Hypoxia inducible factor-1 (HIF-1) is a heterodimeric complex of two basic-helix–loop-helix proteins of the PAS family which is critical for oxygen-dependent expression of many mammalian genes. Regulation is mediated by the alpha subunit (HIF-1α) and sequences from HIF-1α can confer hypoxia-inducible activity on a Gal4 fusion protein. To analyse conservation of this system of gene regulation betweenDrosophilaand mammalian cells we constructed Gal4 fusions with a series ofDrosophilabasic-helix–loop-helix PAS (bHLH-PAS) proteins and tested for hypoxia inducibility in transfected Hep3B cells. We found that Gal4 fusions with Similar (Sima) but not otherDrosophilabHLH-PAS proteins showed inducible activity following exposure to stimuli which classically activate mammalian HIF-1: hypoxia, cobaltous ions, and desferrioxamine. We also found that Sima protein accumulated inDrosophilaSL2 cells following hypoxia. Together these findings indicate the existence of functional homologies between Sima and HIF-1α, and that conservation is such as to enable Sima to interact with the hypoxia signal transduction system in mammalian cells.