Regulation Of A Novel Xenopus Polo-Like Kinase 1 Substrate

新型非洲爪蟾 Polo 样激酶 1 底物的调节

• 批准号: 7762116
• 负责人: Junjun Liu
• 金额: $ 12.94万
• 依托单位: CALIFORNIA STATE POLY U POMONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762116
• 关键词: Affect; Antineoplastic Agents; Apoptosis; Binding Sites; California; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell division; Cellular biology; Chromosomes; Cyclin B; Cytokinesis; Data; Deubiquitination; Development; Disease; Event; Family; Foundations; Gene Expression; Goals; Grant; Histone H2A; Histones; Homologous Gene; Human; Human Ubiquitin; In Vitro; Journals; Knowledge; Laboratory Research; Lead; Literature; Malignant Neoplasms; Mammalian Cell; Manuscripts; Mediating; Mitosis; Mitotic; Modification; Molecular; Oncogenes; Outcome; Peer Review; Peptide Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Polo-Box Domain; Prevention approach; Principal Investigator; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Publications; Regulation; Regulatory Pathway; Reporting; Research; Research Proposals; Rest; Role; Site; Structure; System; Testing; Universities; Work; Xenopus; Xenopus laevis; anaphase-promoting complex; base; cancer cell; cancer therapy; cell transformation; enzyme substrate; experience; human PLK1 protein; human disease; in vivo; innovation; novel; overexpression; public health relevance; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Polo-like kinase 1 (PLK1) plays a pivotal role at multiple steps of mitosis. Recently, PLK1 was implicated as an oncogene and has emerged as a potential target for anti-cancer drugs. Although significant progress has been made towards the understanding of the roles of PLK1 in cell cycle control, the molecular mechanisms by which it executes its functions during some important mitotic events remains elusive, largely due to the lack of identified physiological substrates for PLK1. This applicant presents preliminary data that focuses on a novel substrate for Xenopus polo- like kinase 1 (PLX1). The substrate has been identified and characterized as a deubiquitinase, whose mammalian homologue specifically modifies histone and affects cell division. The long- term goal of this proposed research is to define a novel mechanism by which PLX1 regulates the progression of cell cycle through the phosphorylation of this deubiquitinase. For the purposes of this application, the immediate or short-term goal is to clarify PLX1 regulation of the novel substrate and to determine the impact of such phosphorylation on the deubiquitinase. Since cyclin B/Cdk1 (MPF) is also suggested as a phosphorylating kinase for the deubiquitinase, our hypothesis is that PLX1 regulates the activity and possibly the localization of this deubiquitinase in vivo in coordination with MPF, which in turn, affects the progression of cell cycle. The hypothesis will be tested through the activities associated with following objectives: (1) Identify the main sites in the deubiquitinase phosphorylated by PLX1 and MPF; (2) Determine the impact of PLX1 phosphorylation on activity and localization of this substrate. The possibility that PLX1 phosphorylation activates the deubiquitinase and changes its localization will be examined; and (3) Determine whether phosphorylation of the substrate by PLX1 requires MPF priming. In many cases, PLX1 phosphorylation requires the priming of a PLX1 substrate by a distinct kinase in order to generate a binding site for polo box domain, a unique structure in the polo-like kinase family. The proposed studies are expected to result in accumulation of further preliminary data and lead to the submission of a full research proposal by the end of the project. PUBLIC HEALTH RELEVANCE: Polo-like kinase 1 is a key cell cycle regulator and has recently emerged as a promising target for anti-cancer drugs. This application proposes to study the regulation of a novel substrate for polo-like kinase 1. The study is expected to reveal a new mechanism of cell cycle control and may also provide a foundation for developing innovative strategies for treating human diseases such as cancer.

描述（由申请人提供）：Polo 样激酶 1 (PLK1) 在有丝分裂的多个步骤中发挥关键作用。最近，PLK1被认为是一种癌基因，并已成为抗癌药物的潜在靶点。尽管对于 PLK1 在细胞周期控制中的作用的理解已经取得了重大进展，但它在一些重要的有丝分裂事件中执行其功能的分子机制仍然难以捉摸，这主要是由于缺乏已确定的 PLK1 生理底物。本申请人提供了初步数据，重点关注非洲爪蟾 polo 样激酶 1 (PLX1) 的新型底物。该底物已被鉴定和表征为去泛素酶，其哺乳动物同源物特异性修饰组蛋白并影响细胞分裂。这项研究的长期目标是确定一种新机制，PLX1 通过这种去泛素酶的磷酸化来调节细胞周期的进展。就本申请而言，近期或短期目标是阐明新型底物的 PLX1 调节并确定此类磷酸化对去泛素酶的影响。由于细胞周期蛋白 B/Cdk1 (MPF) 也被认为是去泛素酶的磷酸化激酶，我们的假设是 PLX1 与 MPF 协调调节这种去泛素酶的活性并可能在体内定位，进而影响细胞周期的进展。该假设将通过与以下目标相关的活动进行检验：（1）确定PLX1和MPF磷酸化去泛素酶中的主要位点； (2)确定PLX1磷酸化对该底物的活性和定位的影响。将检查 PLX1 磷酸化激活去泛素酶并改变其定位的可能性； (3)确定PLX1对底物的磷酸化是否需要MPF引发。在许多情况下，PLX1 磷酸化需要通过不同的激酶引发 PLX1 底物，以便生成 polo box 结构域（polo 样激酶家族中的独特结构）的结合位点。拟议的研究预计将积累更多的初步数据，并在项目结束时提交完整的研究提案。 公共健康相关性：Polo 样激酶 1 是一种关键的细胞周期调节因子，最近已成为抗癌药物的一个有前景的靶点。本申请拟研究polo样激酶1的新型底物的调控。该研究有望揭示细胞周期控制的新机制，也可能为开发治疗癌症等人类疾病的创新策略奠定基础。