A 23-base-pair sequence element and its role in JC virus gene transcription
JC virus (JCV) is a common human neurotropic polyomavirus and the causative agent of a fatal demyelinating disease, called Progressive Multifocal Leucoencephalopathy (PML). The virus remains latent in healthy individuals but is reactivated in those who exhibit prolonged underlying immunosupression due to immunosupressive drugs, chronic illness, cancers and AIDS. Reactivation of the virus leads to selective lytic infection of oligodentrocytes which are the myelin producing cells of central nervous system (CNS) and subsequently to PML. The regulatory region of JCV is hypervariable and several variants of which have been described. The prototype strain of JCV, Mad-1, is typically isolated from PML patients and is characterized by having two 98 bp tandem repeats within its regulatory region. The archetype strain (Cy) and some intermediate forms of JCV contain a 23 base pair sequence element (23 bpse) in their regulatory region. It is hypothesized that deletions and duplications within the regulatory region of Cy lead to a more vigorous virus capable of replicating in new cells and tissues. The role of the 23 bpse in JCV gene expression is not well understood. My thesis work centers around understanding of its role in this respect. In the following manuscripts, we provide experimental evidence that the 23 bpse play a role in JCV promoter activity. Data from our studies demonstrate that the sequences present within the 23 bpse not only serve as target binding sites for specific cellular factors and but also confer responsiveness to an extracellular stimulus such as PMA. We also investigated the effect of inducible NF-[special characters omitted]B family of transcription factors, p50 and p65, on the transcriptional activity of JCV promoters through the 23 bpse. Results from these experiments suggest that both factors indirectly involve in the transcriptional activity of JCV promoters through the 23 bpse. Previously identified cellular proteins (YB-1 and Pur[special characters omitted]) and a viral regulatory protein, JCV large T antigen (JCV T) were shown to interact with specific target sequences within the control region of JCV and modulate JCV gene transcription from the viral early and late promoters. Since the 23 bpse also confers potential binding target sequences for these proteins, we also investigated their effect on JCV gene transcription. Results from these studies demonstrate that YB-1 and Pur[special characters omitted] physically and functionally interact with each other and modulate JCV gene transcription through the 23 bpse. We also examined the physical and functional interaction between YB-1 and JCV T and its relevance to JCV gene transcription. We observed that JCV T functionally cooperate with YB-1 in transactivation of viral late genes. Taken together, these results suggest that the 23 bpse plays a role in modulation of JCV gene transcription by serving as target binding sites for specific cellular proteins.
Safak, Mahmut, "A 23-base-pair sequence element and its role in JC virus gene transcription" (1999). ProQuest ETD Collection - Thomas Jefferson University. AAI9923254.