Regulation of GCL activity and cellular glutathione through inhibition of ERK phosphorylation.
Extracellular signal-regulated protein kinase (ERK), one of the mitogen-activated protein kinase, has been known to be involved in diverse cellular functions. In this work, we found that basically inhibition of this kinase in cultured cells markedly increased the gamma-glutamate-cysteine ligase (GCL; EC 6.3.2.2) activity, but without any considerable induction of the GCL genes. The increased GCL activity consequently elevated the cellular GSH level and eventually enhanced the cellular antioxidant capacity. Genetic inhibition of B-Raf, the upstream of ERK, also resulted in increased GCL activity and GSH level. Recent evidence also suggests that chronic pro-oxidant exposure results in the loss of ERK phosphorylation in vivo. Therefore, the findings in the present study suggest that inhibition of B-Raf/MEK/ERK pathway might be a promising physiological approach to up-regulate GCL activity and GSH. This study would also help us to understand the comprehensive role of the Raf/MEK/ERK pathway in overall physio/pathological conditions.
Chen
Zhi-Hua
ZH
Human Stress Signal Research Center (HSSRC), National Institute of Advanced Industrial Science & Technology (AIST), Osaka, Japan.
Saito
Yoshiro
Y
Yoshida
Yasukazu
Y
Noguchi
Noriko
N
Niki
Etsuo
E
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats
D002070:Butadienes; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D020932:Nerve Growth Factor; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione