30 June 2006 Volume 21, Number 3, pp. 395-400

Title	Human Glutathione S-Transferase P1 Suppresses MEKK1-mediated Apoptosis by Regulating MEKK1 Kinase Activity in HEK293 Cells
Author(s)	Xin Zhao, Yumei Fan, Jiayin Shen, Yifan Wu and Zhimin Yin
Abstract	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.
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