repository
Involvement of GSK3 in Mitochondrial Respiratory Defects during Stress-induced Cellular Senescence
- Alternative Title
- Hae-Ok Byun
- Author(s)
- 변해옥
- Alternative Author(s)
- Hae-Ok Byun
- Advisor
- 윤계순
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2013-02
- Language
- eng
- Alternative Abstract
- Transforming growth factor β1 (TGF β1) induces Mv1Lu cell senescence by persistently producing mitochondrial reactive oxygen species (ROS) through decreased complex IV activity. Here, molecular mechanism underlying the effect of TGF β1 on mitochondrial complex IV activity was investigated. TGF β1 progressively phosphorylated the negative regulatory sites of both glycogen synthase kinase 3 (GSK3) α and β, corresponding well to the intracellular ROS generation profile. Pre-treatment of N-acetyl cysteine, an antioxidant, did not alter this GSK3 phosphorylation (inactivation) whereas pharmacological inhibition of GSK3 by SB415286 treatment significantly increased mitochondrial ROS, implying that GSK3 phosphorylation is an upstream event of the ROS generation. GSK3 inhibition by SB415286 decreased complex IV activity and cellular O2 consumption rate, and eventually induced senescence of Mv1Lu cell. Similar results were obtained with siRNA-mediated knockdown of GSK3. Interestingly, substantial amount of GSK3 was found to exist in mitochondria of Mv1Lu cell and bind complex IV subunit 6b which is topologically located in the mitochondrial intermembrane space. TGF β1 treatment decreased the binding of the subunit 6b to GSK3 and subunit 6b phosphorylation. Importance of subunit 6b in complex IV activity and cell growth was tested with siRNA-mediated knockdown of subunit 6b. Finally, physiological importance of serine 63 residue of subunit 6b in controlling complex IV activity was demonstrated by using subunit 6b mutants. Taken together, these results suggest that GSK3 inactivation is importantly involved in TGF β1-induced complex IV defects through decreasing phosphorylation of the subunit 6b, thereby contributing to senescence-associated mitochondrial ROS generation.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
- Files in This Item:
- There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
-
- License
- STATISTICS
- Total Visit :3,636,158
- Total Download :1,804
- Today View :3,337
