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: 8069926
• 负责人: Jason Weber
• 金额: $ 30.59万
• 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/8069926
• 关键词: Acute; Affect; Basic Science; Benign; Binding; Biogenesis; Biology; Cancer Biology; Cancer Patient; Cell Cycle; Cell Nucleolus; Cell Proliferation; Cellular biology; Clinical; Complex; Data; Genes; Growth; Health; Human; In Vitro; Investigation; Knowledge; Label; Malignant Neoplasms; Mus; Mutate; Oncogenic; Organelles; Prevalence; Property; Proteins; Proto-Oncogenes; Ribosomes; Role; Second Primary Cancers; Signal Transduction; 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）：最初被描述为特定染色体区域内的细胞器，核仁在过去的一个世纪中已经发展到了途中，沿此过程中赋予了有关细胞和癌症生物学的很多知识。一旦将标签阻碍为核糖体生物发生的静态中心，近年来已经建立了对这种可见细胞器的新发现的欣赏。哺乳动物核仁的最动态乘员之一是ARF肿瘤抑制蛋白。自发现以来，ARF抑制功能背后的机制一直受到严格的研究。最初被吹捧为p53阴性调节剂MDM2的真正抑制剂，最近的研究已经确定了ARF在抑制小鼠和人类肿瘤形成中的p53独立的作用。最近的许多工作都集中在ARF在Nucleolus中的新定位，这是在转化特性方面看似良性的细胞器。 ARF生物学最了解的方面之一是ARF在核仁中所做的事情。包括我们在内的许多实验室已经确定了核素（NPM）原癌基因是ARF的核仁结合伴侣。我们的初步数据表明，从TSC1肿瘤抑制剂丧失产生的高生长信号刺激NPM和ARF的蛋白质表达，以影响核糖体合成速率。此外，基底核仁ARF蛋白与核仁中NPM池相互作用，这些基底ARF分子的急性损失导致NPM功能失调并增加核糖体生物发生。核仁ARF的丧失改变了核仁的景观，允许蛋白质（例如p68 RNA解旋酶）与NPM更容易相互作用，从而有可能促进核糖体生物发生和细胞转化。我们假设ARF驻留在核仁中，通过感测高生长信号并停止无理的NPM-P68活性来严格调节核糖体生物发生。基于我们的初步数据和陈述的假设，提出了三个具体目的：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的体外和体外能力以ACTACTACTACTACT POSTIONT ACTPOTENT OCTPORT POTCONT PONTIONT Pottoint Point Pottoint Pottoint。公共卫生叙事：ARF肿瘤抑制剂是人类癌症中第二常见的突变基因，仅次于P53。我们才刚刚开始欣赏这种关键肿瘤抑制剂的功能，以防止不必要的细胞生长和增殖。我们试图了解ARF调节体内p53独立生长停滞能力的能力背后的机制，并将这些发现转移到更临床的环境中，新型ARF靶向治疗可能会影响广泛的癌症患者。因此，鉴于其在人类癌症中的突变流行率，对ARF生物学的基础研究是适当的。