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 be en accepted by IARC (International Agency for Research on Cancer) as a cate gory 1 carcinogen. Cadmium-induced up-regulation of intracellular signaling pathways leading to increased mitogenesis is thought to be a major mechani sm for the carcinogenic activity following chronic cadmium exposure. In the present study, we found that exposure of cells to cadmium induced signific ant activation of AP-1 and all three members of the MAP kinase family in mo use 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 cadm ium was blocked by pretreatment of cells with PD98058. Interestingly, the i nduction of AP-1 by cadmium was greatly enhanced by the chemical tumor prom oter, TPA and the growth factor EGF, but not by ultraviolet C radiation. In vivo studies demonstrated that cadmium could also induce transactivation o f AP-1 in AP-1-luciferase report transgenic mice. Considering the role of A P-1 activation in tumor promotion, the results presented in this study prov ide a possible molecular mechanism for cadmium-induced carcinogenesis.