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）最近已成为行业最喜欢的目标之一，因为它在正常和异常细胞的生长中可能作用。从秀丽隐杆线虫到哺乳动物，IGF-IR信号传导在寿命中也起着重要作用。 IGF轴以非冗余的方式控制动物和培养细胞的50％的生长，主要是通过其对接蛋白，胰岛素受体底物-1（IRS-1）的激活。 IRS-1（或其在果蝇中的同源物）的删除会导致大约50％的动物或细胞。我们最近发现，IRS-1易位到核结合并激活UBF1（上游结合因子1），该蛋白质可调节RNA聚合酶I活性，从而调节细胞（体内）大小。在此应用中，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核糖体DNA启动子激活的机制； 3）IRS-1与SV40 T抗原和选择的RNA聚合酶-2导向启动子N的物理和生物学相互作用，细胞的核，这种相互作用可能对细胞的转化至关重要。这些研究直接影响了我们对癌症生物学的基本知识，并可能阐明衰老的机制。