Adenovirus-induced extracellular signal-regulated kinase phosphorylation during the late phase of infection enhances viral protein levels and virus progeny.
The Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling cascade enhances tumor cell proliferation in many cases. Here, we show that adenovirus type 5, a small DNA tumor virus used in experimental cancer therapy, strongly induces ERK phosphorylation during the late phase of infection. Pharmacologic inhibition of ERK phosphorylation reduced virus recovery by >100-fold. Blocking MEK/ERK signaling affected virus DNA replication and mRNA levels only weakly but strongly reduced the amount of viral proteins, independently of the kinases MNK1 and PKR. Hence, adenovirus induces the oncogenic Raf/MEK/ERK signaling pathway to enhance viral progeny by sustaining the levels of viral proteins. Concerning therapy, our results suggest that the use of Raf/MEK/ERK inhibitors will interfere with the propagation of oncolytic adenoviruses.
Schümann
Michael
M
Institut für Virologie, Klinikum der Philipps-Universität Marburg, Marburg, Germany.
Dobbelstein
Matthias
M
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000257:Adenoviridae Infections / Q000201:enzymology* / Q000821:virology; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D014779:Virus Replication / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D000814:Aniline Compounds; C466997:CGP 57380; D004279:DNA, Viral; D005419:Flavonoids; D011687:Purines; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one