Opposite Effect of NF-κB and c-Jun N-terminal Kinase on p53-independent GADD45 Induction by Arsenite

Cell cycle checkpoint, a major genomic surveillance mechanism, is an important step in maintaining genomic stability and integrity in response to environmental stresses. Using cells derived from human bronchial epithelial cells, we demonstrate that NF-κB and c-Jun N-terminal kinase (JNK) reciprocally regulate arsenic trioxide (arsenite)-induced, p53-independent expression of GADD45 protein, a cell cycle checkpoint protein that arrests cells at the G₂/M phase transition. Inhibition of NF-κB activation by stable expression of a kinase-mutated form of IκB kinase caused increased and prolonged induction of GADD45 by arsenite. In contrast, the induction of GADD45 by arsenite was transient and less potent in cells where the NF-κB activation pathway was normal. Analysis of the cell cycle profile by flow cytometry indicated that NF-κB inhibition potentiates arsenite-induced G₂/M cell cycle arrest. Abrogation of JNK activation, on the other hand, decreased GADD45 expression induced by arsenite, suggesting a role for JNK activation in GADD45 induction. These results indicate a molecular mechanism by which NF-κB and JNK may differentially contribute to cell cycle regulation in response to arsenite.