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REGULATION OF FOXO TRANSCRIPTION FACTORS BY OXIDATIVE STRESS: ROLE OF GLUTATHIONE

  • Author / Creator
    Turkistani, Abdullah A
  • FoxO transcription factors are downstream mediators of insulin effects that can bind to DNA and regulate transcription of multiple target genes. These target genes are known for their importance in several biological functions including energy homeostasis, longevity, tumour suppression and development. FoxO activity has been reported to be affected by insulin signaling and oxidative stress. Glutathione (GSH), a potent antioxidant and regulator of cellular redox state could therefore play a role in regulating FoxO activity. Herein, modulators of GSH levels were used to investigate the effect of GSH depletion on insulin-induced FoxO1/3a phosphorylation. HepG2 human hepatoma cells were exposed to diethyl maleate (DEM) to deplete thiols including glutathione, or buthionine sulfoximine (BSO) to inhibit the synthesis of glutathione, followed by insulin treatment, western blotting and immunodetection of FoxO1/3a phosphorylation and other insulin signaling targets. Our results show that DEM and BSO significantly attenuate insulininduced FoxO1/3a phosphorylation. In addition, the mechanism of DEM attenuating phosphorylation of FoxO1/3a has been investigated. DEM was found to be associated with a general impairment of insulin signaling and an activation of stress-induced Jun N-terminal kinases, JNK, which had previously been shown to modulate FoxO activity. In conclusion, depletion of thiols, including glutathione modulates FoxO signaling by interfering with FoxO1/3a phosphorylation.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3BZ61F9G
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Lars Oliver Klotz (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Sharon Marsh (Pharmacy and Pharmaceutical Sciences)
    • Arno Siraki (Pharmacy and Pharmaceutical Sciences)
    • Frank Wuest (Department of Oncology)