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Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction

Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of hetero...

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Autores principales: Chen, Jia-Yun, Hug, Clemens, Reyes, José, Tian, Chengzhe, Gerosa, Luca, Fröhlich, Fabian, Ponsioen, Bas, Snippert, Hugo J.G., Spencer, Sabrina L., Jambhekar, Ashwini, Sorger, Peter K., Lahav, Galit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153468/
https://www.ncbi.nlm.nih.gov/pubmed/36920903
http://dx.doi.org/10.1016/j.celrep.2023.112252
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author Chen, Jia-Yun
Hug, Clemens
Reyes, José
Tian, Chengzhe
Gerosa, Luca
Fröhlich, Fabian
Ponsioen, Bas
Snippert, Hugo J.G.
Spencer, Sabrina L.
Jambhekar, Ashwini
Sorger, Peter K.
Lahav, Galit
author_facet Chen, Jia-Yun
Hug, Clemens
Reyes, José
Tian, Chengzhe
Gerosa, Luca
Fröhlich, Fabian
Ponsioen, Bas
Snippert, Hugo J.G.
Spencer, Sabrina L.
Jambhekar, Ashwini
Sorger, Peter K.
Lahav, Galit
author_sort Chen, Jia-Yun
collection PubMed
description Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAF(V600E) expression. We found that a narrow expression range of BRAF(V600E) generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.
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spelling pubmed-101534682023-05-02 Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction Chen, Jia-Yun Hug, Clemens Reyes, José Tian, Chengzhe Gerosa, Luca Fröhlich, Fabian Ponsioen, Bas Snippert, Hugo J.G. Spencer, Sabrina L. Jambhekar, Ashwini Sorger, Peter K. Lahav, Galit Cell Rep Article Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAF(V600E) expression. We found that a narrow expression range of BRAF(V600E) generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction. 2023-03-28 2023-03-14 /pmc/articles/PMC10153468/ /pubmed/36920903 http://dx.doi.org/10.1016/j.celrep.2023.112252 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Chen, Jia-Yun
Hug, Clemens
Reyes, José
Tian, Chengzhe
Gerosa, Luca
Fröhlich, Fabian
Ponsioen, Bas
Snippert, Hugo J.G.
Spencer, Sabrina L.
Jambhekar, Ashwini
Sorger, Peter K.
Lahav, Galit
Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title_full Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title_fullStr Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title_full_unstemmed Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title_short Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
title_sort multi-range erk responses shape the proliferative trajectory of single cells following oncogene induction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153468/
https://www.ncbi.nlm.nih.gov/pubmed/36920903
http://dx.doi.org/10.1016/j.celrep.2023.112252
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