Biology of the P53 Protein

描述（申请人提供）：1型胰岛素样生长因子受体（IGF-IR）因其在正常和异常细胞的生长中可能发挥的作用，近年来成为工业界最喜欢的靶标之一。从秀丽隐杆线虫到哺乳动物，IGF-IR信号在长寿中也起着重要作用。IGF轴以一种非冗余的方式控制着动物和培养细胞中约50%的生长，主要通过其对接蛋白胰岛素受体底物-1 （IRS-1）的激活。删除IRS-1（或果蝇的同源物）会导致动物或细胞的大小缩小大约50%。我们最近发现IRS-1易位到细胞核，在那里它结合并激活UBF1（上游结合因子1），UBF1是一种调节RNA聚合酶I活性的蛋白质，因此调节细胞（和身体）的大小。在这个应用中，我们建议研究：1)IRS-1调节UBF1活性和/或稳定性的机制；2)核IRS-1与其他核仁蛋白竞争激活核糖体DNA启动子的机制；3) IRS-1与SV40 T抗原和细胞核中选定的RNA聚合酶2导向启动子的物理和生物相互作用，这种相互作用可能对细胞转化至关重要。这些研究对我们对癌症生物学的基本知识有直接的影响，并可能阐明衰老的机制。

DESCRIPTION (provided by applicant): The type 1 insulin-like growth factor receptor (IGF-IR) has recently become one of the favorite targets of industry for its possible role in the growth of normal and abnormal cells. IGF-IR signaling also plays a significant role in longevity, from C. elegans to mammalians. The IGF axis controls, in a non-redundant way, about 50% of growth in animals and cells in culture, largely through the activation of its docking protein, the insulin receptor substrate-1 (IRS-1). Deletion of IRS-1 (or its homologues in Drosophila) results in animals or cells that are roughly 50% in size. We have recently found that IRS-1 translocates to the nuclei where it binds and activates UBF1 (Upstream Binding Factor 1), a protein that regulates RNA polymerase I activity, and therefore cell (and body) size. In this application, we propose to study: 1) the mechanism by which IRS-1 regulates the activity and/or the stability of UBF1; 2) the mechanism(s) by which nuclear IRS-1 competes with other nucleolar proteins for the activation of the ribosomal DNA promoter; and 3) the physical and biological interactions of IRS-1 with the SV40 T antigen and selected RNA polymerase-2-directed promoters n the nuclei of cells, an interaction that may be critical for the transformation of cells. These studies have a direct impact on our basic knowledge of the biology of cancer and may throw light on mechanisms of aging.