CHARACTERIZATION OF P53-INDEPENDENT ARF PATHWAY

P53 独立 ARF 通路的表征

• 批准号: 7953921
• 负责人: Jason Weber
• 金额: $ 0.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953921
• 关键词: Affect; Apoptosis; CDKN2A gene; Cell Cycle Arrest; Cell Nucleolus; Cells; Communication; Computer Retrieval of Information on Scientific Projects Database; Funding; Genes; Genetic; Goals; Grant; Human; Human Development; Individual; Institution; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; Oncogene Proteins; Pathway interactions; Process; Protein p53; Proteins; Research; Research Personnel; Resources; Retinoblastoma; Retinoblastoma Protein; Ribosomes; Signal Transduction; Source; Stress; TP53 gene; Tumor Suppressor Proteins; United States National Institutes of Health; biomedical resource; nucleocytoplasmic transport; p19ARF; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple genetic steps that result in the deregulation of two tumor suppressor pathways, governed by the p53 and retinoblastoma (Rb) tumor suppressors, pave the road to cancer in humans. The p53 and Rb proteins require communication between upstream effectors and activators to sense when a cell is under stress. Two proteins encoded by the INK4a/ARF locus, p16INK4a and p19ARF, functionally target the Rb and p53 tumor suppressors, respectively. These four proteins are among the most frequently affected genes in human cancer. We wish to understand the individual contribution of these proteins to the development of human cancers and how they may be regulated by upstream signals. We previously showed that ARF is induced by inappropriate mitogenic signals, such as those emanating from the Myc and Ras oncoproteins, and it diverts hyperproliferating cells to undergo p53-dependent cell cycle arrest or apoptosis. This is accomplished through ARF's interaction and nucleolar sequestration of the p53-negative regulator Mdm2. However, mounting evidence from our lab suggests that the ARF-p53-Mdm2 pathway is not be strictly linear, opening the door for further research into other ARF functions within the nucleolus. Our goal is to understand the basic mechanisms behind ARF's tumor suppressive capabilities and to relate these processes to our growing knowledge of human cancer progression. Additionally, ARF appears to antagonize ribosome processing as well as the nucleocytoplasmic shuttling of maturing ribosomal components.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 多个遗传步骤导致由 p53 和视网膜母细胞瘤 (Rb) 肿瘤抑制因子控制的两条肿瘤抑制通路失调，为人类癌症铺平了道路。 p53 和 Rb 蛋白需要上游效应子和激活子之间的通信来感知细胞何时处于压力下。 INK4a/ARF 基因座编码的两种蛋白质 p16INK4a 和 p19ARF 分别在功能上靶向 Rb 和 p53 肿瘤抑制因子。这四种蛋白质是人类癌症中最常受影响的基因之一。我们希望了解这些蛋白质对人类癌症发展的个体贡献以及它们如何受到上游信号的调节。我们之前表明，ARF 是由不适当的有丝分裂信号诱导的，例如来自 Myc 和 Ras 癌蛋白的信号，它会使过度增殖的细胞发生 p53 依赖性细胞周期停滞或凋亡。这是通过 ARF 的相互作用和 p53 负调节因子 Mdm2 的核仁隔离来实现的。然而，来自我们实验室的越来越多的证据表明，ARF-p53-Mdm2 通路并不是严格线性的，这为进一步研究核仁内其他 ARF 功能打开了大门。 我们的目标是了解 ARF 肿瘤抑制能力背后的基本机制，并将这些过程与我们不断增长的人类癌症进展知识联系起来。此外，ARF 似乎会拮抗核糖体加工以及成熟核糖体成分的核质穿梭。