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

Abstract

Growth arrest and DNA damage-inducible protein 45α (GADD45α) 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 GADD45α expression in a p53-independent fashion and that this GADD45α induction by arsenite is regulated by NF-κB and c-Jun-N-terminal kinase (JNK) oppositely. In human bronchial epithelial cells overexpressing a kinase-mutated form of IκB kinase β (IKKβ-KM), the activation of NF-κB was inhibited. However, the G2/M cell cycle arrest and expression of GADD45α 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 GADD45α expression. Analysis of GADD45α expression in both wild-type and p53−/− fibroblasts indicated that the induction of GADD45α by arsenite was independent of the status of p53 protein.