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

Chen-F; Lu-Y; Zhang-Z; Vallyathan-V; Ding-M; Castranova-V; Shi-X

J Biol Chem 2001 Apr; 276(14):11414-11419

http://dx.doi.org/10.1074/jbc.M011682200

20021698

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-kappaB 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 G(2)/M phase transition. Inhibition of NF-kappaB activation by stable expression of a kinase-mutated form of IkappaB 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-kappaB 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 mechanism by which NF-kappaB and JNK may differentially contribute to cell cycle regulation in response to arsenite.

Arsenates; Arsenites; Environmental-stress; Environmental-factors; Cell-function; Arsenic-compounds; Cell-division; Cell-biology

PPRB of NIOSH, 1095 Willowdale Road, Morgantown, WV 26505

JBCHA3

1327-53-3; 15502-74-6

20010406

Journal Article

lfd3@cdc.gov

2001

14

0021-9258

HELD

The Journal of Biological Chemistry

WV