Signal transducer and activator of transcription-1 (STAT1), but not STAT5b, regulates IGF-I receptor gene expression in an osteosarcoma cell line. The IGF-I receptor (IGF-IR) exhibits potent mitogenic, antiapoptotic, and transforming activities. Previous studies have suggested that the expression of the IGF-IR gene is negatively regulated by certain cytokines, including interferon-gamma (IFN-gamma). The potential involvement of STAT proteins in transcriptional regulation of the IGF-IR gene by IFN-gamma was addressed by transient coexpression of vectors encoding STAT1 and STAT5b, together with an IGF-IR promoter luciferase reporter, in the osteosarcoma-derived cell line Saos-2. Physical interactions between IFN-gamma-induced transcription factors and the IGF-IR promoter region were examined by electrophoretic mobility shift assays (EMSA). The results obtained indicate that the mechanism of action of IFN-gamma involves stimulation of STAT1 which, in turn, binds IFN-gamma activation sites (GAS) in the IGF-IR regulatory region, thus suppressing promoter activity. Taken together, our results suggest that the IGF-IR gene is a novel target for STAT1 action and that at least part of the inhibitory effects of STAT1 may involve repression of the strongly antiapoptotic IGF-IR gene.