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Journal of Virology, November 2008, p. 10625-10633, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01187-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Targeting the Retinoblastoma Protein by MC007L, Gene Product of the Molluscum Contagiosum Virus: Detection of a Novel Virus-Cell Interaction by a Member of the Poxviruses{triangledown}

Stefan Mohr,1 Stéphanie Grandemange,2 Paola Massimi,4 Gholamreza Darai,3 Lawrence Banks,4 Jean-Claude Martinou,2 Martin Zeier,1 and Walter Muranyi1*

Department of Medicine I, Nephrology, University of Heidelberg, Heidelberg, Germany,1 Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland,2 Department of Virology, University of Heidelberg, Heidelberg, Germany,3 International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy4

Received 7 June 2008/ Accepted 3 August 2008

The human pathogenic poxvirus molluscum contagiosum virus (MCV) is the causative agent of benign neoplasm, with worldwide incidence, characterized by intraepidermal hyperplasia and hypertrophy of cells. Here, we present evidence that the MC007L protein of MCV targets retinoblastoma protein (pRb) via a conserved LxCxE motif, which is present in many viral oncoproteins. The deregulation of the pRb pathway plays a central role in tumor pathogenesis. The oncoproteins of small DNA viruses contain amino acid sequences that bind to and inactivate pRb. Isolated expression of these oncoproteins induces apoptosis, cell proliferation, and cellular transformation. The MC007L gene displays no homology to other genes within the poxvirus family. The protein anchors into the outer mitochondrial membrane via an N-terminal mitochondrial targeting sequence. Through the LxCxE motifs, MC007L induces a cytosolic sequestration of pRb at mitochondrial membranes, leading to the inactivation of the protein by mislocalization. MC007L precipitates the endogenous pRb/E2F-1 complex. Moreover, MC007L is able to cooperate to transform primary rat kidney cells. The interaction between MC007L and pRb provides a novel mechanism by which a virus can perturb the cell cycle.

* Corresponding author. Mailing address: Department of Medicine I, Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Phone: 49 6221 9112-222. Fax: 49 6221 9112-990. E-mail: walter_muranyi{at}med.uni-heidelberg.de

{triangledown} Published ahead of print on 13 August 2008.

Journal of Virology, November 2008, p. 10625-10633, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01187-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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