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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多个基因步骤导致由P53和视网膜母细胞瘤(RB)肿瘤抑制基因控制的两个肿瘤抑制通路的解除调控，为人类的癌症铺平了道路。P53和Rb蛋白需要上游效应器和激活器之间的通信来感知细胞何时处于压力之下。由INK4a/ARF基因座编码的两种蛋白质p16INK4a和p19ARF分别针对Rb和P53抑癌基因。这四种蛋白质是人类癌症中受影响最频繁的基因之一。我们希望了解这些蛋白质在人类癌症发展中的个体贡献，以及它们可能如何受到上游信号的调控。我们以前的研究表明，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，它引导过度增殖的细胞经历P53依赖的细胞周期停滞或凋亡。这是通过ARF的相互作用和p53负调控因子MDM2的核仁隔离实现的。然而，来自我们实验室的越来越多的证据表明，ARF-P53-MDM2通路并不是严格意义上的线性，这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肿瘤抑制能力背后的基本机制，并将这些过程与我们日益增长的对人类癌症进展的了解联系起来。此外，ARF似乎可以对抗核糖体的加工以及成熟核糖体成分的核质穿梭。