title: Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium.
abstract: Cadmium (Cd), a human carcinogen, can induce apoptosis in various cell types. Three major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (ERK), have been shown to regulate apoptosis. In this study we explore the ability of Cd to activate JNK, p38 and ERK, including their effects on Cd-mediated growth inhibition and apoptosis in a human non-small cell lung carcinoma cell line, CL3. The kinase activity of JNK was induced dose-dependently by 30-160 microM CdCl(2). High cytotoxic doses of Cd (130-160 microM) markedly activated p38, but low Cd doses did not. Conversely, the activities of ERK1 and ERK2 were decreased by low cytotoxic doses of Cd (</=80 microM) and moderately activated by high Cd doses. Low cytotoxic doses of Cd transiently activated JNK and simultaneously reduced ERK activity, whereas high cytotoxic doses of Cd persistently activated JNK and p38. PD98059, an inhibitor of ERK upstream activators MAPK kinase (MKK) 1 and MKK2, greatly enhanced cytotoxicity and apoptosis in cells treated with low Cd doses. In contrast, SB202190, an inhibitor of p38, decreased the cytotoxicity and apoptosis induced by high Cd doses. Transient expression of a dominant negative form of JNK1, but not that of JNK2, significantly increased the viability and prevented apoptosis of Cd-treated cells. However, expression of wild-type JNK1 did not affect viability and apoptosis of Cd-treated cells. Transfection of wild-type JNK2 or p38 enhanced apoptosis of cells exposed to low Cd doses but did not affect those exposed to high Cd doses. The JNK activity stimulated by low Cd doses was partially suppressed by expression of a dominant negative form of MKK7, but not a dominant negative form of MKK4, indicating that MKK7 is involved in JNK activation by Cd. Together, the results of this study suggest that JNK and p38 cooperatively participate in apoptosis induced by Cd and that the decreased ERK signal induced by low Cd doses contributes to growth inhibition or apoptosis.
authors.affiliation: Molecular Carcinogenesis Laboratory, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.
authors.forename: S M
authors.initials: SM
authors.lastname: Chuang
authors.forename: I C
authors.initials: IC
authors.lastname: Wang
authors.forename: J L
authors.initials: JL
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002104:Cadmium / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016758:Genes, jun; D006131:Growth Inhibitors / Q000633:toxicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004273:DNA, Neoplasm; D020536:Enzyme Activators; D006131:Growth Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D002104:Cadmium; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases