Glutathione-S-Transferase as a selective inhibitor of oncogenic ras-p21-induced mitogenic signaling through blockade of activation of jun by jun-N-terminal kinase.
We have identified the intracellular detoxification enzyme, glutathione-S-transferase (GST), as a potent inhibitor of the activation of jun by its kinase, jun-N-terminal kinase (JNK), in vitro. All three major isozymes (alpha, mu, and pi) bind to JNK-jun complexes and inhibit activation of jun by JNK. We now find that GST inhibits JNK-induced oocyte maturation in vivo and strongly inhibits oocyte maturation induced by oncogenic ras-p21 protein, but not by insulin-activated normal cellular p21 protein. These results correlate with the finding that oncogenic, but not insulin-activated normal, p21 induces high levels of activated JNK. GST also strongly blocks induction of oocyte maturation by protein kinase C (PKC) which is a critical downstream target of oncogenic but not normal ras-p21. Thus, we have established a new function for GST as a potent physiological inhibitor of the ras-JNK-jun pathway.
Villafania
A
A
Department of Pathology and Laboratory Medicine, VA Medical Center, Brooklyn, New York 11209, USA.
Anwar
K
K
Amar
S
S
Chie
L
L
Way
D
D
Chung
D L
DL
Adler
V
V
Ronai
Z
Z
Brandt-Rauf
P W
PW
Yamaizumii
Z
Z
Kung
H F
HF
Pincus
M R
MR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology; D005982:Glutathione Transferase / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008934:Mitogens / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000201:enzymology / Q000254:growth & development; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D011493:Protein Kinase C / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
D007004:Hypoglycemic Agents; D007328:Insulin; D008934:Mitogens; D016755:Proto-Oncogene Proteins c-jun; D019000:Phosphotyrosine; D005982:Glutathione Transferase; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)