Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction Journal Article
| Authors: | Chen, J. Y.; Hug, C.; Reyes, J.; Tian, C.; Gerosa, L.; Fröhlich, F.; Ponsioen, B.; Snippert, H. J. G.; Spencer, S. L.; Jambhekar, A.; Sorger, P. K.; Lahav, G. |
| Article Title: | Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction |
| Abstract: | 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 BRAFV600E expression. We found that a narrow expression range of BRAFV600E 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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. |
| Keywords: | mitogen activated protein kinase; genetics; mutation; metabolism; cell cycle; cell line, tumor; oncogenes; oncogene; tumor cell line; extracellular signal-regulated map kinases; proliferation; b raf kinase; proto-oncogene proteins b-raf; oncogene-induced senescence; heterogeneity; erk; braf(v600e); humans; human; cp: cancer; non-monotonic |
| Journal Title: | Cell Reports |
| Volume: | 42 |
| Issue: | 3 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2023-03-28 |
| Start Page: | 112252 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2023.112252 |
| PUBMED: | 36920903 |
| PROVIDER: | scopus |
| PMCID: | PMC10153468 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2023 -- Source: Scopus |
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