Biology of the P53 Protein

P53 蛋白的生物学

• 批准号: 7284862
• 负责人: RENATO Luigi BASERGA
• 金额: $ 21.02万
• 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/7284862
• 关键词: Abnormal Cell; Agar; Aging; Animals; Binding; Biogenesis; Biological; Biology; Body Size; Caenorhabditis elegans; Cancer Biology; Cell Communication; Cell Cycle Progression; Cell Line; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cell Size; Cell division; Cells; Cultured Cells; DNA Polymerase I; DNA-Directed RNA Polymerase; Data; Docking; Drosophila genus; Embryo; Fibroblasts; Genes; Genetic Transcription; Grant; Growth; Growth Factor; Growth Factor Receptors; Homologous Gene; Human; Industry; Insulin-Like-Growth Factor I Receptor; Knowledge; Lead; Light; Link; Literature; Longevity; Messenger RNA; Molecular; Mus; Myeloid Cells; Nuclear; Nuclear Translocation; Oncogenic; Personal Satisfaction; Phosphorylation; Play; Protein Binding; Protein p53; Proteins; Proto-Oncogenes; RNA; RNA Polymerase I; RNA chemical synthesis; Reagent; Receptor Signaling; Recombinant DNA; Regulation; Research Personnel; Retinoblastoma Protein; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; SV40 T Antigens; Signal Transduction; Somatomedins; TP53 gene; Tumor Suppressor Proteins; Viral Oncogene; Viral Tumor Antigens; cell growth; cell transformation; in vivo; insight; insulin receptor substrate 1 protein; metaplastic cell transformation; neuronal cell body; programs; promoter; protein activation; research study; sialosyl-T antigen; size; transcription factor UBF

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（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。