权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7593599
负责人：
WILLIAM F SIMONDS
金额：
$ 36.1万
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/7593599
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 Nuclear 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 nuclear localization of the Paf1 complex.

当前工作的目的是了解副纤白蛋白的调控，其生理靶点，以及其功能丧失导致肿瘤转化的机制。为此，我们首先试图确定和描述在昆虫和哺乳动物之间进化保守的副纤白蛋白的功能。人副纤白蛋白通过人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-repeat蛋白Ski8。PAF1复合体的组成部分在果蝇中具有高度的进化保守性，而parafibromin与其在果蝇中的同源物Hyrax （Hyx）具有57%的氨基酸同源性和71%的相似性。如此高度的同源性表明该蛋白在物种间可能具有保守的功能作用。我们实验室目前的工作是利用黑腹果蝇和培养细胞（如人类Hela和HEK-293细胞）作为模型系统来研究这些共享功能。其中一项研究使用了一种昆虫模型系统，其中果蝇Hyx（副纤维蛋白）是由一个半胚等位基因表达的。在这个模型系统中，杂合子和纯合子都有表型。另一个研究方向是研究哺乳动物parafibromin过表达、突变或敲低（通过RNA干扰）对细胞增殖、细胞存活和Paf1复合物核定位的影响。