Elevated transforming growth factor β signaling activation in β-actin-knockout mouse embryonic fibroblasts enhances myofibroblast features

Research output: Contribution to journalArticle

Abstract

Signaling by the transforming growth factor-β (TGF-β) is an essential pathway regulating a variety of cellular events. TGF-β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF-β activation. Using β-actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell-surface biophysical features are dramatically altered, we reveal increased TGF-β1 activation and the upregulation of TGF-β target genes. In β-actin null cells, we show evidence that the enhanced TGF-β signaling relies on the active utilization of latent TGF-β1 in the cell culture medium. TGF-β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β-actin null cells is inhibited by TGF-β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF-β activation, which in turn contributes to the enhanced myofibroblast phenotype.

Original languageEnglish (US)
JournalJournal of Cellular Physiology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Myofibroblasts
Transforming Growth Factors
Fibroblasts
Knockout Mice
Actins
Chemical activation
Actin Cytoskeleton
Null Lymphocytes
Phenotype
Up-Regulation
Genes
Cell signaling
Cell culture
Culture Media
Reactive Oxygen Species
Cell Culture Techniques

Keywords

  • Mouse embryonic fibroblast (MEF)
  • Myofibroblast
  • NADPH oxidase 4 (Nox4)
  • Reactive oxygen species (ROS)
  • TGF-β
  • β-actin

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

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title = "Elevated transforming growth factor β signaling activation in β-actin-knockout mouse embryonic fibroblasts enhances myofibroblast features",
abstract = "Signaling by the transforming growth factor-β (TGF-β) is an essential pathway regulating a variety of cellular events. TGF-β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF-β activation. Using β-actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell-surface biophysical features are dramatically altered, we reveal increased TGF-β1 activation and the upregulation of TGF-β target genes. In β-actin null cells, we show evidence that the enhanced TGF-β signaling relies on the active utilization of latent TGF-β1 in the cell culture medium. TGF-β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β-actin null cells is inhibited by TGF-β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF-β activation, which in turn contributes to the enhanced myofibroblast phenotype.",
keywords = "Mouse embryonic fibroblast (MEF), Myofibroblast, NADPH oxidase 4 (Nox4), Reactive oxygen species (ROS), TGF-β, β-actin",
author = "Xin Xie and Piergiorgio Percipalle",
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journal = "Journal of Cellular Physiology",
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AU - Xie, Xin

AU - Percipalle, Piergiorgio

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N2 - Signaling by the transforming growth factor-β (TGF-β) is an essential pathway regulating a variety of cellular events. TGF-β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF-β activation. Using β-actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell-surface biophysical features are dramatically altered, we reveal increased TGF-β1 activation and the upregulation of TGF-β target genes. In β-actin null cells, we show evidence that the enhanced TGF-β signaling relies on the active utilization of latent TGF-β1 in the cell culture medium. TGF-β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β-actin null cells is inhibited by TGF-β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF-β activation, which in turn contributes to the enhanced myofibroblast phenotype.

AB - Signaling by the transforming growth factor-β (TGF-β) is an essential pathway regulating a variety of cellular events. TGF-β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF-β activation. Using β-actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell-surface biophysical features are dramatically altered, we reveal increased TGF-β1 activation and the upregulation of TGF-β target genes. In β-actin null cells, we show evidence that the enhanced TGF-β signaling relies on the active utilization of latent TGF-β1 in the cell culture medium. TGF-β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β-actin null cells is inhibited by TGF-β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF-β activation, which in turn contributes to the enhanced myofibroblast phenotype.

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KW - Myofibroblast

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KW - β-actin

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