The human neurotropic virus, JCV, is widespread in the human population and is the established etiology agent of the fatal demyelinating disease of the central nervous system (CNS), Progressive Multifocal Leukoencephalopathy (PML). Once a rare disease associated with lymphoproliferative and myeloproliferative disease, PML is now more frequently seen due to the AIDS epidemic. The JCV genome consists of circular double-stranded DNA that is separated into early and late coding sequences by the viral cell type-specific regulatory region. The viral early gene, T-antigen has important regulatory functions in orchestrating the viral lytic cycle and possesses the ability to interact with several important cellular proteins including the tumor suppressor protein, p53, pointing to the oncogenic potential of this virus. In support of this notion, earlier suppressor protein, p53, pointing to the oncogenic potential of this virus. In support of this notion, earlier studies have revealed that JCV has the ability to induce neural origin tumors in several animal models. By using the early genome of JCV, we have created transgenic animals that develop cerebellar primitive neuroectodermal tumors with extraordinary similarity to human medulloblastoma. Results from genetic and biochemical studies have revealed that while in some cells T-antigens is expressed and found in association with p53, there exists a population of tumor cells with extremely low, if any, levels of T-antigen production. Cell lines derived from several tumor tissues have allowed further characterization of T- antigen positive and T-antigen negative cells and are identified the presence of a novel mutant p53 with a deletion between residues 35 and 123. This observation is consistent with a hypothesis in which, at the early stage of the disease, expression of JCV T- antigen in primitive neuroectodermal cells and its association with p53 can functionally inactivate this tumor suppressor protein. As p53 can functionally inactivate this tumor suppressor protein. As p53 controls cell proliferation at the G1 and G2 stages of the cell cycle, and plays an important in genomic stability In this research project, we propose to: i) investigate p53 and its downstream effectors in T-antigen positive and T- antigen negative tumor cells at different phases of the cell cycle in vivo, and in tumor tissues during various stages of brain and tumor development; ii) conditionally knockout the function of p53 in transgenic mice at the desired time during brain development by expression of T- antigen in the rain utilizing an in vivo T-antigen tetracycline inducible system and evaluate p53-dependent cell cycle pathways; and iii) determine the oncogenic potential of mutant p053 as well as T-antigen in the development of medulloblastoma in the absence of wild-type p53 by expressing these proteins in p53 null cells and p53 knockout transgenic animals. In light of recent data pointing to the association of JCV with human medulloblastomas and the potential for the participation of p53 in these tumors, the study of JCV-T antigen transgenic animals should yield information involved in the development of pediatric medulloblastomas.
| Noch, Evan; Khalili, Kamel (2009) Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity. Cancer Biol Ther 8:1791-7 |
