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

基本信息

批准号：
6273945
负责人：
Antonio Giordano
金额：
$ 19.18万
依托单位：
ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 1998-11-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6273945
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

项目摘要

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 神经嗜性病毒多瘤病毒。在免疫功能低下的个体中，这会导致致命的神经退行性疾病的发展，进行性多灶性白质脑病（PML）。在一些实验动物中，感染具有 JCV 的大脑会导致胶质母细胞瘤的形成。脑内在发展之前，给金色叙利亚仓鼠接种 JCV 这些动物中很大一部分（80%）患有恶性脑肿瘤或周围神经母细胞瘤。发现了类似的脑肿瘤表型猫头鹰猴接种 JCV 后，随着表达病毒T抗原的恶性星形细胞瘤。 JCV的能力在这些动物中引起肿瘤是有据可查的。 JC病毒是能够转化原代仓鼠脑细胞和原代人类胎儿神经胶质细胞。 JCV的转化能力归因于它多能早期基因产物，大T抗原。体外研究已经表明 JCV T 抗原能够与抑癌基因：p53、pRb、p107 和 p130。 T抗原被认为使神经胶质细胞中的这些肿瘤抑制基因功能失活，导致这些动物中神经胶质瘤的形成。在这个根据建议，我们将使用我们独特的 JCV 注射新生仓鼠系统研究体内形成和参与的分子机制通过破坏关键的监管机制来促进脑肿瘤的进展细胞周期的因素。我们将研究 Rb 家族的作用和它与 JCV T 抗原的相互作用如何导致 JCV T 抗原的破坏细胞周期的调节过程并允许肿瘤发生转化和肿瘤发生。我们将特别关注 pRb2/p130，我们实验室首次克隆的 Rb 家族成员，在神经胶质瘤细胞中表现出生长抑制特性。具体来说我们将： (1) 确定 pRb2/p130 在仓鼠神经胶质瘤的形成和进展； (2) 表征 pRb2/p130 的生化特性与其相互作用相关 JCV在细胞生长和转化过程中的生化作用这种对细胞周期蛋白和细胞周期蛋白依赖性激酶 (cdks) 的相互作用；和（3）结构和功能表征 JCV T 抗原相互作用在体内系统中使用 pRb2/p130。