Evidence that replication of human neurotropic JC virus DNA in glial cells is regulated by the sequence-specific single-stranded DNA-binding protein Pur alpha

Chang, Chun Fan; Gallia, Gary L.; Muralidharan, Vandhana; Chen, Nancie N.; Zoltick, Philip W.; Johnson, Edward M.; Khalili, Kamel

doi:10.1128/jvi.70.6.4150-4156.1996

Cited by 57 publications

(25 citation statements)

References 41 publications

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“…Pura in the absence of Tat inhibit initiation (Chang et al, 1996). It has previously been observed that Tat of clade B has little effect on the JCV ori in the absence of added Pura in KG-1C cells.…”

Section: Differences In Kg-1c Cell Smad4 Mrna Levels In Response To Tmentioning

confidence: 85%

“…Tat is avidly incorporated by oligodendrocytes (Daniel et al, 2004), where it can exert positive control over both transcription (Krachmarov et al, 1996) and replication (Daniel et al, 2001) of JCV DNA. Tat does not bind directly to JCV DNA, but it interacts with cellular proteins and protein complexes that bind to sequences in the JCV non-coding control region (NCCR) (Chang et al, 1994(Chang et al, , 1996Chen et al, 1995;Daniel et al, 2001Daniel et al, , 2004Gallia et al, 1998Gallia et al, , 1999. The NCCR contains the origin of JCV DNA replication (ori) as well as promoter sequences for both JCV early (E) and late (L) gene transcription.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription

Wright

Nance

Johnson

2013

Journal of General Virology

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Polyomavirus JC (JCV) is the aetiological agent of progressive multifocal leukoencephalopathy (PML), a frequently fatal infection of the brain afflicting nearly 4 % of AIDS patients in the USA. Human immunodeficiency virus type 1 (HIV-1) Tat, acting together with cellular proteins at the JCV non-coding control region (NCCR), can stimulate JCV DNA transcription and replication. Tat in the brain is secreted by HIV-1-infected cells and incorporated by oligodendroglia, cells capable of infection by JCV. Thus far the effects of Tat on JCV have been studied primarily with protein encoded by the HIV-1 B clade most common in North America. Here, we determine the abilities of Tat from different HIV-1 clades to alter JCV early and late gene transcription and DNA replication initiated at the JCV origin. Tat from all clades tested stimulates both JCV early and late gene promoters, with clade B Tat being significantly most effective. Tat proteins from the HIV-1 clades display parallel patterns of differences in their effects on HIV-1 and JCV transcription, suggesting that Tat effects in both cases are mediated by the same cellular proteins. Clade B Tat is most effective at directing Smad mediators of tumour growth factor beta and cellular partner Pura to the NCCR. Tat proteins from all non-B clades inhibit initiation of JCV DNA replication. The effectiveness of HIV-1 clade B Tat at promoting JCV transcriptional and replicative processes highlights a need for further investigation to determine which molecular aspects of Tat from distinct HIV-1 substrains can contribute to the course of PML development in neuroAIDS.

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Section: Differences In Kg-1c Cell Smad4 Mrna Levels In Response To Tmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription

Wright

Nance

Johnson

2013

Journal of General Virology

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“…We next asked, using this fractionation scheme, with what fractions did cytoskeletal components and a nuclear protein, pur ␣ (Chang et al, 1996), elute. Pur ␣ was measured because we observed ODC in the nucleus in many micrographs; therefore, "insoluble" ODC activity could be caused by delayed lysis of the keratinocyte nucleus.…”

Section: Subcellular Fractionation Of Nhek By Detergent and Salt Extrmentioning

confidence: 99%

Phosphorylated Human Keratinocyte Ornithine Decarboxylase Is Preferentially Associated with Insoluble Cellular Proteins

Pomidor

Cimildoro²,

Lazatin³

et al. 1999

MBoC

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Ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, is highly regulated by many trophic stimuli, and changes in its levels and organization correlate with cytoskeletal changes in normal human epidermal keratinocytes (NHEK). NHEK ODC exhibits a filamentous perinuclear/nuclear localization that becomes more diffuse under conditions that alter actin architecture. We have thus asked whether ODC colocalizes with a component of the NHEK cytoskeleton. Confocal immunofluorescence showed that ODC distribution in NHEK was primarily perinuclear; upon disruption of the actin cytoskeleton with cytochalasin D, ODC distribution was diffuse. The ODC distribution in untreated NHEK overlapped with that of keratin in the perinuclear but not cytoplasmic area; after treatment with cytochalasin D, overlap between staining for ODC and for keratin was extensive. No significant overlap with actin and minimal overlap with tubulin filament systems were observed. Subcellular fractionation by sequential homogenizations and centrifugations of NHEK lysates or detergent and salt extractions of NHEK in situ revealed that ODC protein and activity were detectable in both soluble and insoluble fractions, with mechanical disruption causing additional solubilization of ODC activity (three- to sevenfold above controls). Fractionation and ODC immunoprecipitation from [(32)P]orthophosphate-labeled NHEK lysates showed that a phosphorylated form of ODC was present in the insoluble fractions. Taken together, these data suggest that two pools of ODC exist in NHEK. The first is the previously described soluble pool, and the second is enriched in phospho-ODC and associated with insoluble cellular material that by immunohistochemistry appears to be organized in conjunction with the keratin cytoskeleton.

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“…The viral lytic cycle begins with expression of the viral early protein, T antigen, which occurs before replication of the viral DNA. T antigen is a multifunctional protein which interacts with several host regulatory proteins and, by manipulating host gene expression and/or function, orchestrates subsequent steps of the viral life cycle including viral DNA replication (4) and activation of late gene transcription (17). The products of the late genes, the capsid proteins, accumulate in the nucleus and associate with the replicated viral DNA-forming virions which, in turn, lyse the host oligodendrocytes.…”

mentioning

confidence: 99%

Association of JC Virus Large T Antigen with Myelin Basic Protein Transcription Factor (MEF-1/Purα) in Hypomyelinated Brains of Mice Transgenically Expressing T Antigen

Tretiakova

Otte

Croul

et al. 1999

J Virol

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Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by cytolytic destruction of oligodendrocytes, the myelin-producing cells of the central nervous system, by the human neurotropic JC virus (JCV). The early protein of JCV, T antigen, which is produced at the early stage of infection, is important for orchestrating the events leading to viral lytic infection and cytolytic destruction of oligodendrocytes. Results from transgenic mouse studies, however, have revealed that, in the absence of lytic infection, this protein can induce brain hypomyelination and suppression of myelin gene expression. Since expression of the gene encoding myelin basic protein, the major component of myelin, can be regulated by a DNA-binding transcription factor, MEF-1/Purα, (Purα), we have examined the level of this protein in transgenic mouse brains. Results from immunoprecipitation and Western blots showed that while there was no drastic decrease in the level of MEF-1/Purα in transgenic mouse brains, JCV T antigen was found in a complex with MEF-1/Purα. Immunohistological studies revealed abnormal oligodendrocytes in white matter, where MEF-1/Purα and T antigen were detected. Furthermore, immunogold electron microscopic studies revealed that Purα and T antigen are colocalized in the nucleus of the oligodendrocytes and in hippocampal neurons. Interestingly, results from cell culture studies revealed that incubation of oligodendrocytes with JCV led to a drastic decrease in the level of MEF-1/Purα protein. These observations provide insight into the molecular pathogenesis of PML and support a model for a dual effect of JCV on inducing hypomyelination by (i) affecting myelin gene expression via interaction of JCV T antigen and the myelin gene transcription factor, MEF-1/Purα, and (ii) causing a decline in the level of the host regulatory proteins, including MEF-1/Purα, which are involved in myelin gene expression.

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Evidence that replication of human neurotropic JC virus DNA in glial cells is regulated by the sequence-specific single-stranded DNA-binding protein Pur alpha

Cited by 57 publications

References 41 publications

Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription

Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription

Phosphorylated Human Keratinocyte Ornithine Decarboxylase Is Preferentially Associated with Insoluble Cellular Proteins

Association of JC Virus Large T Antigen with Myelin Basic Protein Transcription Factor (MEF-1/Purα) in Hypomyelinated Brains of Mice Transgenically Expressing T Antigen

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