The role of MKK1/2 kinase activity in human cytomegalovirus infection

Human cytomegalovirus infection of quiescent fibroblasts was found to induc e a bi-phasic activation of mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MKK1/2) and two of their downstream targets, extracellular signal regulated kinase 1 and 2 (ERK1/2), as determined by Western blot analysis u sing phospho-specific antibodies. Treatment of infected fibroblasts with UO 126, a potent and specific inhibitor of MKK1/2 kinase activity, completely blocked ERK1/2 activation following HCMV infection without affecting cell v iability. Anti-viral studies demonstrate that in the presence of UO126, vir al titres are reduced and viral DNA replication is inhibited. In addition, protein levels of two viral early genes that are required for viral DNA rep lication, UL44 and UL84, are significantly decreased in the presence of UO1 26, These results suggest that HCMV-mediated activation of MKK1/2 kinase ac tivity enhances virus infectivity by ensuring timely initiation of viral DN A replication, possibly by regulating early gene expression.