Role of the SCF/FBX011 ubiquitin ligase in the control of cell proliferation

SCF/FBX011 泛素连接酶在细胞增殖控制中的作用

基本信息

批准号：
8325492
负责人：
MICHELE PAGANO
金额：
$ 5.34万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-28 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8325492
关键词：
Address Animal Model Apoptosis Applications Grants Argentina Award Basic Science Binding Biological Biological Assay Cell Cycle Cell Differentiation process Cell Fate Control Cell Proliferation Cell division Cell physiology Cells Characteristics Commit Complex Country Cullin Proteins DNA Damage DNA biosynthesis DNA damage checkpoint DNA-Directed DNA Polymerase Data Development Disease E2F1 gene Enzymes Eukaryotic Cell F-Box Proteins Family Fingers Functional disorder Future Gene Mutation Genetic Transcription Genomic Instability Genotoxic Stress Grant Human IL27RA gene In Vitro Income Institutes International Laboratories Ligase Link Malignant - descriptor Malignant Neoplasms Mediating Molecular Molecular Mechanisms of Action Mutation Normal Cell Orphan Pathology Pathway interactions Phenotype Play Process Protein Biosynthesis Proteins Proteolysis Proteomics RNA Interference Recruitment Activity Research Role Site Societies Somatic Cell Genetics Specificity Substrate Specificity Supervision System Testing Therapeutic Ubiquitin United States National Institutes of Health Vertebrates Viral base cancer cell circadian pacemaker combinatorial human disease in vivo insight member multicatalytic endopeptidase complex mutant novel overexpression parent grant protein complex protein degradation receptor reconstitution research study response scaffold tissue culture tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Unidirectional progression through the cell cycle depends on the specific, rapid, and temporally controlled proteolysis of key regulators by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases confer substrate specificity to the UPS. Therefore, it is not surprising that alteration of the functions of these enzymes contribute to the development of a wide variety of diseases, including cancer. SCF (Skp1, Cul1, F-box protein) complexes (also known as Cul1-Ring-ligases or CRL1) represent a family of E3 ubiquitin ligases involved in crucial cellular pathways as gene transcription, protein synthesis, cell division, DNA-damage checkpoints, the circadian clock, and apoptosis. F-box proteins play a pivotal role in the SCF complex by functioning as receptors that directly bind to and recruit substrates. Although certain F-box proteins have been characterized, most of them have not yet been matched to their cognate substrates and, therefore, are defined "orphan." FBXO11 is an orphan F-box protein involved in regulating cell fate determination, and mutations of the gene encoding this protein have been associated with the onset and progression of pathological conditions both in humans and in animal models. Using unbiased proteomic screens, we have identified Cdt2 as a novel, putative substrate of SCFFBXO11. Cdt2 belongs to the family of DCAF proteins that are the substrate receptors of multi-subunit E3 complexes known as CRL4 (Cul4-Ring- ligase). CRL4Cdt2 controls the degradation of key regulators of proliferation (Cdt1, p21, Set8, etc.) in both normal and cancer cells; however, the mechanisms controlling the degradation of Cdt2 itself have remained unknown. Under the present application, we will study the molecular mechanisms and pathways regulated by both FBXO11 and Cdt2. To this end we will address how, when (Aim1), and why (Aim2) the SCFFBXO11 control the degradation of Cdt2. Taking together, our studies will provide novel insights into the regulatory circuits that control cell proliferation and differentiation. Moreover, they may offer a platform for future studies to explore the role of FBXO11 and Cdt2 in various cellular proliferative disorders. The proposed research is an extension of the NIH grant R37-CA076584 (07/01/1-06/30/2016) and represents a collaborative effort with Dr. Mario Rossi, a Group Leader at the BioMedicine Institute of Buenos Aires-CONICET-Partner Institute of the Max Planck Society in Argentina, the low- to middle-income countries (LMIC) site associated with this application, where the largest part of the project will be carried out under the supervision of Dr. Rossi.

描述（由申请人提供）：细胞周期的单向进展取决于泛素蛋白酶体系统（UPS）对关键调节因子的特异性、快速和时间控制的蛋白水解作用。 E3 泛素连接酶赋予 UPS 底物特异性。因此，这些酶功能的改变导致包括癌症在内的多种疾病的发生也就不足为奇了。 SCF（Skp1、Cul1、F-box 蛋白）复合物（也称为 Cul1-Ring-ligases 或 CRL1）代表 E3 泛素连接酶家族，参与基因转录、蛋白质合成、细胞分裂、DNA 损伤检查点等关键细胞通路、生物钟和细胞凋亡。 F-box 蛋白作为直接结合和招募底物的受体，在 SCF 复合物中发挥着关键作用。尽管某些 F-box 蛋白已被表征，但其中大多数尚未与其同源底物匹配，因此被定义为“孤儿”。 FBXO11 是一种孤儿 F-box 蛋白，参与调节细胞命运决定，编码该蛋白的基因突变与人类和动物模型中病理状况的发生和进展有关。使用无偏见的蛋白质组学筛选，我们已将 Cdt2 鉴定为 SCFFBXO11 的新型假定底物。 Cdt2 属于 DCAF 蛋白家族，该家族是称为 CRL4（Cul4-Ring-ligase）的多亚基 E3 复合物的底物受体。 CRL4Cdt2 控制正常细胞和癌细胞中增殖关键调节因子（Cdt1、p21、Set8 等）的降解；然而，控制 Cdt2 本身降解的机制仍然未知。在本申请中，我们将研究FBXO11和Cdt2调节的分子机制和途径。为此，我们将讨论 SCFFBXO11 如何、何时（目标 1）以及为何（目标 2）控制 Cdt2 的降解。总而言之，我们的研究将为控制细胞增殖和分化的调节回路提供新的见解。此外，它们可能为未来研究探索 FBXO11 和 Cdt2 在各种细胞增殖性疾病中的作用提供一个平台。拟议的研究是 NIH 拨款 R37-CA076584 (07/01/1-06/30/2016) 的延伸，代表了与布宜诺斯艾利斯生物医学研究所组长 Mario Rossi 博士的合作成果-CONICET-阿根廷马克斯·普朗克学会的合作伙伴研究所是与此应用相关的中低收入国家 (LMIC) 站点，该项目的最大部分将在该研究所下进行罗西博士的监督。