Human glutathione S-transferase P1 suppresses MEKK1-mediated apoptosis by regulating MEKK1 kinase activity in HEK293 cells.
Glutathione S-transferase P1 (GSTP1) plays an important role in detoxification and the metabolism of xenobiotics. Here we show that GSTP1 also regulates the MEKK1-MKK7 signaling pathway. Over-expression of GSTP1 in HEK293 cells inhibited both DMEKK1- and etoposide-induced apoptosis, and inhibited pro-caspase-3 activation and PARP cleavage. MEKK1-induced apoptosis requires both its kinase activity and proteolytic cleavage. DMEKK1 activity was inhibited by over-expression of GSTP1 in vivo and MEKK1 kinase activity was also inhibited by GSTP1 in vitro when assayed with bacterially-expressed MKK7(KM) protein as substrate. GSTP1 inhibition of etoposide-induced cell apoptosis was mainly due to its ability to suppress MEKK1 kinase activity. The glutathione-conjugating activity of GSTP1 was essential for the above effects. These findings provide insight into the mechanism by which GSTP1 protects cells from genotoxin-induced apoptosis.
Zhao
Xin
X
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210097, China.
Fan
Yumei
Y
Shen
Jiayin
J
Wu
Yifan
Y
Yin
Zhimin
Z
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D051549:Glutathione S-Transferase pi; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases