Deficiency in Ikkβ gene enhances arsenic-induced gadd45α expression

Chronic arsenic exposure is implicated in the pathophysiology of various human diseases, including cancer and diabetes. Using Ikkβ gene knockout mouse embryonic fibroblast cells (Ikkβ^-/-), in the present study we demonstrated that NF-κB inhibition due to Ikkβ deficiency up-regulated basal and arsenic-induced expression of gadd45α. In addition to gadd45α, the basal expression of other gadd family members including gadd45β, gadd45γ and gadd153 was substantially increased in Ikkβ^-/- cells. Ikkβ deficiency prevented the induction of gadd45β and gadd45γ by arsenic, whereas the induction of gadd45α and gadd153 was appreciably enhanced in Ikkβ^-/- cells. Furthermore, a substantial decrease in the expression of c-myc, an established endogenous transcriptional repressor of gadd45α and gadd153 genes, was noted. Thus, these results uncover the molecular mechanism by which NF-κB signalling contributes to the regulation of gadd family gene expression induced by arsenic.