Deficiency in Ikkbeta gene enhances arsenic-induced gadd45alpha expression.
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.
Zhang
Yadong
Y
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, P.R. China.
Lu
Yongju
Y
Ding
Min
M
Castranova
Vince
V
Shi
Xianglin
X
Chen
Fei
F
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts; D015870:Gene Expression; D051550:I-kappa B Kinase / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
D001151:Arsenic; D018797:Cell Cycle Proteins; D051550:I-kappa B Kinase; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; C497250:Ddit3 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C489428:Myc protein, mouse; C496562:Ikbkb protein, mouse