The function of RhoBTB proteins

RhoBTB 蛋白的功能

基本信息

批准号：
7176226
负责人：
Stephen Paul Soltoff
金额：
$ 29.3万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-06 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176226
关键词：
8p21 Advanced Malignant Neoplasm Apoptosis Autophagocytosis BTB/POZ Domain Binding Biochemical Biological Assay Biology Breast Caenorhabditis elegans Cancer Biology Cancer Etiology Cancer cell line Cell Cycle Cell Cycle Regulation Cells Chromosomes Collaborations Complex Coupled Cullin Proteins DNA Repair Data Development Dictyostelium Drosophila Proteins Drosophila genus Eukaryota Eukaryotic Cell Family Frequencies Genes Goals Guanosine Triphosphate Phosphohydrolases Human Chromosomes Incidence Investigation Knockout Mice Letters Loss of Heterozygosity Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mantle Cell Lymphoma Messenger RNA Mutation N-terminal Names Ovary Pathway interactions Phenotype Predisposition Primary Neoplasm Prostate Protein Binding Proteins Recruitment Activity Research Research Personnel Rewards Role Role playing therapy Site Thinking Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitination Yeasts insight interest lung small cell carcinoma malignant breast neoplasm member mutant rho salivary cell tumor ubiquitin ligase yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The study of tumor suppressor genes (TSGs) has resulted in many important insights into the basic biology of cancer and normal cellular pathways including the cell cycle, apoptosis and DNA repair. RhoBTB2 was recently identified as a candidate TSG located at chromosome 8p21, a site of frequent loss of heterozygosity in breast, lung, prostate and ovarian cancer. RhoBTB2 contains an N-terminal GTPase domain, related to those of Rho family GTPases, and tandem BTB domains. We began investigations to understand the function of RhoBT2 and to determine whether it is a TSG. We identified RhoBTB2 interacting proteins using yeast two hybrid screens. Our initial screen revealed that RhoBTB2 binds to the ubiquitin ligase Cul3. RhoBTB2 is ubiquitinated in a Cul3-dependent manner and the cellular levels of RhoBTB2 are regulated by Cul3-dependent degradation. A RhoBTB2 mutant found in a lung cancer cell line fails to bind to Cul3 and its expression is not regulated by Cul3, indicating that interaction with Cul3 is probably an essential component of the function of RhoBTB2 as a tumor suppressor. These data also suggest that RhoBTB2 may be an adaptor whose primary role is to recruit another protein(s) to Cul3 for degradation. Adaptors for other cullin proteins are also tumor suppressors. We conducted additional two hybrid screens and have identified other interacting proteins that indicate the function of RhoBTB2. Our goals in this proposal are to determine whether RhoBTB2 is a TSG, understand in detail the pathways in which RhoBTB2 functions, and delineate the roles played by Cul3 and ubiquitination in regulating RhoBTB2 function. We plan to achieve these goals through three specific aims. We will: 1) Define the role of RhoBTB2 as a tumor suppressor; 2) Determine the function of RhoBTB2; and 3) Delineate the role of Cul3 in RhoBTB2 function. The results of these studies may reveal a new pathway involved in the development of cancer and advance our understanding of the basic biology of transformation.

描述（由申请人提供）：肿瘤抑制基因（TSG）的研究对癌症的基础生物学和正常细胞途径（包括细胞周期、细胞凋亡和 DNA 修复）产生了许多重要的见解。 RhoBTB2 最近被确定为候选 TSG，位于染色体 8p21，这是乳腺癌、肺癌、前列腺癌和卵巢癌中杂合性经常丢失的位点。 RhoBTB2 包含一个 N 端 GTP 酶结构域（与 Rho 家族 GTP 酶相关）和串联 BTB 结构域。我们开始研究以了解 RhoBT2 的功能并确定它是否是 TSG。我们使用酵母两种杂交筛选鉴定了 RhoBTB2 相互作用蛋白。我们的初步筛选显示 RhoBTB2 与泛素连接酶 Cul3 结合。 RhoBTB2 以 Cul3 依赖性方式泛素化，并且 RhoBTB2 的细胞水平受到 Cul3 依赖性降解的调节。在肺癌细胞系中发现的 RhoBTB2 突变体无法与 Cul3 结合，并且其表达不受 Cul3 调节，表明与 Cul3 的相互作用可能是 RhoBTB2 作为肿瘤抑制因子的功能的重要组成部分。这些数据还表明，RhoBTB2 可能是一种接头，其主要作用是招募另一种蛋白质至 Cul3 进行降解。其他 cullin 蛋白的接头也是肿瘤抑制因子。我们进行了另外两次混合筛选，并鉴定了表明 RhoBTB2 功能的其他相互作用蛋白。我们在此提案中的目标是确定 RhoBTB2 是否是 TSG，详细了解 RhoBTB2 功能的途径，并描述 Cul3 和泛素化在调节 RhoBTB2 功能中所发挥的作用。我们计划通过三个具体目标来实现这些目标。我们将： 1) 定义 RhoBTB2 作为肿瘤抑制因子的作用； 2）确定RhoBTB2的功能； 3) 描述 Cul3 在 RhoBTB2 功能中的作用。这些研究的结果可能揭示癌症发展的新途径，并增进我们对转化基础生物学的理解。