Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Deltagamma(1)34.5 mutants of herpes simplex virus 1.
Herpes simplex virus mutants lacking the gamma(1)34.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Deltagamma(1)34.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Deltagamma(1)34.5 mutant viruses to replicate in and destroy tumor cells.
Smith
Kerrington D
KD
Department of Radiation and Cellular Oncology, The University of Chicago Hospitals, Center for Advanced Medicine, Room 1329, Mail Code 9006, 5758 South Maryland Avenue, Chicago, IL 60637, USA.
Mezhir
James J
JJ
Bickenbach
Kai
K
Veerapong
Jula
J
Charron
Jean
J
Posner
Mitchell C
MC
Roizman
Bernard
B
Weichselbaum
Ralph R
RR
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000628:therapy; D050130:Oncolytic Virotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D019892:eIF-2 Kinase; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one