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Journal of Virology, June 2007, p. 6412-6418, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02658-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

MEK1/2 Inhibitors Block Basal and Transforming Growth Factor ß1-Stimulated JC Virus Multiplication{triangledown}

Veerasamy Ravichandran, Peter N. Jensen, 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 1 December 2006/ Accepted 14 March 2007

The multiplication of the human neurotropic polyomavirus JC virus (JCV) is regulated by cell membrane receptors and nuclear transcription factors. Signaling pathways also play a role in determining the extent to which JCV can productively infect cells. These data show that constitutively active MEK1 protein (CA-MEK1), overexpressed in cultures of human glia, supports a substantial increase in late JCV protein (Vp-1) synthesis. The specificity of this pathway was indicated by no significant enhancement of JCV multiplication through activation of other components of mitogen-activated protein kinase pathways such as p38, Jun N-terminal protein kinase, and protein kinase A. Further evidence supporting the importance of signaling in JCV infection came from addition of transforming growth factor ß1 (TGF-ß1), which stimulated a 200% increase of Vp-1 expression. Specific MEK1/2 inhibitors, flavenoid PD98059 and U0126, decreased the basal and TGF-ß1-stimulated Vp-1 expression by 95% or more. TGF-ß1 is known to phosphorylate/activate Smad DNA binding proteins that could subsequently bind or increase binding to JCV promoter sequences, linking the effects of signaling with JCV transcriptional regulation. The effectiveness with which MEK1/2 inhibitors block JCV multiplication provides insight that may contribute to development of compounds directed against JCV.

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

{triangledown} Published ahead of print on 4 April 2007.

Journal of Virology, June 2007, p. 6412-6418, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02658-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Beckham, J. D., Tuttle, K., Tyler, K. L. (2009). Reovirus Activates Transforming Growth Factor {beta} and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection. J. Virol. 83: 5035-5045 [Abstract] [Full Text]  
  • Ravichandran, V., Major, E. O. (2008). DNA-binding transcription factor NF-1A negatively regulates JC virus multiplication. J. Gen. Virol. 89: 1396-1401 [Abstract] [Full Text]  


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