Role of the SUMO Protease Ulp1 in Cell Cycle Progression

SUMO 蛋白酶 Ulp1 在细胞周期进展中的作用

• 批准号: 7515830
• 负责人: Oliver none Kerscher
• 金额: $ 21.6万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7515830
• 关键词: Address; Affect; Age; Binding; Biochemical Genetics; Biological; Biological Models; Cancer Model; Cell Cycle; Cell Cycle Progression; Cell Death; Cell division; Cell physiology; Cells; Complex; Defect; Developmental Process; Endopeptidases; Ensure; Enzymes; Eukaryota; Eukaryotic Cell; Excision; Exhibits; Family; Future; Genetic; Goals; Homologous Protein; Human; Individual; Institution; Life; Link; Localized; Malignant Neoplasms; Malignant neoplasm of prostate; Mammalian Cell; Mediating; Mitosis; Mitotic; Modeling; Molecular; Molecular Biology; Mus; Nuclear Envelope; Nuclear Pore Complex; Numbers; Orthologous Gene; Pathogenesis; Peptide Hydrolases; Phenotype; Play; Post-Translational Protein Processing; Process; Production; Proteins; Public Health; Purpose; Reporting; Research; Research Design; Research Project Grants; Research Proposals; Role; Saccharomycetales; Small Ubiquitin-Related Modifier Proteins; Spontaneous abortion; Students; Techniques; Time; Ubiquitin; Ulp1 protease; Work; Yeasts; college; design; interest; leukemia; member; mutant; novel; protein function; therapeutic target; tissue culture; ubiquitin ligase

DESCRIPTION (provided by applicant): Cells utilize the dynamic addition and removal of SUMO, a small ubiquitin-like modifier to modulate protein function. SUMO protein modification exist in yeast, humans and possibly all eukaryotes. In humans, dysregulation of SUMO dynamics plays a role in certain forms of leukemia and prostate cancer. Furthermore, several gene products that are involved in cancer pathogenesis are regulated by the addition and removal of SUMO. Production of mature, conjugation competent SUMO as well as desumoylation substrates depends on proteases of the Ulp family. Mammalian cells have at least 7 Ulp-like molecules. The founding members of the Ulp family are the yeast Ulp1 and Ulp2 proteins, two SUMO proteases that were identified in the Hochstrasser lab. Absence of Ulp1p mediated desumoylation leads to mitotic arrest and cell death in budding yeast. Despite a growing number of known sumoylated proteins in yeast, little is known about which individual substrates Ulp1 must desumoylate in order to ensure proper cell cycle progression. Since Ulp1p localizes to the nuclear pore complex we hypothesize that this SUMO protease may help to control important cell cycle regulators in transit across the nuclear envelope. The main goal of this project is to identify evolutionarily conserved proteins that interact with Ulp1p and may be important for the cell division cycle. To achieve this goal cell biological, genetic, and biochemical approaches will be used. Specifically, 1) the exact time at which Ulp1p function is required during mitosis will be determined using cell biological techniques. 2) Using a ulp1 mutant ULP1 interactors will be isolated genetically and characterized. 3) The function of a novel Ulp1 interactor that can bind SUMO, Hex3, will be analyzed. In particular, our studies are designed to understand the functional roles of Ulp1p and to lay the framework for future studies of similar situations and homologous proteins in mammalian cancer models. PUBLIC HEALTH RELEVANCE: Budding yeast cells expressing a defective SUMO protease enzyme (Ulp1) exhibit aberrant mitosis and altered cell cycle progression. In humans these phenomena are linked to spontaneous abortions, ageing and cancer. Studying the ulp1 mutant has helped us to identify some of the responsible molecules.

描述（由申请人提供）：细胞利用SUMO（一种小的泛素样修饰剂）的动态添加和去除来调节蛋白质功能。SUMO蛋白修饰存在于酵母、人类和可能所有的真核生物中。在人类中，SUMO动力学的失调在某些形式的白血病和前列腺癌中起作用。此外，参与癌症发病机制的几种基因产物通过SUMO的添加和去除来调节。成熟的、有缀合能力的SUMO以及去小糖基化底物的产生取决于Ulp家族的蛋白酶。哺乳动物细胞至少有7个Ulp样分子。Ulp家族的创始成员是酵母Ulp 1和Ulp 2蛋白，这两种SUMO蛋白酶是在Hochstrasser实验室中鉴定的。在芽殖酵母中，缺乏Ulp1p介导的去小糖基化导致有丝分裂停滞和细胞死亡。尽管酵母中已知的sumoylated蛋白越来越多，但很少有人知道Ulp 1必须去sumoylate以确保适当的细胞周期进程。由于Ulp1p定位于核孔复合物，我们推测，这种SUMO蛋白酶可能有助于控制重要的细胞周期调节剂在整个核膜的运输。该项目的主要目标是鉴定与Ulp1p相互作用的进化保守蛋白，这些蛋白可能对细胞分裂周期很重要。为了实现这一目标，将使用细胞生物学、遗传学和生物化学方法。具体而言，1）将使用细胞生物学技术确定有丝分裂期间需要Ulp1p功能的确切时间。2)使用ulp1突变体，将从遗传上分离ULP1相互作用物并进行表征。3)一种新的Ulp1相互作用，可以结合SUMO，Hex3的功能进行了分析。特别是，我们的研究旨在了解Ulp1p的功能作用，并为将来在哺乳动物癌症模型中研究类似情况和同源蛋白奠定框架。公共卫生关系：表达缺陷SUMO蛋白酶（Ulp 1）的芽殖酵母细胞表现出异常的有丝分裂和改变的细胞周期进程。在人类中，这些现象与自然流产、衰老和癌症有关。对ulp1突变体的研究帮助我们确定了一些负责的分子。