Mechanism of Action of the HRPT2 Tumor Suppressor Gene Product Parafibromin

HRPT2抑癌基因产物Para纤维蛋白的作用机制

基本信息

批准号：
7734130
负责人：
WILLIAM F SIMONDS
金额：
$ 31.92万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7734130
关键词：
1q25 Affect Alleles Amino Acids Bilateral Biological Models C-terminal Cell Proliferation Cell Survival Cells Complex Critical Pathways Cultured Cells Cystic kidney Drosophila genus Drosophila melanogaster Family Procaviidae Genes Goals Hela Cells Heterozygote Homozygote Human Hyperparathyroidism Inherited Insecta Jaw Kidney Neoplasms Laboratories Lead Link Mammals Minority Mutation Names Neoplasms Neoplastic Cell Transformation Orthologous Gene Penetrance Phenotype Physiological Predisposition Protein Overexpression Proteins Purpose RNA Interference RNA Polymerase II Regulation Research Role Sequence Homology Signal Transduction Solid Syndrome Tumor Suppressor Genes Tumor-Suppressor Gene Inactivation Work cell growth fly insight loss of function malignant parathyroid gland tumor research study trait transmission process tumor yeast protein

项目摘要

The purpose of the current work is to understand the regulation of parafibromin, its physiologic targets, and the mechanism(s) by which its loss of function can lead to neoplastic transformation. To this end we are first trying to identify and characterize the functions parafibromin that are evolutionarily conserved between insects and mammals. Human parafibromin interacts with RNA polymerase II via a human PAF1 complex, whose other protein components include human Paf1, CTR9, Leo1, and the WD40-repeat protein Ski8. The components of the PAF1 complex are highly evolutionarily conserved in Drosophila and parafibromin shares 57% amino acid identity and 71% similarity with Hyrax (Hyx), its ortholog in the fly. Such a high degree of homology suggests a possible conserved functional role of the protein across species. Current work in our laboratory examines such shared functions using Drosophila melanogaster and cultured cells, such as human Hela and HEK-293 cells, as model systems. One line of research uses an insect model system in which Drosophila Hyx (parafibromin) is expressed from a hypomorphic allele. In this model system both hetero- and homozygotes have phenotypes. The other line of research studies the effect of mammalian parafibromin overexpression, mutation or knockdown (by RNA interference) on cell proliferation, cell survival, and expression of other genes important in cell growth and proliferation.

目前工作的目的是了解副纤维蛋白的调节、其生理目标以及其功能丧失导致肿瘤转化的机制。为此，我们首先尝试识别和表征昆虫和哺乳动物之间进化保守的副纤维蛋白功能。人副纤维蛋白通过人 PAF1 复合物与 RNA 聚合酶 II 相互作用，该复合物的其他蛋白质成分包括人 Paf1、CTR9、Leo1 和 WD40 重复蛋白 Ski8。 PAF1 复合体的组成部分在果蝇中高度进化保守，并且 parabacterin 与其在果蝇中的直系同源物 Hyrax (Hyx) 具有 57% 的氨基酸同一性和 71% 的相似性。如此高度的同源性表明该蛋白质在不同物种之间可能具有保守的功能作用。我们实验室目前的工作使用果蝇和培养细胞（例如人类 Hela 和 HEK-293 细胞）作为模型系统来检查此类共享功能。其中一项研究使用昆虫模型系统，其中果蝇 Hyx（副纤维蛋白）由亚等位基因表达。在这个模型系统中，杂合子和纯合子都具有表型。另一项研究研究哺乳动物副纤维蛋白过度表达、突变或敲低（通过 RNA 干扰）对细胞增殖、细胞存活以及对细胞生长和增殖重要的其他基因表达的影响。