The regulation of IGF-I receptor gene expression by positive and negative zinc-finger transcription factors.
The IGF-I-R gene promoter is a TATA-less, CAAT-less, GC-rich promoter which contains potential binding sites for the Sp1 and WT1 zinc-finger transcription factors. We have shown that Sp1 positively activates the IGF-I-R promoter. Since both the Sp1 and IGF-I-R genes are widely expressed, it is possible that Sp1 is one of the main regulators of IGF-I-R gene expression. This is supported by the correlation between the distribution and developmental regulation of Sp1 and IGF-I-R gene expression, in that both genes appear to be co-regulated during normal development. In a model of human neoplasm, WT, we have demonstrated increased expression of the IGF-I-R gene, which may result from loss of repression of the IGF-I-R promoter by another Zn(2+)-finger protein, the WT1 tumor suppressor gene product. Future studies will define whether other disease states in which the IGF-I-R gene is highly expressed are also associated with loss of negative regulation of the IGF-I-R promoter by WT1 or other tumor suppressor gene products.
Werner
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Section on Molecular and Cellular Physiology, National Institutes of Health, NIDDK, Bethesda, Maryland 20892.
Roberts
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LeRoith
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D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016385:TATA Box; D014157:Transcription Factors / Q000378:metabolism*; D009396:Wilms Tumor / Q000378:metabolism; D016335:Zinc Fingers
D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D017526:Receptor, IGF Type 1