Requirement of Erk, but not JNK, for arsenite-induced cell transformation

Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associat ed with cancers of skin, lung, liver, and bladder. However, the mechanism b y which arsenite causes cancer is not well understood, In this study, we fo und that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 mu M) i nduces cell transformation. Interestingly, arsenite induces Erk phosphoryla tion and increased Erk activity at doses ranging from 0.8 to 200 mu M, whil e higher doses (more than 50 mu M) are required for activation of JNK. Arse nite-induced Erk activation was markedly inhibited by introduction of domin ant negative Erk2 into cells, while expression of dominant negative Erk2 di d not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2, In contrast, overexpression of dominant negative JNK1 was shown to increas e cell transformation even though it inhibits arsenite induced JNK activati on. Our results not only show that arsenite induces Erk activation, but als o for the first time demonstrates that activation of Erk, but not JNK, by a rsenite is required for its effects on cell transformation.