonnet, Grégoire |
author_sort | Vogel, Robert M. |
collection | PubMed |
description | Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the digital/analogue dichotomy of cellular response as revealed on short (signal transduction) timescales, translates into similar dichotomy on longer (proliferation) timescales. Our single-cell analysis of drug action illustrates the strength of quantitative approaches to translate in vitro pharmacology into functionally relevant cellular settings. |
format | Online Article Text |
id | pubmed-5056434 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50564342016-10-24 Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis Vogel, Robert M. Erez, Amir Altan-Bonnet, Grégoire Nat Commun Article Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the digital/analogue dichotomy of cellular response as revealed on short (signal transduction) timescales, translates into similar dichotomy on longer (proliferation) timescales. Our single-cell analysis of drug action illustrates the strength of quantitative approaches to translate in vitro pharmacology into functionally relevant cellular settings. Nature Publishing Group 2016-09-30 /pmc/articles/PMC5056434/ /pubmed/27687249 http://dx.doi.org/10.1038/ncomms12428 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Vogel, Robert M. Erez, Amir Altan-Bonnet, Grégoire Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title | Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title_full | Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title_fullStr | Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title_full_unstemmed | Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title_short | Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
title_sort | dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056434/ https://www.ncbi.nlm.nih.gov/pubmed/27687249 http://dx.doi.org/10.1038/ncomms12428 |
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