GLIAL SPECIFIC TRANSCRIPTIONAL REPRESSION IN PML

Project: Research project

Project Details

Description

DESCRIPTION (adapted from the Abstract): Progressive multifocal
leukoencephalopathy (PML) is a fatal, immunodeficiency-associated
demyelinating brain disease that results from selective, lytic infection of
oligodendrocytes by a 5.1 kb DNA virus, JC virus. PML is no longer a rare
condition, as it is now diagnosed in 5% of patients with AIDS. Although JC
virus oligodendrocyte specificity is known to arise from glial-specific
transcriptional regulation of viral early gene expression, the molecular
mechanism of this regulation remains unclear. Study of JC virus biology is
important because new therapies for this currently untreatable infection are
most likely to result from scientific advances.

JC virus early promoters have been cloned directly from human brain. By
using a deletion/mutation approach to functional analysis, these researchers
found that glial-specificity is directed by the basal promoter region,
instead of the stream enhancer-like tandem repeats. Furthermore, they
showed that the viral protein, large T-antigen regulates the basal promoter
in a cell-specific manner, strongly activating expression in nonglial cells,
but repressing expression in glial cells. This cell-specific regulation is
dependent upon the JC virus TATA box. These findings strongly suggest that
the basal region of the JC virus early promoter is selectively repressed in
nonglial cells.

Because preliminary data suggest that the JC virus early promoter in
nonglial cells, the Investigator hypothesizes that a repressor protein is
required to block default expression of the promoter in nonglial cells. The
goal of the proposed research is to test this hypothesis by identification
of the putative repressor. In Aim #1 the Investigator and associates will
seek to identify DNA sequences in the basal promoter region that mediate
cell-specificity. In Aim #2 they will examine cell-specific regulation of
the JC virus early promoter by large T-antigen, in anticipation that
differential regulation of the JC virus promoter by T-antigen is related to
the mechanism of cell specificity and, thus, offers a window into
understanding the promoter. In Aim #3 they will employ a candidate protein
approach to the identification of the putative repressor, using the
transcriptional repressors p53 and Dr1.
StatusNot started