Contrasting roles of NF-κB and JNK in arsenite-induced p53-independent expression of GADD45α

Growth arrest and DNA damage-inducible protein 45 alpha (GADD45 alpha) is an important cell cycle checkpoint protein that arrests cells at G2/M phase by inhibiting the activity of G2-specific kinase, cyclin B/p34cdc2. We report here that arsenite induces GADD45 alpha expression in a p53-independent fashion and that this GADD45a induction by arsenite is regulated by NF-KB and c-Jun-N-terminal kinase (JNK) oppositely. In human bronchial epithelial cells overexpressing a kinase-mutated form of I kappaB kinase beta (IKK beta -KM), the activation of NF-kappaB was inhibited. However, the G2/M cell cycle arrest and expression of GADB45 alpha was substantially enhanced in response to arsenite in these cells. Expression of a dominant-negative mutant of SEK1 that blocks JNK activation decreased arsenite-induced GADD45a expression. Analysis of GADD45 alpha expression in both wild-type and p53-/- fibroblasts indicated that the induction of GADD45a by arsenite was independent of the status of p53 protein.