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.