Transactivation of AP-1 in AP-1-luciferase reporter transgenic mice by arsenite and arsenate.

Arsenic is a recognized carcinogen, which acts as a tumor promoter rather than as an initiator. Signal transduction pathways leading to activation of AP-1 and mitogen-activated protein kinases are proposed to be responsible for the tumor promotion activity by arsenic. Induction of AP-1 DNA binding activity and c-jun and c-fos expression was reported to be only observed in cells responding to arsenite, but not to arsenate. However, in this study, we found that both arsenite and arsenate could induce transactivation of AP-1 in mouse epidermal JB6 AP-1-luciferase reporter stable transfectants, P+1-1. This induction of AP-1 activity by arsenic appears to be through activation of mitogen-activated protein kinases and protein kinase C because increased AP-1 activity by arsenite could be blocked by either treatment of cells with PD98059 or overexpression of dominant negative protein kinase Ca. Furthermore, both arsenite and arsenate could induce transactivation of AP-1 in AP-1-luciferase reporter transgenic mice.