title: MEK1/2 inhibitors block basal and transforming growth factor 1beta1-stimulated JC virus multiplication.
abstract: 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 beta1 (TGF-beta1), which stimulated a 200% increase of Vp-1 expression. Specific MEK1/2 inhibitors, flavenoid PD98059 and U0126, decreased the basal and TGF-beta1-stimulated Vp-1 expression by 95% or more. TGF-beta1 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.
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1296, USA.
authors.forename: Veerasamy
authors.initials: V
authors.lastname: Ravichandran
authors.forename: Peter N
authors.initials: PN
authors.lastname: Jensen
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007577:JC Virus / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013234:Stem Cells / Q000821:virology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2