The role of MKK1/2 kinase activity in human cytomegalovirus infection.
Human cytomegalovirus infection of quiescent fibroblasts was found to induce 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 using phospho-specific antibodies. Treatment of infected fibroblasts with U0126, a potent and specific inhibitor of MKK1/2 kinase activity, completely blocked ERK1/2 activation following HCMV infection without affecting cell viability. Anti-viral studies demonstrate that in the presence of U0126, viral titres are reduced and viral DNA replication is inhibited. In addition, protein levels of two viral early genes that are required for viral DNA replication, UL44 and UL84, are significantly decreased in the presence of U0126. These results suggest that HCMV-mediated activation of MKK1/2 kinase activity enhances virus infectivity by ensuring timely initiation of viral DNA replication, possibly by regulating early gene expression.
Johnson
Robert A
RA
Department of Microbiology and Immunology1, 32026 Lineberger Comprehensive Cancer Center, CB# 72952, Department of Medicine3 and Curriculum of Genetics and Molecular Biology4, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Ma
Xiu-Li
XL
Department of Microbiology and Immunology1, 32026 Lineberger Comprehensive Cancer Center, CB# 72952, Department of Medicine3 and Curriculum of Genetics and Molecular Biology4, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Yurochko
Andrew D
AD
Department of Microbiology and Immunology1, 32026 Lineberger Comprehensive Cancer Center, CB# 72952, Department of Medicine3 and Curriculum of Genetics and Molecular Biology4, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Huang
Eng-Shang
ES
Department of Microbiology and Immunology1, 32026 Lineberger Comprehensive Cancer Center, CB# 72952, Department of Medicine3 and Curriculum of Genetics and Molecular Biology4, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism
D002070:Butadienes; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D014764:Viral Proteins; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases