Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter.
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.
Romagnoli
Luca
L
Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19122, USA.
Sariyer
Ilker K
IK
Tung
Jacqueline
J
Feliciano
Mariha
M
Sawaya
Bassel E
BE
Del Valle
Luis
L
Ferrante
Pasquale
P
Khalili
Kamel
K
Safak
Mahmut
M
White
Martyn K
MK
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
C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG