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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 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。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 多个遗传步骤导致两种肿瘤抑制因子的失调 由p53和视网膜母细胞瘤（Rb）肿瘤抑制因子控制的通路，为肿瘤的发生铺平了道路。 人类的癌症之路p53和Rb蛋白需要在 上游效应子和激活子来感知细胞何时处于压力下。两种蛋白质 由INK4a/ARF基因座编码的p16INK4a和p19ARF功能性靶向Rb， p53肿瘤抑制因子。这四种蛋白质是人类 人类癌症中经常受影响的基因。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 由上游信号调节。我们先前表明，ARF是由 不适当的促有丝分裂信号，如Myc和Ras发出的信号 癌蛋白，并使过度增殖的细胞进行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 p53负调节因子Mdm 2的螯合。然而，越来越多的证据表明， 我们的实验室表明，ARF-p53-Mdm 2通路不是严格的线性， 为进一步研究核仁内的其他ARF功能打开了大门。 我们的目标是了解ARF的肿瘤抑制的基本机制， 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似乎拮抗核糖体加工以及 成熟核糖体成分的核质穿梭。