Novel Substrates of SCF Ubiquitin Ligases in Cell Cycle Control and Cancer

SCF 泛素连接酶在细胞周期控制和癌症中的新型底物

• 批准号: 7382542
• 负责人: MICHELE PAGANO
• 金额: $ 20.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-04 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382542
• 关键词: Apoptosis; Area; Binding; Biology, Other; Bortezomib; Boxing; CDKN1A gene; Cancer Biology; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell physiology; Cells; Class; Clinic; Complex; Cyclin E; DNA Repair; Disease; Elements; Ensure; Epithelial; F-Box Proteins; Grant; Gusperimus; Human; Immune response; In Vitro; Ligase; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Numbers; Oncogenic; Orphan; Pharmaceutical Preparations; Pharmacologic Substance; Process; Proteasome Inhibitor; Protein Overexpression; Proteins; Proteolysis; Proto-Oncogenes; RNA Interference; Recruitment Activity; Research; Rest; Role; SKP Cullin F-Box Protein Ligases; Screening procedure; Signal Transduction Pathway; Specificity; Speed; System; Testing; Therapeutic; Time; Tissues; Tumor Suppressor Proteins; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitin-mediated Proteolysis Pathway; Variant; Work; base; inhibitor/antagonist; interest; mouse model; multicatalytic endopeptidase complex; novel; oncoprotein p21; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; protein degradation; response; small molecule libraries; tissue culture

The ubiquitin system is a major regulatory mechanism of cellular processes in which speed, specificity, and timing are critical. Ubiquitin-mediated proteolysis of key substrates controls cell cycle progression, signal transduction pathways, differentiation,apoptosis, DNA repair and the immune response. This process is mediated by a multimericmachine, composed of a regulatory ubiquitin-targeting component and an effector protein degradation engine. Theregulatory component, which targets ubiquitin to proteins destined for degradation, is itself composed of several multimeric elements (e.g., the SCFubiquitin ligase complexes) that contribute much of the specificity inherent in the process. In humans, there are sixty-eight SCFligases, each characterized by a different F-boxprotein subunit that provides specificity by directly recruiting the substrate to the rest of the ligase and,ultimately, to the ubiquitin-conjugating enzyme. Notably, only three out of 68 human SCFubiquitin ligases (containing the F-box proteins UTrcp, Fbw7 and Skp2, respectively) have well-established substrates, many of which are involved in cell cycle control. The remaining 65F-box proteins are considered as "orphan" since their substrates still await discovery. We have recently developed a novel immunopurification strategy that enriches for substrates of F-box proteins followed by mass spectrometry analysis. We will systematicallyidentify biologically significantsubstrates of human orphan F-boxproteins (Specific Aim 1). Because of our research interest, we will focus particularly on those orphan F-boxproteins that our preliminary results suggest to be involved in cell cycle control and cancer. Under Aim 2,we will validate the biologically most significantsubstrates identifiedunder Aim 1. Given their critical role in regulating cell proliferation, SCFligases are often the target of cancer- related deregulation and involved in oncogenic transformation. Therefore,the information gained from the proposed studies will be of direct relevance to cancer biology and other proliferative diseases.

泛素系统是细胞过程的主要调节机制， 特异性和时机至关重要。泛素介导的关键底物蛋白水解控制细胞 细胞周期进程、信号转导通路、分化、凋亡、DNA修复和细胞凋亡 免疫反应这一过程是由一个多聚体机器介导的， 泛素靶向组分和效应蛋白降解引擎。监管 将泛素靶向降解蛋白的组分本身由以下组成： 几个多聚体元件（例如，SCFubiquitin连接酶复合物），其贡献了大部分的 过程中固有的特殊性。在人类中，有68种SCF连接酶，每一种的特征在于： 通过不同的F盒蛋白亚基，通过直接募集底物来提供特异性， 连接酶的其余部分，并最终连接到泛素缀合酶。值得注意的是， 68种人SCFubiquitin连接酶（含有F-box蛋白UTrcp，Fbw 7和Skp 2， 分别）具有完善的底物，其中许多参与细胞周期控制。 剩余的65 F-box蛋白被认为是“孤儿”，因为它们的底物仍在等待 的发现 我们最近开发了一种新的免疫纯化策略， F-box蛋白，随后进行质谱分析。我们将系统地识别 人孤儿F-box蛋白的生物学重要底物（特异性目的1）。因为我们的 研究兴趣，我们将特别关注那些孤儿F-boxproteins，我们的初步 结果表明，它与细胞周期控制和癌症有关。在目标2下，我们将验证 目标1下确定的生物学上最重要的底物。 鉴于它们在调节细胞增殖中的关键作用，SCF连接酶通常是癌症的靶点。 相关的失调，并参与致癌转化。因此，获得的信息 从拟议的研究将直接相关的癌症生物学和其他增殖 疾病