title: Exogenous induction of unphosphorylated PTEN reduces TGFβ-induced extracellular matrix expressions in lung fibroblasts.
abstract: Transforming growth factor β (TGFβ) plays an important role in regulating aberrant extracellular matrix (ECM) production from alveolar/epithelial cells (AECs) and fibroblasts in pulmonary fibrosis. Although the tumor suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) can negatively control many TGFβ-activated signaling pathways via the phosphatase activity, hyperactivation of the TGFβ-related signaling pathways is often observed in fibrosis. Loss of PTEN expression might cause TGFβ-induced ECM production. In addition, TGFβ was recently shown to induce loss of PTEN enzymatic activity by phosphorylating the PTEN C-terminus. Therefore, we hypothesized that exogenous transfer of unphosphorylated PTEN (PTEN4A) might lead to reduce TGFβ-induced ECM expression in not only epithelial cells but also fibroblasts. Adenovirus-based exogenous PTEN4A induction successfully reduced TGFβ-induced fibronectin expression and retained β-catenin at the cell membrane in human epithelial cells. Exogenous unphosphorylated PTEN also attenuated TGFβ-induced ECM production and inhibited TGFβ-induced β-catenin translocation in a human fibroblast cell line and in mouse primary isolated lung fibroblasts. Conversely, TGFβ-induced α-smooth muscle actin expression did not seem to be inhibited in these fibroblasts. Our data suggest that exogenous administration of unphosphorylated PTEN might be a promising strategy to restore TGFβ-induced loss of PTEN activity and reduce aberrant TGFβ-induced ECM production from epithelial cells and fibroblasts in lung fibrosis as compared with wild-type PTEN induction.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kusunose
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoyama
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ando
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Omote
authors.affiliation: Department of Respiratory Medicine and allergy, Fujita Health University, Toyoake, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.affiliation: Department of Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D002460:Cell Line; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000008:administration & dosage* / Q000378:metabolism; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005353:Fibronectins; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human