title: Glycogen Synthase Kinase 3 Inactivation Induces Cell Senescence through Sterol Regulatory Element Binding Protein 1-Mediated Lipogenesis in Chang Cells.
abstract: BACKGROUND
  Enhanced lipogenesis plays a critical role in cell senescence via induction of expression of the mature form of sterol regulatory element binding protein 1 (SREBP1), which contributes to an increase in organellar mass, one of the indicators of senescence. We investigated the molecular mechanisms by which signaling molecules control SREBP1-mediated lipogenesis and senescence.
  
  
  METHODS
  We developed cellular models for stress-induced senescence, by exposing Chang cells, which are immortalized human liver cells, to subcytotoxic concentrations (200 µM) of deferoxamine (DFO) and H2O2.
  
  
  RESULTS
  In this model of stress-induced cell senescence using DFO and H2O2, the phosphorylation profile of glycogen synthase kinase 3α (GSK3α) and β corresponded closely to the expression profile of the mature form of SREBP-1 protein. Inhibition of GSK3 with a subcytotoxic concentration of the selective GSK3 inhibitor SB415286 significantly increased mature SREBP1 expression, as well as lipogenesis and organellar mass. In addition, GSK3 inhibition was sufficient to induce senescence in Chang cells. Suppression of GSK3 expression with siRNAs specific to GSK3α and β also increased mature SREBP1 expression and induced senescence. Finally, blocking lipogenesis with fatty acid synthase inhibitors (cerulenin and C75) and siRNA-mediated silencing of SREBP1 and ATP citrate lyase (ACL) significantly attenuated GSK3 inhibition-induced senescence.
  
  
  CONCLUSIONS
  GSK3 inactivation is an important upstream event that induces SREBP1-mediated lipogenesis and consequent cell senescence.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: You-Mie
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Insun
authors.initials: I
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea. ; Department of Biomedical Science, The Graduate School of Ajou University, Suwon, Korea.
authors.forename: Yong-Hak
authors.initials: YH
authors.lastname: Seo
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea. ; Department of Biomedical Science, The Graduate School of Ajou University, Suwon, Korea.
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
keywords: Cell aging; Glycogen synthase kinase 3; Lipogenesis; Sterol regulatory element binding protein 1