Retinoblastoma (Rb) protein pathway in human cytomegalovirus infected cells

人巨细胞病毒感染细胞中视网膜母细胞瘤 (Rb) 蛋白途径

基本信息

批准号：
8651405
负责人：
ROBERT F KALEJTA
金额：
$ 35.6万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651405
关键词：
Angiogenic Factor Area Blood Vessels Cancer Etiology Cardiovascular Diseases Cell Cycle Progression Cell Proliferation Cell physiology Cells Complement Complex Coronary Restenosis Cytomegalovirus Cytomegalovirus Infections DNA biosynthesis Deoxyribonucleosides Disease Endothelial Cells Enzymes Family Fibroblasts Gene Expression Genes Genetic Transcription Goals Health Herpesviridae Lytic Phase Malignant Glioma Mediating Newborn Infant Nucleotides Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Phenotype Play Principal Investigator Process Protein Binding Protein Kinase Proteins Research Design Retinoblastoma Retinoblastoma Protein Role Sclerosis Smooth Muscle Myocytes Transplant Recipients Transplantation Viral Viral Pathogenesis Virus Wound Healing angiogenesis cancer therapy cancer type cell growth cofactor member metaplastic cell transformation pathogen programs restenosis retinoblastoma tumor suppressor therapy design transcription factor viral DNA

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a ubiquitous and significant pathogen that stimulates cell cycle progression. HCMV is a cofactor for cardiovascular diseases with significant proliferative components such as coronary restenosis and transplant vascular sclerosis (TVS), and may play a role in certain types of cancers, most notably, malignant gliomas (GBMs). Cellular proliferation and transformation is regulated by the retinoblastoma family of tumor suppressors (Rb, p107, and p130). The Rb proteins, in conjunction with the E2F family of transcription factors, regulate the expression of cellular genes required for DNA replication such as nucleotide biosynthetic enzymes (NBEs) of the de novo pathway, as well as secreted factors involved in wound healing and angiogenesis. The expression of E2F-responsive genes is inhibited when the hypophosphorylated forms of the Rb proteins are bound to the E2F proteins. Degradation of the hypophosphorylated Rb proteins, or their hyperphosphorylation disrupts their complexes with E2F, thus allowing free E2F to activate gene expression. HCMV encodes four proteins that modulate the Rb-E2F pathway: pp71, IE1, IE2, and the focus of this application, UL97. Because HCMV is associated with proliferative diseases and encodes multiple proteins that modulate the Rb-E2F pathway, we hypothesize that the Rb-E2F pathway plays a critical role in HCMV replication and pathogenesis. Here we propose to explore the roles of the Rb, E2F, and UL97 proteins during HCMV infection. UL97 is a member of a family of conserved herpesvirus protein kinases (CHPKs) that directly phosphorylates the Rb protein and inactivates it, leading to the induction of cellular E2F-responsive genes. We hypothesize that some of these E2F-responsive gene products (the NBEs) are responsible for the UL97-mediated stimulation of viral DNA replication. We further speculate that other E2F-responsive gene products induced by UL97 (secreted wound healing and angiogenesis factors) may in turn be partially responsible for proliferative pathologies associated with HCMV infection, such as restenosis, TVS, and GBMs. The long-term goal of this project is to determine how Rb inactivation by UL97 and other HCMV proteins impacts cell cycle progression, HCMV replication, and viral pathogenesis in both cell autonomous and non-cell-autonomous manners, and to use this information to design therapies to treat proliferative diseases associated with HCMV infection. PHS 398/2590 (Rev. 05/01) Page 1 Continuation Format Page

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种无处不在且重要的病原体，可刺激细胞周期的进展。 HCMV是具有重要增生成分（例如冠状动脉再狭窄和移植血管硬化症（TVS））的心血管疾病的辅助因子，并且可能在某些类型的癌症中发挥作用，最值得注意的是，恶性神经胶质瘤（GBMS）。细胞增殖和转化受肿瘤抑制剂的视网膜母细胞瘤家族（RB，P107和P130）调节。 RB蛋白与转录因子的E2F家族一起调节了从头途径的DNA复制所需的细胞基因表达，例如核苷酸生物合成酶（NBE），以及与伤口愈合和血管生成有关的分泌因子。当RB蛋白的下磷酸化形式与E2F蛋白结合时，E2F响应基因的表达被抑制。低磷酸化的RB蛋白的降解或其高磷酸化会破坏其与E2F的络合物，从而允许游离E2F激活基因表达。 HCMV编码了调节RB-E2F途径的四种蛋白质：PP71，IE1，IE2，以及该应用程序的重点UL97。由于HCMV与增殖性疾病有关，并编码调节RB-E2F途径的多种蛋白质，因此我们假设RB-E2F途径在HCMV复制和发病机理中起关键作用。在这里，我们建议在HCMV感染过程中探索RB，E2F和UL97蛋白的作用。 UL97是由保守的疱疹病毒蛋白激酶（CHPK）家族的成员，该家族直接磷酸化RB蛋白并使其失活，从而导致细胞E2F反应基因的诱导。我们假设这些E2F响应基因产物（NBE）中的某些是导致UL97介导的病毒DNA复制刺激。我们进一步推测，由UL97诱导的其他E2F反应性基因产物（分泌的伤口愈合和血管生成因子）可能又可能部分负责与HCMV感染相关的增殖病理，例如再狭窄，TVS和GBM。该项目的长期目标是确定UL97和其他HCMV蛋白的RB灭活如何影响细胞周期的进展，HCMV复制和病毒性发病机理，并在细胞自主和非细胞自主界中使用此信息来设计此信息来设计此信息。治疗与HCMV感染相关的增生性疾病的疗法。 PHS 398/2590（修订05/01）第1页延续格式页面