Requirement of MKK4 and MKK7 for CdCl2- or HgCl2-induced activation of c-Jun NH2-terminal kinase in mouse embryonic stem cells.
c-Jun NH(2)-terminal kinase (JNK), also known as stress-activated protein kinase (SAPK), is activated primarily by inflammatory cytokines and environmental stresses including toxic metal exposure. To reveal the upstream kinase responsible for JNK activation by toxic metals, the phosphorylation status and the activity of JNK were examined in mouse embryonic stem (ES) cells lacking MKK4 or MKK7 following exposure to CdCl(2) or HgCl(2). Treatment with CdCl(2) or HgCl(2) induced the phosphorylation of JNK in a dose- and time-dependent manner in wild-type ES cells. In both mkk4(-/-) and mkk7(-/-) ES cells, CdCl(2)- or HgCl(2)-induced phosphorylation and activation of JNK were suppressed significantly. However, in mkk7(-/-) ES cells treated with CdCl(2) and HgCl(2), JNK activation was not abolished (suppressed by 56% and 78%, respectively). These findings suggest that the full activation of JNK by toxic metal exposure requires both MKK4 and MKK7, and these upstream kinases might contribute differentially in JNK activation between mouse ES cells exposed to CdCl(2) and HgCl(2).
Department of Hygiene and Public Health, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. matsuoka@research.twmu.ac.jp
Masato
M
Matsuoka
Hideki
H
Igisu
Kentaro
K
Nakagawa
Toshiaki
T
Katada
Hiroshi
H
Nishina
D000818:Animals; D015153:Blotting, Western; D019256:Cadmium Chloride / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D008627:Mercuric Chloride / Q000633:toxicity*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
D008627:Mercuric Chloride; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482562:Map2k4 protein, mouse; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D019256:Cadmium Chloride