Abstract
JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells. This cell specificity results from glial-specific expression of viral early genes (large and small T antigens). Analysis of transcriptional regulation by the MH1 JC virus early promoter demonstrates that glial specificity is directed by the basal promoter. Because T antigen regulates the basal region of several viral and cellular promoters, we investigated whether it controls the JC virus basal promoter in a glial-specific manner. A JC virus T antigen expression plasmid generated a 95-kDa protein which exhibited nuclear localization and physical association with p53. T antigen repressed the JC virus and SV40 early promoters 4- to 5-fold in glioma cells. Conversely, T antigen induced 100- to 200-fold activation of the JC virus early promoter in nonglial cells, whereas the SV40 promoter was repressed. Activation required the JC virus TATA box sequence and a pentanucleotide repeat immediately upstream of the TATA box, but was independent of the upstream enhancer region. These data demonstrate that the JC virus basal promoter is responsible for glial-specific gene expression and suggest a mechanism for this regulation.
Highlights
JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells
Oligodendrocytes are the only cells in the body known to be lytically infected by JC virus, but viral early genes are expressed in astrocytes, which take on a bizarre, transformed appearance [1]
The unique feature of PML is the selective destruction of oligodendrocytes by JC virus and selective expression of viral genes in astrocytes
Summary
JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells This cell specificity results from glial-specific expression of viral early genes (large and small T antigens). Activation required the JC virus TATA box sequence and a pentanucleotide repeat immediately upstream of the TATA box, but was independent of the upstream enhancer region These data demonstrate that the JC virus basal promoter is responsible for glialspecific gene expression and suggest a mechanism for this regulation. Using a sensitive luciferase assay, we found that upstream promoter elements activated expression in both glial and nonglial cells [5] These results implicated the JC virus basal promoter in the regulation of glial specificity, and, we undertook a functional analysis of the basal promoter region
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