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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：
8741448
负责人：
WILLIAM F SIMONDS
金额：
$ 55.78万
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/8741448
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 In Vitro Inherited Insecta Jaw Kidney Neoplasms Laboratories Lead Leukocytes Link Mammals Minority Mutation Names Neoplasms Neoplastic Cell Transformation Orthologous Gene Patients Penetrance Phenotype Physiological Predisposition Proteins RNA Interference RNA Polymerase II Regulation Research Role Saccharomycetales 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 overexpression 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. White blood cells from patients heterozygous for CDC73/HRPT2 are also studied in vitro.

目前工作的目的是了解副纤维蛋白的调节，其生理靶点，以及其功能丧失可能导致肿瘤转化的机制。为此，我们首先试图识别和表征昆虫和哺乳动物之间进化上保守的功能parafibromin。人副纤维蛋白通过人PAF 1复合物与RNA聚合酶II相互作用，该复合物的其他蛋白质组分包括人Paf 1、CTR 9、Leo 1和WD 40重复蛋白Ski 8。PAF 1复合物的组分在果蝇中是高度进化保守的，并且parafibromin与其在果蝇中的直系同源物Hyrax（Hyx）共享57%的氨基酸同一性和71%的相似性。这种高度的同源性表明，跨物种的蛋白质可能保守的功能作用。我们实验室目前的工作是使用果蝇和培养的细胞，如人Hela和HEK-293细胞作为模型系统来研究这种共享功能。一种研究方法是使用一种昆虫模型系统，其中果蝇Hyx（parafibromin）是从一个亚型等位基因表达的。在这个模型系统中，杂合子和纯合子都有表型。另一系列研究研究哺乳动物parafibromin过表达，突变或敲低（通过RNA干扰）对细胞增殖，细胞存活以及细胞生长和增殖中重要的其他基因表达的影响。还在体外研究了来自对CDC 73/HRPT 2杂合的患者的白色血细胞。