Involvement of Erks activation in cadmium-induced AP-1 transactivation in vitro and in vivo.
Cadmium is a potent and effective carcinogen in rodents and has recently been accepted by IARC (International Agency for Research on Cancer) as a category I carcinogen. Cadmium-induced up-regulation of intracellular signaling pathways leading to increased mitogenesis is thought to be a major mechanism for the carcinogenic activity following chronic cadmium exposure. In the present study, we found that exposure of cells to cadmium induced significant activation of AP-1 and all three members of the MAP kinase family in mouse epidermal JB6 cells. The induction of AP-1 activity by cadmium appears to involve activation of Erks, since the induction of AP-1 activity by cadmium was blocked by pretreatment of cells with PD98058. Interestingly, the induction of AP-1 by cadmium was greatly enhanced by the chemical tumor promoter, TPA and the growth factor EGF, but not by ultraviolet C radiation. In vivo studies demonstrated that cadmium could also induce transactivation of AP-1 in AP-1-luciferase report transgenic mice. Considering the role of AP-1 activation in tumor promotion, the results presented in this study provide a possible molecular mechanism for cadmium-induced carcinogenesis.
Huang
C
C
Nelson Institute of Environmental Medicine, New York University School of Medicine, NY 10016, USA.
Zhang
Q
Q
Li
J
J
Shi
X
X
Castranova
V
V
Ju
G
G
Costa
M
M
Dong
Z
Z
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000528:radiation effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D002273:Carcinogens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018808:Transcription Factor AP-1; D002104:Cadmium; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one