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AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition

Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-...

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Autores principales: Fan, Jia-Rong, Chang, Sung-Nian, Chu, Ching-Tung, Chen, Hong-Chen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291577/
https://www.ncbi.nlm.nih.gov/pubmed/37378334
http://dx.doi.org/10.1016/j.isci.2023.106992
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author Fan, Jia-Rong
Chang, Sung-Nian
Chu, Ching-Tung
Chen, Hong-Chen
author_facet Fan, Jia-Rong
Chang, Sung-Nian
Chu, Ching-Tung
Chen, Hong-Chen
author_sort Fan, Jia-Rong
collection PubMed
description Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGFβ to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGFβ stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGFβ. These findings reveal a molecular mechanism for TGFβ-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition.
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spelling pubmed-102915772023-06-27 AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition Fan, Jia-Rong Chang, Sung-Nian Chu, Ching-Tung Chen, Hong-Chen iScience Article Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGFβ to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGFβ stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGFβ. These findings reveal a molecular mechanism for TGFβ-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition. Elsevier 2023-05-29 /pmc/articles/PMC10291577/ /pubmed/37378334 http://dx.doi.org/10.1016/j.isci.2023.106992 Text en © 2023 The Author(s) 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/).
spellingShingle Article
Fan, Jia-Rong
Chang, Sung-Nian
Chu, Ching-Tung
Chen, Hong-Chen
AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title_full AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title_fullStr AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title_full_unstemmed AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title_short AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
title_sort akt2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291577/
https://www.ncbi.nlm.nih.gov/pubmed/37378334
http://dx.doi.org/10.1016/j.isci.2023.106992
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