Nickel-induced 1,4-alpha-glucan branching enzyme 1 up-regulation via the hypoxic signaling pathway.

Using the mouse Affymetrix gene chip, we found that 1,4-alpha-glucan branching enzyme 1 (GBE1) was one of the most up-regulated genes following nickel exposure. This result was confirmed by Northern blot in two mouse cell lines, four mouse tissues, and three human cell lines. We further found that this gene was also up-regulated by cobalt, hypoxia, the iron chelator (deferoxamine, or DFO), and the prolyl hydroxylase (PH) inhibitor (dimethyloxalyglycine, DMOG), suggesting that hypoxia inducible factor-1alpha (HIF-1alpha) was involved in the up-regulation of this gene. Experiments using HIF-1alpha +/+ and HIF-1alpha -/- mouse cells demonstrated this gene was up-regulated through a HIF-1alpha-dependent hypoxic signaling pathway. Because the hypoxic signaling pathway is believed to be important in the initiation and progression of carcinogenesis, it is important to study genes regulated by this pathway.