| The glutathione-S'-transferase (GST) super family comprises multiple isozymes (Alpha, Mu, Pi, Omega, Theta, and Zeta) with compelling evidence of functional polymorphic variation. GST isozymes possess the capacity to regulate mitogen activated protein kinases presents an alternative explanation. This dual functionality has contributed to the recent efforts to target GSTs with novel small molecule therapeutics.Glutathione S-transferase P1 (GSTP1) plays an important role in the detoxification and xenobiotic metabolism.MEK kinase 1 (MEKK1) is a 196-kDa protein that, in response to genotoxic agents, was found to undergo phosphorylation-dependent activation. Following activation by genotoxins, MEKK1 was cleaved in a caspase-dependent manner into an active 91-kDa kinase fragment. Expression of MEKK1 stimulated DEVD-directed caspase activity and induced apoptosis. MEKK1 is itself a substrate for CPP32 (caspase-3).Here, we reveal a novel function for GSTP1 in regulating MEKK1-MKK7 signaling pathway. Over-expression of GSTP1 in HEK293 cells has been shown to inhibit both AMEKK1 and etoposide-induced apoptosis. The inhibition of cell apoptosis by GSTP1 is well co-ordinated with the inhibition of procaspase-3 activation and PARP cleavage. AMEKK1 activity is blocked in a dose dependent manner by over-expression of GSTP1 in vivo and MEKK1 kinase activity is also suppressed by GSTP1 protein dose-dependently using bacteria-expressed MKK7 (KM) protein as substrate in vitro. Moreover, the glutathione-conjugating activity of GSTP1 is essential for this inhibition. Etoposide-induced apoptosis has been confirmed via activation of MEKK1, thus GSTP1 suppressed etoposide-induced cell apoptosis is largely contributed by its ability in suppression of MEKK1 kinase activity. Taken together, these findings provide a new insight for analyzing the mechanism utilized by GSTP1 in protecting cells from genotoxin-induced apoptosis through regulation of MEKK1 kinase activity.
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