INTEGRATION OF ONCOGENIC SIGNALS BY THE NUCLEOLAR ARF-NPM NETWORK

通过核仁 ARF-NPM 网络整合致癌信号

• 批准号: 7524819
• 负责人: Jason Weber
• 金额: $ 31.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524819
• 关键词: Acute; Affect; Basic Science; Benign; Binding; Biogenesis; Biology; Cancer Biology; Cancer Patient; Cell Cycle; Cell Nucleolus; Cells; Clinical; Complex; Data; Genes; Growth; Human; In Vitro; Investigation; Knowledge; Label; Malignant Neoplasms; Mus; Mutate; Oncogenic; Organelles; Prevalence; Property; Proteins; Proto-Oncogenes; Public Health; Rate; Ribosomes; Role; Second Primary Cancers; Signal Transduction; TP53 gene; TSC1 gene; Time; Tumor Suppressor Proteins; Work; base; cell growth; cell transformation; in vivo; inhibitor/antagonist; mutant; novel; nucleophosmin; prevent; protein expression; protein p68; stoichiometry; therapeutic target; tumor

DESCRIPTION (provided by applicant): Initially described as an organelle contained within specific chromosomal regions, the nucleolus has advanced through the past century imparting much knowledge about cell and cancer biology along the way. Once hindered with the label as being the static center of ribosome biogenesis, a newfound appreciation for this visible organelle has been established in recent years. One of the most dynamic occupants of the mammalian nucleolus is the ARF tumor suppressor protein. Since its discovery, the mechanism behind ARF's tumor suppressive function has been under intense investigation. Initially touted as a bona fide inhibitor of the p53 negative regulator, Mdm2, more recent studies have identified a p53-independent role for ARF in suppressing tumor formation in mice and humans. Much of the more recent work has focused on the novel localization of ARF in the nucleolus, a seemingly benign organelle in terms of transformation properties. One of the least understood aspects of ARF biology is what is ARF doing in the nucleolus. Numerous labs, including ours, have identified the nucleophosmin (NPM) proto-oncogene as a nucleolar binding partner of ARF. Our preliminary data demonstrates that hypergrowth signals emanating from the loss of the Tsc1 tumor suppressor stimulate the protein expression of both NPM and ARF in an effort to influence ribosome synthesis rates. Additionally, basal nucleolar ARF proteins interact with a pool of NPM in the nucleolus and acute loss of these basal ARF molecules results in dysregulated NPM function and increased ribosome biogenesis. Loss of nucleolar ARF alters the landscape of the nucleolus, allowing for proteins, such as the p68 RNA helicase, to interact more readily with NPM to potentially promote ribosome biogenesis and cell transformation. We hypothesize that ARF resides in the nucleolus to tightly regulate ribosome biogenesis through the sensing of hypergrowth signals and to halt unwarranted NPM-p68 activities. Based on our preliminary data and our stated hypothesis, three specific aims are proposed: 1) Determine how oncogenic growth signals are interpreted by the nucleolar ARF-NPM complex, 2) Establish the physical and functional interaction of the p68 RNA helicase with NPM, and 3) Determine the in vitro and in vivo ability of ARF to act as a nucleolar checkpoint protein. PUBLIC HEALTH NARRATIVE: The ARF tumor suppressor is the second most commonly mutated gene in human cancers, second only to p53. We are just beginning to appreciate how this critical tumor suppressor functions to prevent unwarranted cell growth and proliferation. We seek to understand the mechanism behind ARF's ability to regulate p53-independent growth arrest in vivo and to move these findings into a more clinical setting where novel ARF-targeted therapeutics might affect a broad spectrum of cancer patients. Thus, basic research into ARF biology is appropriate given its mutational prevalence in human cancers.

描述（由申请人提供）：核仁最初被描述为包含在特定染色体区域内的细胞器，在过去的一个世纪中不断发展，一路传授了许多有关细胞和癌症生物学的知识。曾经因为核糖体生物发生的静态中心这一标签而受到阻碍，但近年来人们对这种可见细胞器有了新的认识。 ARF 肿瘤抑制蛋白是哺乳动物核仁中最具活力的占据者之一。自发现以来，ARF 的肿瘤抑制功能背后的机制一直在深入研究中。最初被吹捧为 p53 负调节因子 Mdm2 的真正抑制剂，最近的研究发现 ARF 在抑制小鼠和人类肿瘤形成方面具有独立于 p53 的作用。最近的大部分工作都集中在 ARF 在核仁中的新定位，就转化特性而言，核仁是一种看似良性的细胞器。 ARF 生物学最不为人所知的方面之一是 ARF 在核仁中的作用。包括我们在内的许多实验室已确定核磷蛋白 (NPM) 原癌基因是 ARF 的核仁结合伴侣。我们的初步数据表明，Tsc1 肿瘤抑制因子缺失所发出的过度生长信号会刺激 NPM 和 ARF 的蛋白表达，从而影响核糖体合成速率。此外，基础核仁 ARF 蛋白与核仁中的 NPM 库相互作用，这些基础 ARF 分子的急性丢失会导致 NPM 功能失调和核糖体生物合成增加。核仁 ARF 的缺失会改变核仁的结构，使 p68 RNA 解旋酶等蛋白质更容易与 NPM 相互作用，从而潜在地促进核糖体生物发生和细胞转化。我们假设 ARF 存在于核仁中，通过感知过度生长信号来严格调节核糖体生物合成，并阻止不必要的 NPM-p68 活性。根据我们的初步数据和我们提出的假设，提出了三个具体目标：1）确定核仁 ARF-NPM 复合物如何解释致癌生长信号，2）建立 p68 RNA 解旋酶与 NPM 的物理和功能相互作用，以及 3）确定 ARF 作为核仁检查点蛋白的体外和体内能力。公共卫生叙述：ARF 肿瘤抑制基因是人类癌症中第二常见的突变基因，仅次于 p53。我们才刚刚开始了解这种关键的肿瘤抑制因子如何发挥作用来防止不必要的细胞生长和增殖。我们试图了解 ARF 在体内调节不依赖于 p53 的生长停滞的能力背后的机制，并将这些发现转移到更临床的环境中，在这种环境中，新型 ARF 靶向疗法可能会影响广泛的癌症患者。因此，考虑到 ARF 在人类癌症中的突变流行率，对 ARF 生物学进行基础研究是适当的。