The function of RhoBTB proteins

RhoBTB 蛋白的功能

• 批准号: 7575717
• 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
• 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/7575717
• 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; 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; Play; Predisposition; Primary Neoplasm; Prostate; Protein Binding; Proteins; Recruitment Activity; Research; Research Personnel; Rewards; Role; Site; 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

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 CulS-dependent manner and the cellular levels of RhoBTB2 are regulatedby 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.

肿瘤抑制基因（TSG）的研究导致了许多重要的见解 癌症和正常细胞途径，包括细胞周期，凋亡和DNA修复。 Rhobtb2是 最近被确定为位于8p21染色体的候选TSG，这是一个经常丧失杂合性的部位 在乳房，肺，前列腺和卵巢癌中。 RHOBTB2包含一个N末端GTPase结构域，与 Rho家族GTPases和Tandem BTB域的。我们开始调查以了解 Rhobt2的功能并确定它是否是TSG。我们使用 酵母两个混合动力屏幕。我们的初始屏幕显示RhoBTB2与泛素连接酶Cul3结合。 Rhobtb2以Culs依赖性的方式被泛素化，Rhobtb2的细胞水平受到调节 CUL3依赖性降解。在肺癌细胞系中发现的Rhobtb2突变体未与Cul3及其结合 表达不受CUL3的调节，表明与Cul3的相互作用可能是必不可少的组成部分 RhoBTB2作为肿瘤抑制剂的功能。这些数据还表明Rhobtb2可能是 主要作用是将另一种蛋白质募集到Cul3降解的适配器。其他Cullin的适配器 蛋白质也是肿瘤抑制剂。我们进行了其他两个混合动力屏幕，并确定了其他 相互作用的蛋白质，指示RHOBTB2的功能。我们在此提案中的目标是确定 Rhobtb2是否为TSG，详细了解RhoBTB2功能的途径，并描绘 CUL3和泛素化在调节RhoBTB2功能中扮演的角色。我们计划实现这些目标 通过三个特定目标。我们将：1）将Rhobtb2的作用定义为肿瘤抑制剂； 2）确定 Rhobtb2的功能; 3）描述Cul3在RhoBTB2函数中的作用。这些研究的结果 可能会揭示涉及癌症发展的新途径，并促进我们对 转型的基本生物学。