CHARACTERIZATION OF P53-INDEPENDENT ARF PATHWAY

P53 独立 ARF 通路的表征

• 批准号: 8361355
• 负责人: Jason Weber
• 金额: $ 1.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361355
• 关键词: Affect; Apoptosis; CDKN2A gene; Cell Cycle Arrest; Cell Nucleolus; Cells; Communication; Funding; Genes; Genetic; Goals; Grant; Human; Human Development; Individual; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; National Center for Research Resources; Oncogene Proteins; Pathway interactions; Principal Investigator; Process; Protein p53; Proteins; Research; Research Infrastructure; Resources; Retinoblastoma; Retinoblastoma Protein; Ribosomes; Signal Transduction; Source; Stress; TP53 gene; Tumor Suppressor Proteins; United States National Institutes of Health; biomedical resource; cost; nucleocytoplasmic transport; p19ARF; retinoblastoma tumor suppressor; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 导致两种肿瘤抑制因子失调的多个遗传步骤 由 p53 和视网膜母细胞瘤 (Rb) 肿瘤抑制因子控制的通路，为 人类癌症之路。 p53 和 Rb 蛋白之间需要通讯 上游效应器和激活器来感知细胞何时处于压力下。两种蛋白质 由 INK4a/ARF 位点 p16INK4a 和 p19ARF 编码，功能上靶向 Rb 和 p53 肿瘤抑制因子。这四种蛋白质是最重要的 经常影响人类癌症的基因。我们希望了解个人 这些蛋白质对人类癌症发展的贡献以及它们如何可能 受上游信号调节。我们之前表明 ARF 是由 不适当的有丝分裂信号，例如来自 Myc 和 Ras 的信号 癌蛋白，它可以使过度增殖的细胞转向 p53 依赖性细胞周期 停滞或凋亡。这是通过 ARF 的相互作用和核仁来完成的 p53 负调节因子 Mdm2 的隔离。然而，越来越多的证据来自 我们的实验室表明 ARF-p53-Mdm2 通路不是严格线性的，打开了 进一步研究核仁内其他 ARF 功能的大门。 我们的目标是了解 ARF 抑制肿瘤的基本机制 能力并将这些过程与我们不断增长的人类癌症知识联系起来 进展。此外，ARF 似乎会拮抗核糖体加工以及 成熟核糖体成分的核细胞质穿梭。