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Journal of Virology, November 2006, p. 10506-10513, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01355-06

Interactions between c-Jun, Nuclear Factor 1, and JC Virus Promoter Sequences: Implications for Viral Tropism{triangledown}

Veerasamy Ravichandran, Bruce F. Sabath, Peter N. Jensen, Sidney A. Houff, and Eugene O. Major*

Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Received 27 June 2006/ Accepted 14 August 2006

The infectious cycle of the human polyomavirus JC (JCV) is ultimately regulated in cellular nuclei at the level of viral protein expression and genomic replication. Such activity is prompted by interactions between variant nucleotide sequences within the JCV regulatory region (promoter) and cellular transcription factors that bind specific DNA consensus sites. In previous work we identified an NF-1 class member, NF-1X, as a critical transcription factor affecting the JCV cellular host range. Within variant JCV promoters, as well as other viral and cellular promoters, adjacently located NF-1 and AP-1 consensus sites are often found. The close proximity of these two binding sites suggests the opportunity for interaction between NF-1 and AP-1 proteins. Here, by electrophoretic mobility shift assays, we show temporal and dose-dependent interference by an AP-1 family member, c-Jun, upon NF-1 proteins binding an NF-1 consensus site derived from JCV promoter sequence. Moreover, as demonstrated by protein-protein interaction assays, we identify specific binding affinity independent of DNA binding between NF-1X and c-Jun. Finally, to compare the binding profiles of NF-1X and c-Jun on JCV promoter sequence in parallel with in vivo detection of viral activity levels, we developed an anchored transcriptional promoter (ATP) assay. With use of extracts from JCV-infected cells transfected to overexpress either NF-1X or c-Jun, ATP assays showed concurrent increases in NF-1X binding and viral protein expression. Conversely, increased c-Jun binding accompanied decreases in both NF-1X binding and viral protein expression. Therefore, inhibition of NF-1X binding by c-Jun appears to play a role in regulating levels of JCV activity.

* Corresponding author. Mailing address: Laboratory of Molecular Medicine and Neuroscience, NINDS, NIH, 10 Center Drive, Building 10, Room 3B14, MSC1296, Bethesda, Maryland 20892-1296. Phone: (301) 496-1635. Fax: (301) 594-5799. E-mail: majorg{at}ninds.nih.gov.

{triangledown} Published ahead of print on 23 August 2006.

Journal of Virology, November 2006, p. 10506-10513, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01355-06




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