Biology of the P53 Protein

P53 蛋白的生物学

• 批准号: 7138945
• 负责人: RENATO Luigi BASERGA
• 金额: $ 21.65万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7138945
• 关键词: DNA directed RNA polymerase; antigens; cell morphology; growth factor receptors; p53 gene /protein; proteins; role

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.

描述（由申请人提供）：1型胰岛素样生长因子受体（IGF-IR）最近因其在正常和异常细胞生长中可能发挥的作用而成为工业界最喜爱的靶标之一。 IGF-IR 信号传导在从秀丽隐杆线虫到哺乳动物的长寿中也发挥着重要作用。 IGF 轴以非冗余的方式控制动物和培养细胞约 50% 的生长，主要是通过激活其对接蛋白胰岛素受体底物 1 (IRS-1)。 IRS-1（或其在果蝇中的同源物）的缺失导致动物或细胞的大小大约减少 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，从而调节细胞（和身体）大小的蛋白质。在本申请中，我们拟研究：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与细胞核中SV40 T抗原和选定的RNA聚合酶2定向启动子的物理和生物相互作用，这种相互作用对于细胞的转化可能至关重要。这些研究对我们对癌症生物学的基础知识有直接影响，并可能揭示衰老机制。