GSTT1 is upregulated by oxidative stress through p38-MK2 signaling pathway in human granulosa cells: possible association with mitochondrial activity.
We previously reported that GSTT1 was upregulated in human granulosa cells during aging and that activation and localization of p38 MAPK was changed in parallel. Although oxidative stress is responsible for these changes, the age-associated expression of GSTT1 regulated by MAPKs and the role of GSTT1 in aged granulosa cells remain unclear. Therefore, we examined the relationship between the expression of GSTT1 and MAPK signaling pathways using human granulosa-like KGN cells stimulated with H(2)O(2) in the presence or absence of various MAPK inhibitors. Interestingly, H(2)O(2)-induced GSTT1 was only inhibited by a p38 inhibitor. An inhibitor of MK2, a downstream regulator of p38, also diminished H(2)O(2)-induced GSTT1 upregulation. Notably, both p38 and MK2 were significantly inactivated in cells carrying an shRNA construct of GSTT1 (∆GSTT1 cells), suggesting that the p38-MK2 pathway is essential for age-associated upregulation of GSTT1. The relevance of GSTT1 in mitochondrial activity was then determined. ∆GSTT1 cells displayed enhanced polarization of mitochondrial membrane potential without increasing the apoptosis, suggesting that the age-associated upregulation of GSTT1 may influence the mitochondrial activity of granulosa cells.
Division of Reproductive Medicine, Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, Tokyo, Japan.
Megumu
M
Ito
Misa
M
Imai
Miho
M
Muraki
Kenji
K
Miyado
Junwen
J
Qin
Shigeru
S
Kyuwa
Yasuhiro
Y
Yoshikawa
Yoshihiko
Y
Hosoi
Hidekazu
H
Saito
Yuji
Y
Takahashi
D017209:Apoptosis / Q000502:physiology; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D048051:p38 Mitogen-Activated Protein Kinases