Molecular models for studying CNS associated tumors and dysmyelination
JC virus is the etiologic agent of the rapidly fatal demyelinating disease Progressive Multifocal Leukoencephalopathy. This virus has an extremely narrow host range and tissue tropism. It replicates efficiently only in human oligodendrocytes in vivo. An interesting feature of the papovaviral family is its ability to integrate into the host genome and cause tumorigenesis in cells which are not permissive for viral DNA replication. In the work presented here, the intention is to investigate the ability of T antigen to cause neuroectodermal tumors in an animal model: a transgenic mouse line containing the JC viral early region. The potential association of JC virus with human brain tumors is explored using tissue obtained from a human oligoastrocytoma arising in an immunocompetent individual. In both of these studies DNA and RNA were detected using PCR and RT-PCR respectively. Protein was identified using immunoprecipitation techniques. These preliminary studies lay the groundwork for more intensive investigation. PCR screening of human glial brain tumors to identify papovaviral DNA may prove that these viruses indeed contribute to human tumorigenesis, while the animal model may be used to dissect more clearly the molecular mechanism of oncogenesis. Additionally, the role of the p107, which is known to be functionally inactivated by T antigen, will be examined through transient transfections using chloramphenicol acetyl transferase assays, as well as immunoprecipitation studies to assess protein-protein interactions among the transcription factors known to be involved in murine myelination. A novel interaction between p107 and the transcription factor, pur$\alpha,$ and the interaction between pur$\alpha$ and Sp1. Pur$\alpha$ and Sp1 activate MBP transcription, while p107 represses. A potential mechanism for p107 repression of the MBP promoter is through its interaction with these transcription factors, which normally activate transcription. The amino terminus of p107 is known to interact with Sp1, while preliminary data suggests that the pocket region is responsible for the p107-pur$\alpha$ interaction. The ability of each of these proteins to interact with one another, different regions of each appear to mediate their interaction suggests the attractive model that all three proteins may form a complex together to developmentally regulate transcription of MBP.
Rencic, Adrienne, "Molecular models for studying CNS associated tumors and dysmyelination" (1998). ETD Collection for Thomas Jefferson University. AAI9829089.