ROLE OF RB FAMILY IN JC VIRUS INDUCED GLIOBLASTOMA

RB 家族在 JC 病毒诱发的胶质母细胞瘤中的作用

• 批准号: 6243927
• 负责人: Antonio Giordano
• 金额: $ 18.96万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243927
• 关键词: Papovaviridae; astrocytoma; cell cycle proteins; cellular oncology; gene mutation; molecular oncology; neoplastic growth; retinoblastoma protein; tissue /cell culture; virus antigen; virus related neoplasm /cancer

Nearly 70% of the adult population is infected with the JC neurotropic polyoma virus. In immunocompromised individuals this results in the development of the fatal neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). In several experimental animals, infection of brain with JCV results in the formation of glioblastoma. Intracerebral inoculation of golden Syrian hamsters with JCV preceded the development in a great (80%) proportion of these animals of malignant brain tumors or peripheral neuroblastomas. A similar phenotype of brain tumors was seen upon the inoculation of owl monkeys with JCV, with the development of malignant astrocytomas expressing the viral T-antigen. The ability of JCV to cause tumors in these animals is well documented. The JC virus is capable of transforming primary hamster brain cells and primary human fetal glial cells. The transforming ability of JCV is attributed to its multipotent early gene product, the large T-antigen. In vitro studies have indicated that the JCV T-antigen is capable of interaction with the tumor suppressor genes, p53, pRb, p107, and p130. T-antigen is thought to functionally inactivate these tumor suppressor genes in glial cells, resulting in the formation of glial tumors in these animals. In this proposal, we will use our unique JCV-injected newborn hamster system to study in vivo the molecular mechanisms involved in the formation and progression of brain tumors through the disruption of the key regulatory factors of the cell cycle. We will examine the role of the Rb family and how its interaction with JCV T-antigen results in the disruption of the regulatory processes of the cell cycle and allows for neoplastic transformation and tumorigenesis. In particular, we will focus on the pRb2/p130, the Rb family member first cloned in our laboratory and exhibits growth suppressive properties in glioma cells. Specifically we will: (1) Determine the biological importance of pRb2/p130 in the formation and progression of hamster gliomas; (2) Characterize the biochemical properties of pRb2/p130 associated with its interaction with JCV during cell growth and transformation, and the biochemical effects of this interaction on cyclins and cyclin-dependent kinases (cdks); and (3) structurally and functionally characterize the JCV T-antigen interaction with pRb2/p130 in an in vivo system.

近70%的成年人感染了JC嗜神经性 多瘤病毒 在免疫功能低下的个体中，这导致 发生致死性神经退行性疾病，进行性多灶性 白质脑病（PML）。 在一些实验动物中， JCV导致胶质母细胞瘤的形成。 脑 用JCV接种金黄色叙利亚仓鼠， 这些动物中有很大比例（80%）患有恶性脑肿瘤，或 外周神经母细胞瘤 脑肿瘤的表型相似 在用JCV接种猫头鹰猴后，随着 表达病毒T抗原的恶性星形细胞瘤。 JCV的能力 在这些动物身上引起肿瘤的证据是充分的。 JC病毒是 能够转化原代仓鼠脑细胞和原代人 胎儿神经胶质细胞 JCV的转化能力归功于其 多能早期基因产物，大T抗原。 体外研究 已经表明JCV T抗原能够与 肿瘤抑制基因p53、pRb、p107和p130。 T抗原被认为 在神经胶质细胞中功能性地表达这些肿瘤抑制基因， 导致这些动物中神经胶质肿瘤的形成。 在这 我们将使用我们独特的JCV注射新生仓鼠系统， 在体内研究参与形成的分子机制， 脑肿瘤的进展，通过破坏关键的调节 细胞周期的因素。 我们将研究Rb家族的作用， 它与JCV T抗原的相互作用如何导致 调节过程的细胞周期，并允许肿瘤 转化和肿瘤发生。 特别是，我们将重点关注 pRb 2/p130是本实验室首次克隆的Rb家族成员， 在神经胶质瘤细胞中表现出生长抑制特性。 另外还 目的：（1）确定pRb 2/p130在肿瘤细胞中的生物学意义。 仓鼠胶质瘤的形成和进展;（2）表征 pRb 2/p130的生化特性与其与 JCV在细胞生长和转化过程中的作用，以及JCV的生化效应。 这种对细胞周期蛋白和细胞周期蛋白依赖性激酶（cdk）的相互作用;和（3） JCV T-抗原相互作用的结构和功能特征 与pRb 2/p130在体内系统中的结合。