Polyomaviruses are DNA tumor viruses with small circular genomes encoding only six proteins including three structural capsid proteins. Despite this simplicity, our understanding of the mechanisms of polyomavirus-mediated tumorigenesis is far from complete. The archetypal primate polyomavirus, SV40, was isolated more than 40 years ago and has been used extensively as a model system for the study of basic eukaryotic cellular processes such as DNA replication and transcription. Two human polyomaviruses have been isolated from clinical samples: JC virus (JCV) and BK virus (BKV). In this review, SV40, JCV, and BKV will be compared based on what is known about their molecular biology from experiments performed in vitro, in cell culture and in laboratory animals. The association of these viruses with clinical tumors is discussed along with the possible roles of these polyomaviruses in the etiology of human malignant disease.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.

SUMMARY About a fifth of all human cancers worldwide are caused by infectious agents. In 12% of cancers, seven different viruses have been causally linked to human oncogenesis: Epstein-Barr virus, hepatitis B virus, human papillomavirus, human T-cell lymphotropic virus, hepatitis C virus, Kaposi's sarcoma herpesvirus, and Merkel cell polyomavirus. Here, we review the many molecular mechanisms of oncogenesis that have been discovered over the decades of study of these viruses. We discuss how viruses can act at different stages in the complex multistep process of carcinogenesis. Early events include their involvement in mutagenic events associated with tumor initiation such as viral integration and insertional mutagenesis as well as viral promotion of DNA damage. Also involved in tumor progression is the dysregulation of cellular processes by viral proteins, and we describe how this has been investigated by studies in cell culture and in experimental animals and by molecular cellular approaches. Also important are the molecular mechanisms whereby viruses interact with the immune system and the immune evasion strategies that have evolved.

Protein kinase C-epsilon (PKC-⑀) contains a putative actin binding motif that is unique to this individual member of the PKC gene family. We have used deletion mutagenesis to determine whether this hexapeptide motif is required for the physical association of PKC-⑀ and actin. Full-length recombinant PKC-⑀, but not PKC-␤II, -␦, -, or -, bound to filamentous actin in a phorbol ester-dependent manner. Deletion of PKC-⑀ amino acids 222-230, encompassing a putative actin binding motif, completely abrogated this binding activity. When NIH 3T3 cells overexpressing either PKC-⑀ or the deletion mutant of this isozyme were treated with phorbol ester only wild-type PKC-⑀ colocalized with actin in zones of cell adhesion. In binary reactions, it was possible to demonstrate that purified filamentous actin is capable of directly stimulating PKC-⑀ phosphotransferase activity. These and other findings support the hypothesis that a conformationally hidden actin binding motif in the PKC-⑀ sequence becomes exposed upon activation of this isozyme and functions as a dominant localization signal in NIH 3T3 fibroblasts. This protein-protein interaction is sufficient to maintain PKC-⑀ in a catalytically active conformation.

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