title: 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.
abstract: 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.
authors.affiliation: Department of Medicine I, Nephrology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mohr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Grandemange
authors.forename: Paola
authors.initials: P
authors.lastname: Massimi
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Darai
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Walter
authors.initials: W
authors.lastname: Muranyi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D051336:Mitochondrial Membranes / Q000737:chemistry; D008969:Molecular Sequence Data; D008977:Molluscum contagiosum virus / Q000502:physiology*; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; D014764:Viral Proteins