Adaptation to hypoxia is essential for tumor progression. Transcriptional activation of hypoxia-regulated genes is mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and ARNT (Ah receptor nuclear translocator; HIF-1beta). Using representational difference analysis, we identified three novel hypoxia-inducible genes: MIG-6 (gene 33), adipophilin and tuftelin. The mRNAs for these genes were inducible by 1% O(2) in the human HepG2 and MCF-7 cell lines. Hypoxic induction of the MIG-6 and tuftelin proteins was also observed. Induction was ARNT-dependent. Induction also occurred in livers of mice treated with CoCl(2), which mimics hypoxia. The potential roles of these genes in adaptation to hypoxia and in tumorigenesis will be of considerable interest.