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.
Shalita-Chesner
Michal
M
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Glaser
Tova
T
Werner
Haim
H
D001665:Binding Sites; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008894:Milk Proteins; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D004247:DNA; D017526:Receptor, IGF Type 1