RRC ID 35797
Author Ishikawa F, Kaneko E, Sugimoto T, Ishijima T, Wakamatsu M, Yuasa A, Sampei R, Mori K, Nose K, Shibanuma M.
Title A mitochondrial thioredoxin-sensitive mechanism regulates TGF-β-mediated gene expression associated with epithelial-mesenchymal transition.
Journal Biochem. Biophys. Res. Commun.
Abstract Transforming growth factor (TGF)-β is a pro-oncogenic cytokine that induces the epithelial-mesenchymal transition (EMT), a crucial event in tumor progression. During TGF-β-mediated EMT in NMuMG mouse mammary epithelial cells, we observed sustained increases in reactive oxygen species (ROS) levels in the cytoplasm and mitochondria with a concomitant decrease in mitochondrial membrane potential and intracellular glutathione levels. In pseudo ρ0 cells, whose respiratory chain function was impaired, the increase in intracellular ROS levels was abrogated, suggesting an important role of mitochondrial activity as a trigger for TGF-β-stimulated ROS generation. In line with this, TGF-β-mediated expression of the EMT marker fibronectin was inhibited not only by chemicals that interfere with ROS signaling but also by exogenously expressed mitochondrial thioredoxin (TXN2) independent of Smad signaling. Of note, TGF-β-mediated induction of HMGA2, a central mediator of EMT and metastatic progression, was similarly impaired by TXN2 expression, revealing a novel mechanism involving a thiol oxidation reaction in mitochondria, which regulates TGF-β-mediated gene expression associated with EMT.
Volume 443(3)
Pages 821-7
Published 2014-1-17
DOI 10.1016/j.bbrc.2013.12.050
PII S0006-291X(13)02109-8
PMID 24342608
MeSH Animals Cell Line Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial-Mesenchymal Transition / drug effects Epithelial-Mesenchymal Transition / genetics* Female Gene Expression Regulation / drug effects* HEK293 Cells HMGA Proteins / metabolism Humans Intracellular Space / drug effects Intracellular Space / metabolism Mammary Glands, Animal / cytology Mice Mitochondria / drug effects Mitochondria / metabolism* Mitochondrial Proteins / metabolism* Oxidation-Reduction / drug effects Reactive Oxygen Species / metabolism Signal Transduction / drug effects Signal Transduction / genetics Thioredoxins / metabolism* Transforming Growth Factor beta / pharmacology*
IF 2.705
Times Cited 23
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).