Stress-activated protein kinase-dependent induction of c-fos by Cd(2+) is mediated by MKK7.
Exposure of mesangial cells to ionic Cd(2+) induces the proto-oncogene c-fos, while activating both Erk and stress-activated protein kinase (SAPK) MAP kinase pathways. While we have previously used a pharmacological inhibitor of Erk activation to implicate involvement of this pathway in the induction of c-fos by Cd(2+), the consequences of SAPK activation remained unknown. Here we use dominant negative inhibitors of the SAPK kinases, SEK1 and MKK7, to show that Cd(2+) activates SAPK through MKK7, but that partial inhibition of SAPK alone is insufficient to significantly affect the magnitude of the Cd(2+)-dependent increase in c-fos mRNA. However, inhibition of Erk and SAPK pathways together abrogates the increase, suggesting that these pathways act in concert in the induction of c-fos by this toxic metal.
Ding
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Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building Room 6302, 1 King's College Circle, Toronto, M5S 1A8, Canada.
Templeton
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D000818:Animals; D001483:Base Sequence; D002104:Cadmium / Q000633:toxicity*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D014162:Transfection
D017931:DNA Primers; D012333:RNA, Messenger; D002104:Cadmium; D020928:Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases