REGULATION OF AURORA-A KINASE ACTIVITIES BY AURORA-A INTERACTING PROTEINS

AURORA-A 相互作用蛋白对 AURORA-A 激酶活性的调节

• 批准号: 8168386
• 负责人: Ming-Ying Tsai
• 金额: $ 27.39万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168386
• 关键词: Address; Antineoplastic Agents; Binding; Biological Assay; Bladder; Breast; Cell Cycle; Cell Cycle Progression; Cell Polarity; Cell division; Centrosome; Colon; Complex; Computer Retrieval of Information on Scientific Projects Database; Coupled; Coupling; Cytokinesis; Diagnosis; Ensure; Epithelial; Functional disorder; Funding; Goals; Grant; In Vitro; Institution; Lead; Link; Malignant Neoplasms; Mitosis; Molecular; Neoplasm Metastasis; Neoplasms; Nuclear Envelope; Oncogenic; Ovarian; Pancreas; Pathway interactions; Pharmacogenomics; Phosphotransferases; Positioning Attribute; Process; Proteins; Publishing; Regulation; Research; Research Personnel; Resources; Role; Running; Signal Transduction; Source; Specificity; Target Populations; Therapeutic; United States National Institutes of Health; Xenopus; aurora-A kinase; cancer therapy; cancer type; cell transformation; egg; human STK6 protein; in vivo; inhibitor/antagonist; leukemia; novel; prevent; rapid diagnosis; scaffold; technology development; treatment strategy; tumor initiation; tumorigenesis

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. A major challenge facing cancer researchers is the development of technologies that significantly increase cure rates. This can only be achieved when we more fully understand cancer pathophysiology so that new anticancer agents can be discovered and better integration of pharmacogenomics can be developed. Aurora-A regulates multiple processes during the cell cycle and mitosis, including centrosome maturation, mitosis entry, nuclear envelope breakdown, bi-polar spindle formation and orientation, cytokinesis and cell polarity for asymmetric cell division. Thus, it is not surprising that Aurora-A is found to be amplified in a plethora of cancers particularly leukemia and those of epithelial origin, namely, breast, colon, bladder, ovarian, and pancreatic. Aurora-A may promote tumor initiation, progression and metastasis, and its malfunction may lead to cell transformation and cancer in a number of different ways. By interacting with distinct Aurora-A interacting proteins (AurAIPs), Aurora-A could assemble into different signaling modules, and its misregulation could transform cells into different cancer types that would differentially respond to Aurora-A inhibitors. Thus, there is an urgent need to understand how these pathways are activated and the result of their activation in order to understand their role in neoplasia and develop strategies for treatment. The long-term goal of our lab is to develop an effective diagnosis and therapeutic approach for cancer treatment utilizing the Aurora A kinase (Aurora-A) pathways. We proposed to use our understanding of how Aurora-A is activated by Aurora-A interacting proteins (AurAIPs) to develop translational applications, which will enhance the potential for population-targeted therapy. Our lab has characterized one of the several oncogenic AurAIPs, TPX2 as the first activator identified for Aurora-A. We have identified HURP as another AurAIP that activates Aurora-A in Xenopus egg extract. We will utilize novel assays developed by our lab to understand how Aurora-A is regulated by these structurally-unrelated AurAIPs in the various steps of mitosis. Understanding how each Aurora-A activation pathway links to tumorigenesis will facilitate rapid diagnosis and ensure appropriate population targeting of the Aurora-A pathway for anti-cancer therapy. A.1. Examine how AurAIPs interaction with Aurora-A is regulated Our published studies have characterized how one AurAIP, TPX2, spatiotemporally interacts with Aurora-A. Briefly, active TPX2 interacts with Aurora-A and targets Aurora-A to the spindle. Binding of Importin ¿/¿ to TPX2 prevents TPX2 from interacting with Aurora-A. Ran is a spatial regulator of spindle assembly that can release TPX2 from the inhibitory binding of Importin ¿/¿. In this aim, we will characterize how the interaction of other AurAIPs with Aurora-A is regulated in cell cycle progression. A.2. Examine whether the association of Aurora-A with its substrates is regulated by AurAIPs To function as molecular scaffolds, AurAIPs should be able to increase the efficiency of signaling by locally concentrating proteins and positioning Aurora-A in close proximity to its substrates. We will investigate whether AurAIPs also regulate pathway-specificity of Aurora-A by selectively bringing specific substrate(s) to Aurora-A. A.3. Examine how AurAIPs regulate Aurora-A function Although much effort has been devoted to studying the functions of AurAIPs individually, very few studies have been directed at understanding how the actions of these AurAIPs are coupled with one another and whether this coupling is important in the regulation of Aurora-A function. Studies addressing this question have been hampered by a lack of assays allowing one to address the complex issue of cross regulation. We plan to use a number of in vitro and in vivo assays to study how four AurAIPs might coordinately regulate Aurora-A function.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 癌症研究人员面临的主要挑战是发展可显着提高治愈率的技术。只有在我们更充分了解癌症病理生理学以便可以发现新的抗癌药并可以更好地整合药物基因组学时，才能实现这一目标。 Aurora-A在细胞周期和有丝分裂过程中调节多个过程，包括中心体成熟，有丝分裂进入，核包膜崩溃，双极纺锤体形成和方向，细胞因子和细胞极性的非对称细胞分裂。这是毫不奇怪的是，发现Aurora-A被发现在多种癌症和上皮起源的癌症中被放大，即，乳房，结肠，膀胱，卵巢，卵巢和胰腺。 Aurora-A可能会促进肿瘤的启动，进展和转移，其故障可能会以多种不同方式导致细胞转化和癌症。通过与不同的Aurora-A相互作用蛋白（AURAIPS）相互作用，Aurora-A可以组装成不同的信号传导模块，并且其不正调可能会将细胞转化为不同的癌症类型，这些癌症类型对Aurora-A抑制剂的反应不同。这是迫切需要了解这些途径是如何被激活的以及它们激活的结果，以了解它们在肿瘤中的作用并制定治疗策略。我们实验室的长期目标是开发一种利用Aurora A激酶（Aurora-A）途径的有效诊断和治疗方法来进行癌症治疗。我们建议利用对Aurora-A如何通过Aurora-A相互作用蛋白（AURAIP）激活Aurora-A来开发转化应用的理解，这将增强靶向人群靶向治疗的潜力。 我们的实验室已经将几种致癌的Auraips之一TPX2描述为第一个用于Aurora-A的激活剂。我们已经将Hurp确定为另一个激活Xenopus鸡蛋提取物中Aurora-A的Auraip。我们将利用实验室开发的新颖测定方法来了解Aurora-A如何受这些与结构无关的Auraips在有丝分裂的各个步骤中调节。了解每种Aurora-A激活途径如何与肿瘤发生联系将有助于快速诊断，并确保适当的人群靶向Aurora-A途径以进行抗癌治疗。 A.1。检查如何调节Auraips与Aurora-A的相互作用 我们已发表的研究表征了一个Auraip如何在空间上与Aurora-A暂时相互作用。简而言之，主动TPX2与Aurora-A相互作用，并将Aurora-A靶向主轴。与tpx2的结合与TPX2的结合可防止TPX2与Aurora-A相互作用。 RAN是主轴组件的空间调节剂，可以从importin» /€的抑制性结合中释放TPX2。在此目标中，我们将表征其他Auraips与Aurora-A的相互作用如何在细胞周期进程中调节。 A.2。检查Aurora-A与其底物的关联是否受Auraips的调节 为了充当分子支架，Auraips应该能够通过局部浓缩蛋白质并将Aurora-A定位在其底物附近，从而提高信号传导的效率。我们将研究Auraips是否还通过选择性将特定底物带到Aurora-A来调节Aurora-A的途径特异性。 A.3。检查Auraips如何调节Aurora-A功能 尽管已经大力研究了Auraips单独研究的功能，但很少有研究旨在了解这些Auraips的作用是如何相互耦合的，并且这种耦合在调节Aurora-A功能方面是否重要。缺乏解决问题的研究阻碍了解决这个问题的研究，这使人们无法解决复杂的交叉调节问题。我们计划使用许多体外和体内测定法研究四个Auraips如何协调调节Aurora-A功能。