RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation.

Autor: Chippalkatti R; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg., Parisi B; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg., Kouzi F; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg., Laurini C; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg., Ben Fredj N; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg., Abankwa DK; Cancer Cell Biology and Drug Discovery group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg. Electronic address: daniel.abankwa@uni.lu.
Jazyk: angličtina
Zdroj: European journal of cell biology [Eur J Cell Biol] 2024 Jun; Vol. 103 (2), pp. 151425. Date of Electronic Publication: 2024 May 22.
DOI: 10.1016/j.ejcb.2024.151425
Abstrakt: The RAS-MAPK-pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While typically the impact of Ras on the proliferation of various cancer cell lines is assessed, it is poorly established how Ras affects cellular differentiation. Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that a minor pool of Pax7+ progenitors replenishes a major pool of transit amplifying cells that are ready to differentiate. Our data indicate that Ras isoforms have distinct roles in the differentiating culture, where K-Ras depletion increases and H-Ras depletion decreases terminal differentiation. This assay could therefore provide significant new insights into Ras biology and Ras-driven diseases. In line with this, we found that all oncogenic Ras mutants block terminal differentiation of transit amplifying cells. By contrast, RASopathy associated K-Ras variants were less able to block differentiation. Profiling of eight targeted Ras-pathway drugs on seven oncogenic Ras mutants revealed their allele-specific activities and distinct abilities to restore normal differentiation as compared to triggering cell death. In particular, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTOR-inhibitor rapamycin broadly suppressed differentiation. We expect that this quantitative assessment of the impact of Ras-pathway mutants and drugs on cellular differentiation has great potential to complement cancer cell proliferation data.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze: MEDLINE
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