A potential mechanism for fumonisin B-1-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3 beta activity
D. Ramljak et al., A potential mechanism for fumonisin B-1-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3 beta activity, CARCINOGENE, 21(8), 2000, pp. 1537-1546
Fumonisin B-1 (FB1) is a worldwide corn contaminant and has been epidemiolo
gically linked to the high incidence of human esophageal cancer in South Af
rica and China. FB1 is hepatocarcinogenic in rats by an unknown mechanism.
Inhibition of ceramide synthase and disruption of membrane phospholipids ha
ve been shown to be mechanisms of toxicity. Here we show overexpression of
cyclin D1 protein in both preneoplastic and neoplastic liver specimens obta
ined from a long-term feeding study of FB1 in rats. In rats fed FB1 short-t
erm, cyclin D1 protein levels in liver were increased up to five-fold in a
dose-responsive manner. Northern blot analysis demonstrated no increase in
mRNA levels of cyclin D1, 2D electrophoresis of cyclin D1 protein in FB1-tr
eated samples showed a distinct pattern of migration (presence of less nega
tively charged form of the protein) that differed from controls. Recently,
it has been shown that phosphorylation of cyclin D1 by glycogen synthase ki
nase 3 beta (GSK-3 beta) on a single threonine residue (Thr-286) positively
regulates proteosomal degradation of cyclin D1, In FB1-treated samples we
detected GSK-3 beta phosphorylated on serine 9; activated protein kinase B
(Akt) appears to be responsible for this activity-inhibiting phosphorylatio
n, These findings suggest that overexpression of cyclin D1 results from sta
bilization due to a lack of phosphorylation mediated by GSK-3 beta, We also
observed an increase in cyclin dependent kinase 4 (Cdk4) complexes with cy
clin D1 in FB1-treated samples; additionally, elevated Cdk4 activity was sh
own by increased phosphorylation of the retinoblastoma protein. In summary,
the activation of Akt leads to increased survival, inhibition of GSK-3 bet
a activity and post-translational stabilization of cyclin D1, all events re
sponsible for disruption of the cell cycle G(1)/S restriction point in hepa
tocytes, This is the first report suggesting the mechanism by which FB1 act
s as a carcinogen.