Deficiency in Ikkβ gene enhances arsenic-induced gadd45α expression
- 89 Downloads
Chronic arsenic exposure is implicated in the pathophysiology of various human diseases, including cancer and diabetes. Using Ikkβ gene knockout mouse embryonic fibroblast cells (Ikkβ−/−), in the present study we demonstrated that NF-κB inhibition due to Ikkβ deficiency up-regulated basal and arsenic-induced expression of gadd45α. In addition to gadd45α, the basal expression of other gadd family members including gadd45β, gadd45γ and gadd153 was substantially increased in Ikkβ−/− cells. Ikkβ deficiency prevented the induction of gadd45β and gadd45γ by arsenic, whereas the induction of gadd45α and gadd153 was appreciably enhanced in Ikkβ−/− cells. Furthermore, a substantial decrease in the expression of c-myc, an established endogenous transcriptional repressor of gadd45α and gadd153 genes, was noted. Thus, these results uncover the molecular mechanism by which NF-κB signalling contributes to the regulation of gadd family gene expression induced by arsenic.
Key WordsIkk gadd45 arsenic c-myc
Unable to display preview. Download preview PDF.
- 10.Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ Jr: Genomic instability in Gadd45a-deficient mice. Nat Genet 23: 176–184, 1999CrossRefPubMedGoogle Scholar
- 24.Zerbini LF, Wang Y, Czibere A, Correa RG, Cho JY, Ijiri K, Wei W, Joseph M, Gu X, Grall F, Goldring MB, Zhou JR, Libermann TA: NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45 alpha and gamma is essential for cancer cell survival. Proc Natl Acad Sci USA 101: 13618–13623, 2004CrossRefPubMedGoogle Scholar