The IGF-I-R mediates the biological actions of the IGFs, and has been implicated in malignant transformation. The long-term objectives of this proposal are (1) to determine how p53 (a widely distributed nuclear protein which functions as a tumor suppressor by blocking progression of cells through the cell cycle by binding to components of basal transcription machinery) and WT1 (an organ-specific transcription factor which represses IGF-I-R expression by binding to specific sites in the IGF-I-R promoter) cooperate to repress IGF-I-R gene expression, and (2) to determine how mutations of either WT1 or p53 may disrupt the interactions between both proteins and/or between these proteins and the IGF-I-R promoter, resulting in deregulated expression of the receptor. Pilot studies suggest that p53 repression of IGF-I-R results from binding of p53 to TBP, presumably precluding the formation of a functional transcription initiation complex.
The specific aims of the proposal are to demonstrate functional interaction between WT1 and p53, to analyze the WT1/p53 interaction on the IGF-I-R promoter in vitro, and to verify this interaction in the regulation of endogenous IGF-I-R.
