WT1 P53 INTERACTIONS IN IGF I RECEPTOR REGULATION

描述 IGF-I-R介导IGFS的生物学作用，并已被 与恶变有关。这个项目的长期目标是 建议是(1)确定P53(一种广泛分布的核蛋白)如何 它通过阻止细胞的进展而发挥肿瘤抑制作用 通过与基础转录的组成部分结合来完成细胞周期 机械)和WT1(一种器官特异性转录因子，它抑制 通过结合IGF-I-R启动子中的特定位点来表达IGF-I-R) 合作抑制IGF-I-R基因表达，以及(2)确定如何 WT1或P53的突变可能会破坏两者之间的相互作用 蛋白质和/或这些蛋白质和IGF-I-R启动子之间，导致 在受体的表达失控方面。初步研究表明，P53 IGF-I-R的抑制可能是由于P53与TBP结合所致 排除了功能性转录起始复合体的形成。 该提案的具体目标是演示功能交互 在WT1和P53之间，分析WT1/P53对IGF-I-R的相互作用 启动子在体外，并验证这种相互作用在调节 内源性IGF-I-R

DESCRIPTION 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.