Deficiency in Ikk beta gene enhances arsenic-induced gadd45alpha expression.
Zhang-Y; Lu-Y; Ding-M; Castranova-V; Shi-X; Chen-F
Mol Cell Biochem 2005 Nov; 279(1-2):163-168
Chronic arsenic exposure is implicated in the pathophysiology of various human diseases, including cancer and diabetes. Using Ikkbeta gene knockout mouse embryonic fibroblast cells (Ikkbeta(-/-)), in the present study we demonstrated that NF-kappaB inhibition due to Ikkbeta deficiency up-regulated basal and arsenic-induced expression of gadd45alpha. In addition to gadd45alpha, the basal expression of other gadd family members including gadd45beta, gadd45gamma and gadd153 was substantially increased in Ikkbeta(-/-) cells. Ikkbeta deficiency prevented the induction of gadd45beta and gadd45gamma by arsenic, whereas the induction of gadd45alpha and gadd153 was appreciably enhanced in Ikkbeta(-/-) cells. Furthermore, a substantial decrease in the expression of c-myc, an established endogenous transcriptional repressor of gadd45alpha and gadd153 genes, was noted. Thus, these results uncover the molecular mechanism by which NF-kappaB signalling contributes to the regulation of gadd family gene expression induced by arsenic.
Arsenic-compounds; Chronic-exposure; Diseases; Cancer; Laboratory-animals; Animals; Animal-studies
F. Chen, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA
Molecular and Cellular Biochemistry