Regulation of cell homeostasis by fbx4

fbx4 对细胞稳态的调节

• 批准号: 8145722
• 负责人: John Alan Diehl
• 金额: $ 36.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145722
• 关键词: Address; Alleles; Area; Attention; B-Cell Lymphomas; Binding; Biochemical; Biological; Breast Carcinoma; C-terminal; Cancerous; Cell Cycle; Cell Cycle Progression; Cell Maintenance; Cell Nucleus; Cell Proliferation; Cells; Chromosomal translocation; Colon Carcinoma; Complex; Crystallins; Cultured Cells; Cyclin D1; Cyclins; Data; Development; Doctor of Philosophy; Down-Regulation; Epithelial Cells; Esophageal carcinoma; Event; Exhibits; F Box Domain; G1 Phase; Gene Amplification; Genes; Grant; Growth; Head and Neck Neoplasms; Homeostasis; Human; In Vitro; Knock-out; Laboratories; Lead; Ligase; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Mus; Mutation; Nature; Neoplasms; Normal tissue morphology; Nuclear; Oncogenes; Oncogenic; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Regulation; Principal Investigator; Process; Property; Proteins; Proteolysis; Regulation; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Specificity; Substrate Domain; Substrate Specificity; Tissues; Tumor Suppression; Ubiquitin; Ubiquitination; Work; base; cell transformation; cofactor; deletion analysis; effective therapy; falls; in vivo; insight; melanoma; mutant; neoplastic cell; overexpression; prevent; programs; protein degradation; public health relevance; research study; tool; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The long-term objective of my research centers on elucidation of the mechanisms whereby extra-cellular signals are sensed by the cell cycle machinery and regulate cell cycle progression in normal versus tumor cells. This information will provide the necessary framework to elucidate how growth regulatory pathways are subverted in neoplasia. Our current studies focus on how growth-signaling pathways regulate the mitogenically responsive D-type cyclins and more specifically, how these pathways regulate accumulation of an active, nuclear cyclin D1-dependent kinase in normal versus cancerous cells. The noted overexpression of cyclin D1 in multiple human cancers highlights the importance of elucidating the mechanisms that regulate cyclin D1 activity. While cyclin D1 overexpression is a consequence of gene amplification and chromosome translocation in a subset of cancers, decreased cyclin D1 protein degradation, which depends on its phosphorylation on Thr286, is thought to be the key factor in a majority of cancers. Our progress in the characterization of this mechanism of cyclin D1 overexpression in cancer has been hindered by lack of information regarding the nature of the E3 ubiquitin ligase that directs cyclin D1 proteolysis. We have recently identified the SCF(Fbx4-(B crystallin) that controls cyclin D1 ubiquitination and degradation. This discovery has provided essential information and tools to assess the mechanisms that contribute to regulation of cyclin D1 accumulation during normal tissue development and the potential deregulation of cyclin D1 during malignant transformation. The identification of this E3 ligase as well as our recent preliminary studies lead to the overarching hypothesis that the SCF(Fbx4 -(B crystallin) ligase, via coordinated recognition of phospho- cyclin D1 by Fbx4 and (B crystallin, plays a critical role in the maintenance of cell growth and tissue maintenance. Experiments proposed in this grant will determine the contribution of Fbx4 to tissue homeostasis in vivo (Aim 1). We will utilize fbx4-/- cells to conclusively define the role of Fbx4 in the regulation of cyclin D1 and cell proliferation (Aim 2). The identification of residues in Fbx4 necessary for substrate recognition will be identified through characterization of mutant Fbx4 alleles identified in melanoma. PUBLIC HEALTH RELEVANCE: Overexpression of cyclin D1 in human cancer occurs frequently as a consequence of mutations in the machinery that destroys the cyclin D1 protein. In order to develop effective therapies that counter these events, it is necessary to identify proteins that direct cyclin D1 destruction and determine their role in the development of neoplasia. We have identified a critical component of the machinery, Fbx4, which directs destruction of the cyclin D1 protein, and the experiments described in this proposal will evaluate the biochemical and biological properties of Fbx4 with respect to human cancer.

描述（由申请人提供）：我的研究中心关于阐明机制的长期目标，从而通过细胞周期机制感知细胞外信号并调节正常细胞与肿瘤细胞的细胞周期进程。该信息将提供必要的框架，以阐明在肿瘤中如何颠覆生长调节途径。我们目前的研究集中于生长信号途径如何调节有丝分裂响应的D型细胞周期蛋白，更具体地说，这些途径如何调节正常细胞中活性的核细胞周期蛋白D1依赖性激酶的积累。多种人类癌症中细胞周期蛋白D1的过表达强调了阐明调节细胞周期蛋白D1活性的机制的重要性。虽然细胞周期蛋白D1的过表达是基因扩增和一部分癌症中染色体易位的结果，但降低了细胞周期蛋白D1蛋白降解，这取决于其对THR286的磷酸化，被认为是大多数癌症的关键因素。由于缺乏有关指导Cyclin d1蛋白水解的E3泛素连接酶的性质，我们在癌症中这种细胞周期蛋白D1过表达机制的表征的进展受到了阻碍。我们最近已经确定了控制细胞周期蛋白D1泛素化和降解的SCF（FBX4-（B晶蛋白））。这一发现提供了必不可少的信息和工具，以评估有助于细胞周期蛋白D1在正常组织发展过程中促进细胞周期蛋白D1积累的机制。总体假设，即通过FBX4和（B晶蛋白，在维持细胞生长和组织维持中对磷酸细胞周期蛋白D1的协调识别，通过对磷酸蛋白D1进行协调的识别，在维持该授予的实验中起着至关重要的作用。提出了FBX4对FBX4的贡献，将确定FBX4对组织的贡献。细胞最终定义了FBX4在调节细胞周期D1和细胞增殖中的作用（AIM 2）。 公共卫生相关性：人类癌症中细胞周期蛋白D1的过表达经常发生，这是由于破坏了细胞周期蛋白D1蛋白的机械突变。为了开发应对这些事件的有效疗法，有必要鉴定导致细胞周期蛋白D1破坏的蛋白质并确定其在肿瘤发育中的作用。我们已经确定了指导细胞周期蛋白D1蛋白的机械FBX4的关键组成部分，该提案中描述的实验将评估FBX4在人类癌症方面的生化和生物学特性。