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

基本信息

批准号：
8005172
负责人：
Oliver none Kerscher
金额：
$ 4.05万
依托单位：
COLLEGE OF WILLIAM AND MARY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-19 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005172
关键词：
Address Affect Age Binding Biochemical Biological Biological Models Cancer Model Cell Cycle Cell Cycle Progression Cell Death Cell division Cell physiology Cells Complex Defect Developmental Process Ensure Enzymes Eukaryota Eukaryotic Cell Excision Exhibits Family Future Genetic Goals Homologous Protein Human Individual Institution Life Link Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Mediating Mitosis Mitotic Modeling Molecular Molecular Biology Mus Nuclear Envelope Nuclear Pore Complex Orthologous Gene Pathogenesis Peptide Hydrolases Phenotype Play Post-Translational Protein Processing Process Production Proteins 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 public health relevance therapeutic target tissue culture ubiquitin ligase

项目摘要

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的动态添加和去除，Sumo（一种小型泛素样修饰符）来调节蛋白质功能。酵母，人类和所有真核生物中都存在相扑蛋白的修饰。在人类中，相扑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，与Sumo的添加和去除相关的几种参与癌症发病机理的基因产物受到调节。成熟，共轭合作的相扑以及desumoylation底物的产生取决于ULP家族的蛋白酶。哺乳动物细胞至少具有7个ULP样分子。 ULP家族的创始成员是酵母ULP1和ULP2蛋白，这是Hochstrasser Lab中鉴定出的两个SUMO蛋白酶。缺乏ULP1P介导的desumoylation会导致酵母出现的有丝分裂停滞和细胞死亡。尽管在酵母中越来越多的已知sumoytated蛋白质，但对哪些单个底物ULP1必须去果皮几乎了解，以确保适当的细胞周期进展。由于ULP1P定位于核孔复合物，因此我们假设这种EMO蛋白酶可能有助于控制重要的细胞周期调节剂在整个核包膜中的过境中。该项目的主要目标是识别与ULP1P相互作用的进化保守蛋白，并且对于细胞分裂周期可能很重要。为了实现此目标细胞生物学，遗传和生化方法。具体而言，1）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ULP1相互作用子将在遗传上分离并表征。 3）将分析可以结合Sumo Hex3的新型ULP1相互作用的功能。特别是，我们的研究旨在了解ULP1P的功能作用，并为在哺乳动物癌症模型中对类似情况和同源蛋白质的未来研究奠定框架。公共卫生相关性：表达不良emo蛋白酶酶（ULP1）的萌芽酵母细胞表现出异常有丝分裂和细胞周期进展的改变。在人类中，这些现象与自发堕胎，衰老和癌症有关。研究ULP1突变体有助于我们确定一些负责的分子。