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：
8513435
负责人：
MICHELE PAGANO
金额：
$ 5.08万
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/8513435
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）：通过细胞周期的单向进程取决于泛素蛋白 - 蛋白酶体系统（UPS）对关键调节剂的特定，快速和时间控制的蛋白水解。 E3泛素连接酶赋予UPS的底物特异性。因此，毫不奇怪，这些酶功能的改变有助于包括癌症在内的多种疾病的发展。 SCF（SKP1，CUL1，F-box蛋白）复合物（也称为CUL1-RING-LIGASE或CRL1）代表参与关键细胞途径的E3泛素连接酶家族，例如基因转录，蛋白质合成，细胞分裂，DNA-tamage检查点，DNA-taMage检查点，昼夜节律和凋亡。 F-box蛋白通过作为直接结合并募集底物的受体发挥作用，在SCF复合物中起关键作用。尽管已经表征了某些F-box蛋白，但其中大多数尚未与它们的同源底物相匹配，因此定义了“孤儿”。 FBXO11是一种参与调节细胞命运测定的孤儿F-box蛋白，编码该蛋白的基因的突变与人类和动物模型中病理条件的发作和进展有关。使用无偏的蛋白质组学筛选，我们将CDT2确定为SCFFFBXO11的新型，推定的底物。 CDT2属于DCAF蛋白的家族，该家族是称为CRL4（Cul4-环韧带）的多生育E3配合物的底物受体。 CRL4CDT2控制正常和癌细胞中增殖的关键调节剂（CDT1，P21，SET8等）的降解。但是，控制CDT2本身降解的机制尚不清楚。在本应用下，我们将研究由FBXO11和CDT2调节的分子机制和途径。为此，我们将解决（AIM1）以及为什么（AIM2）SCFFFBXO11控制CDT2的降解。综上所述，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，他们可能会为将来的研究提供一个平台，以探索FBXO11和CDT2在各种细胞增殖性疾病中的作用。 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该项目的最大部分将在Rossi博士的监督下进行。