title: Decreased expression of glutaredoxin 1 is required for transforming growth factor-beta1-mediated epithelial-mesenchymal transition of EpRas mammary epithelial cells.
abstract: Transforming growth factor-beta (TGF-beta) is a cytokine important in inducing epithelial-mesenchymal transition (EMT), a crucial morphological event in a wide range of physiological and pathological cellular processes. In this study, we demonstrate that TGF-beta1 induces the EMT phenotype through decreasing the expression of the glutaredoxin 1 (Grx1) gene, an anti-oxidant enzyme, in H-Ras transformed EpH4 mammary epithelial cells (EpRas), but not in the parental EpH4 cells. TGF-beta1-induced reduction of Grx1 expression caused an increase of intracellular reactive oxygen species (ROS) in EpRas cells, and pre-treatment of the ROS scavenger N-acetylcysteine (NAC) inhibited TGF-beta1-induced EMT. Grx1-overexpressing EpRas cells showed a reduction in intracellular ROS generation and suppressed the expression of mesenchymal markers upon treatment of TGF-beta1. In addition, MEK/MAP kinase and phosphatidylinositol-3 kinase (PI3K) signaling were found to mediate the decrease in Grx1 expression upon TGF-beta1 treatment, depending on the presence of Ras protein. Thus our findings strongly suggest that TGF-beta1 promotes EMT by increasing intracellular ROS levels via down-regulation of the Grx1 gene in EpRas cells.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Woo-Kwang
authors.initials: WK
authors.lastname: Jeon
authors.forename: Min Young
authors.initials: MY
authors.lastname: Chae
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Hong
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Lee
authors.forename: Jun Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Kwon
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D054477:Glutaredoxins / Q000096:biosynthesis* / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases