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 Zn²⁺-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.