Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium.
Cadmium is a toxic divalent cation that can initiate either mitogenic signals or apoptosis, possibly as a consequence of inducing different patterns of oncogene expression in different cells. We previously showed that Cd(2+) caused transcriptional activation of the c-fos protooncogene in mesangial cells (Wang and Templeton, J. Biol. Chem. 273, 73-79, 1998). The present study was undertaken to identify the signaling pathways that might be involved. Exposure to 10 microM CdCl(2) for 8 h caused a prolonged activation of Erk kinase and accumulation of c-fos mRNA. Inhibition of Erk activation with PD98059 only partially inhibited c-fos induction, indicating that additional pathways are involved. The c-Jun kinase/stress-activated protein kinase (SAPK) was also activated by Cd(2+). All three signals, i.e., Erk activity, SAPK activity, and c-fos mRNA levels in response to Cd(2+) showed a similar biphasic time course with an initial increase at 15-30 min and then a larger and more prolonged increase several hours later. Each signal also showed a similar concentration dependence, with less than 1 microM Cd(2+) causing the initial increase but values above 3 microM being required for the prolonged phase. These events showed high specificity for Cd(2+); other divalent metals tested under the same conditions (Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), and Hg(2+)) were without significant effects. We conclude that Cd(2+) is a specific inducer of c-fos in mesangial cells, probably through activation of both Erk kinase and SAPK pathways. The similar time and concentration dependence of the response of both pathways to Cd(2+) suggests a common basis for activation.
Ding
W
W
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1L5, Canada.
Templeton
D M
DM
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D011519:Proto-Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D002104:Cadmium; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases