Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite

Chen, F Lu, YJ Zhang, Z Vallyathan, V Ding, M Castranova, V Shi, XL

F. Chen et al., Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite, J BIOL CHEM, 276(14), 2001, pp. 11414-11419

44

INGLESE

Article

Biochemistry & Biophysics

JOURNAL OF BIOLOGICAL CHEMISTRY

0021-9258 → ACNP

276

14

2001

11414 - 11419

ISI

0021-9258(20010406)276:14<11414:OEONBA>2.0.ZU;2-E

Cell cycle checkpoint, a major genomic surveillance mechanism,is an importa nt step in maintaining genomic stability and integrity in response to envir onmental stresses. Using cells derived from human bronchial epithelial cell s, we demonstrate that NF-kappaB and c-Jun N-terminal kinase (JNK) reciproc ally regulate arsenic trioxide (arsenite)-induced, p53-independent expressi on of GADD45 protein, a cell cycle checkpoint protein that arrests cells at the G(2)/M phase transition. Inhibition of NF-kappaB activation by stable expression of a kinase-mutated form of I kappaB kinase caused increased and prolonged induction of GADD45 by arsenite. In contrast, the induction of G ADD45 by arsenite was transient and less potent in cells where the NF-kappa B activation pathway was normal. Analysis of the cell cycle profile by flow cytometry indicated that NF-kappaB inhibition potentiates arsenite-induced G(2)/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 mechani sm by which NF-kappaB and JNK may differentially contribute to cell cycle r egulation in response to arsenite.