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Adenovirus-Induced Extracellular Signal-Regulated Kinase Phosphorylation during the Late Phase of Infection Enhances Viral Protein Levels and Virus Progeny

¹ Institut für Virologie, Klinikum der Philipps-Universität Marburg, Marburg, Germany; ² Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, Winsløwparken, Denmark; and ³ Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, University of Göttingen, Göttingen, Germany

Requests for reprints: Matthias Dobbelstein, Department of Molecular Oncology, University of Göttingen, Justus von Liebeg Weg 11, Göttingen, Lower Saxony, Germany 37077. Phone: 49-551-39-13840; Fax: 49-51-39-13713; E-mail: mdobbel{at}uni-goettingen.de.

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. (Cancer Res 2006; 66(3): 1282-8)

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