Retinoblastoma (Rb) protein pathway in human cytomegalovirus infected cells

人巨细胞病毒感染细胞中的视网膜母细胞瘤 (Rb) 蛋白途径

• 批准号: 8259782
• 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
• 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/8259782
• 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

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 PUBLIC HEALTH RELEVANCE: Some viruses cause cancer, a disease of uncontrolled cellular growth. Human cytomegalovirus (HCMV) infects almost everyone, causes severe disease especially in newborn infants and transplant patients, and may play a role in many different types of cancer. We are studying how HCMV causes cells to grow in the hopes of finding drugs to stop that process, and that could be used as anti-viral and anti-cancer treatments.

描述（由申请人提供）：人巨细胞病毒（HCMV）是一种普遍存在且重要的病原体，可刺激细胞周期进程。 HCMV 是心血管疾病的辅助因子，具有显着的增殖成分，例如冠状动脉再狭窄和移植血管硬化 (TVS)，并且可能在某些类型的癌症中发挥作用，尤其是恶性神经胶质瘤 (GBM)。细胞增殖和转化受肿瘤抑制因子视网膜母细胞瘤家族（Rb、p107 和 p130）的调节。 Rb 蛋白与 E2F 转录因子家族一起调节 DNA 复制所需的细胞基因的表达，例如从头途径的核苷酸生物合成酶 (NBE)，以及参与伤口愈合和血管生成的分泌因子。当低磷酸化形式的 Rb 蛋白与 E2F 蛋白结合时，E2F 响应基因的表达受到抑制。低磷酸化 Rb 蛋白的降解或其过度磷酸化会破坏其与 E2F 的复合物，从而允许游离的 E2F 激活基因表达。 HCMV 编码四种调节 Rb-E2F 途径的蛋白质：pp71、IE1、IE2，以及本申请的重点 UL97。由于 HCMV 与增殖性疾病相关并编码多种调节 Rb-E2F 途径的蛋白质，因此我们假设 Rb-E2F 途径在 HCMV 复制和发病机制中发挥关键作用。在这里，我们建议探讨 Rb、E2F 和 UL97 蛋白在 HCMV 感染过程中的作用。 UL97 是保守疱疹病毒蛋白激酶 (CHPK) 家族的成员，可直接磷酸化 Rb 蛋白并使其失活，从而诱导细胞 E2F 响应基因。我们假设其中一些 E2F 响应基因产物 (NBE) 负责 UL97 介导的病毒 DNA 复制刺激。我们进一步推测，由 UL97（分泌性伤口愈合和血管生成因子）诱导的其他 E2F 反应基因产物可能反过来部分负责与 HCMV 感染相关的增殖病理学，例如再狭窄、TVS 和 GBM。该项目的长期目标是确定 UL97 和其他 HCMV 蛋白使 Rb 失活如何以细胞自主和非细胞自主方式影响细胞周期进程、HCMV 复制和病毒发病机制，并利用这些信息来设计治疗与 HCMV 感染相关的增殖性疾病的疗法。 PHS 398/2590 (Rev. 05/01) 第 1 页 继续格式页 公共卫生相关性：一些病毒会导致癌症，这是一种细胞生长不受控制的疾病。人类巨细胞病毒 (HCMV) 几乎感染所有人，引起严重疾病，尤其是新生儿和移植患者，并且可能在许多不同类型的癌症中发挥作用。我们正在研究 HCMV 如何导致细胞生长，希望找到阻止该过程的药物，并可用于抗病毒和抗癌治疗。