Regulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and interferon-gamma.
The insulin-like growth factor-I receptor (IGF-l-R) plays a critical role in normal and pathological growth processes. The expression of the IGF-l-R gene is regulated by various stimuli, including hormones and growth factors. We have investigated the molecular mechanisms by which two inhibitory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), regulate IGF-l-R gene expression. TNF-alpha and IFN-gamma reduced the proliferation rates of the osteogenic sarcoma cell line, Saos-2, and the human salivary gland cell line, HSG, in a dose- and time-dependent fashion. This effect was associated with significant reductions in the levels of IGF-l-R mRNA and protein, and with inhibition of IGF-l-R promoter activity, suggesting that TNF-alpha and IFN-gamma affect IGF-l-R gene expression at the transcriptional level. In addition, TNF-alpha significantly decreased IGF-l-R mRNA stability. Combined cytokine treatment inhibited cellular proliferation and promoter activity in an additive manner. Taken together, these results suggest that a novel potential mechanism by which TNF-alpha and IFN-gamma affect cellular proliferation involves suppression of IGF-l-R promoter activity, as well as destabilization of IGF-l-R transcripts.
Shalita-Chesner
M
M
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Katz
J
J
Shemer
J
J
Werner
H
H
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1