title: Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter.
abstract: JC virus (JCV) is a human polyomavirus that can emerge from a latent state to cause the cytolytic destruction of oligodendrocytes in the brain resulting in the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Previous studies described a cis-acting transcriptional regulatory element in the JCV non-coding control region (NCCR) that is involved in the response of JCV to cytokines. This consists of a 23 base pair GGA/C rich sequence (GRS) near the replication origin (5112 to +4) that contains potential binding sites for Sp1 and Egr-1. Gel shift analysis showed that Egr-1, but not Sp1, bound to GRS. Evidence is presented that the GRS gel shift seen on cellular stimulation is due to Egr-1. Thus, TPA-induced GRS gel shift could be blocked by antibody to Egr-1. Further, the TPA-induced GRS DNA/protein complex was isolated and found to contain Egr-1 by Western blot. No other Egr-1 sites were found in the JCV NCCR. Functionally, Egr-1 was found to stimulate transcription of JCV late promoter but not early promoter reporter constructs. Mutation of the Egr-1 site abrogated Egr-1 binding and virus with the mutated Egr-1 site showed markedly reduced VP1 expression and DNA replication. Infection of primary astrocytes by wild-type JCV induced Egr-1 nuclear expression that was maximal at 5-10 days post-infection. Finally, upregulation of Egr-1 was detected in PML by immunohistochemistry. These data suggest that Egr-1 induction may be important in the life cycle of JCV and PML pathogenesis.
authors: Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19122, USA.
authors: Luca
authors: L
authors: Romagnoli
authors: Ilker K
authors: IK
authors: Sariyer
authors: Jacqueline
authors: J
authors: Tung
authors: Mariha
authors: M
authors: Feliciano
authors: Bassel E
authors: BE
authors: Sawaya
authors: Luis
authors: L
authors: Del Valle
authors: Pasquale
authors: P
authors: Ferrante
authors: Kamel
authors: K
authors: Khalili
authors: Mahmut
authors: M
authors: Safak
authors: Martyn K
authors: MK
authors: White
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007577:JC Virus / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D007968:Leukoencephalopathy, Progressive Multifocal / Q000378:metabolism* / Q000821:virology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014774:Virulence
chemical_list: C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG