New concepts on the role of human papillomavirus in cell cycle regulation.
Human papillomaviruses (HPVs) are strictly host-specific and also show a distinct tropism to squamous epithelial cells. Upon HPV infection, only a portion of the virus reaching the nucleus seems to undergo replication, suggesting that HPV replication remains confined to a small number of cells. HPVs critically depend on the cellular machinery for the replication of their genome. Viral replication is restricted to differentiated keratinocytes that are normally growth arrested. Hence, HPVs have developed strategies to subvert cellular growth regulatory pathways and are able to uncouple cellular proliferation and differentiation. Endogenous growth factors and cellular oncogenes modify HPV E (early) and L (late) gene expression and influence on the pathogenesis of HPV infections. HPV oncoproteins (E5, E6, E7) are important proteins not only in cell transformation but also in the regulation of the mitotic cycle of the cell, thus allowing the continuous proliferation of the host cells. Cyclins are important regulators of cell cycle transitions through their ability to bind cyclin-dependent kinases (cdks). Cdks have no kinase activity unless they are associated with a cyclin. Several classes of cyclins exist which are thought to coordinate the timing of different events necessary for cell cycle progression. Each cdk catalytic subunit can associate with different cyclins, and the associated cyclin determines which proteins are phosphorylated by the cdk-cyclin complex. The effects of HPVs on the cell cycle are mediated through the inhibition of antioncogens (mostly p53 and retinoblastoma) and through interference with the cyclins and cdks, resulting in target cell proliferation, their delayed differentiation, and as a side-effect, in malignant transformation.
Syrjänen
S M
SM
Department of Oral Pathology and Oral Radiology, Institute of Dentistry, University of Turku, Finland. stina.syrjanen@utu.fi
Syrjänen
K J
KJ
D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006801:Humans; D015513:Oncogene Proteins; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D016159:Tumor Suppressor Protein p53
D016213:Cyclins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases