Transforming functions of Simian Virus 40.

Abstract

Oncogene (2001) 20, 7899–7907.Keywords: SV40; tumor suppressor; chaperone; tumorvirusIntroductionCancer is thought to progress through multiple stageswith each stage giving rise to cells showing increasedmalignant characteristics. Progression through thesestages is driven by genetic events such as mutations intumor suppressor genes or oncogenes, or the acquisi-tion of specific viral transforming sequences. Thesetumor suppressor genes and oncogenes encode proteinsthat are key components of regulatory pathways thatgovern genomic stability, cell proliferation, andapoptosis. Three key questions in cancer research are:(1) what specific genetic pathways, and which specificproteins within each pathway must be altered at eachstage of tumor progression?; (2) how is cellularbehavior changed by altering each specific pathway?and (3) are the cellular consequences the same foraltering a given pathway in every cell type, or does asingle pathway govern multiple cellular propertiesdepending on the cell-type?DNA tumor viruses are important both because theyprovide us with powerful tools to address mechanismsof tumorigenesis, and because, in some cases, theycontribute directly to cancer. Rather than alter cellularpathways by mutation, DNA tumor viruses encodedominant acting transforming proteins. Each of thesetransforming proteins target one or more key regula-tory proteins within a cell, thus altering the cell’sgrowth/survival properties. Because the viral trans-forming proteins must directly associate with theirtarget, they serve as ‘proteo-divining rods,’ guidinginvestigators through a milieu of cellular pathways andproteins irrelevant to the tumorigenic process anddirectly to the key players involved in malignanttransformation. In addition, insights into how thesekey pathways are regulated can be gleaned fromstudies of the biochemical mechanisms by which theviral transforming proteins alter their target. Finally,cell culture and transgenic mouse systems have allowedstudies of the role that each regulatory pathway playsin controlling cellular behavior.SV40 and the polyomavirusesSV40 is a prototype member of the polyomavirusgroup (for a complete review, see: Fields, 1996), havinga 45 nm diameter virion containing a single moleculeof closed circular double-stranded DNA of 5243 bp.There are seven known virus-encoded proteins gener-ated by di•erential splicing of two transcription units(Figure 1). The viral T antigens, large T antigen (LT),small T antigen (ST) and 17K T antigen (17KT) areexpressed soon after infection from a transcriptinitiating at the early promoter. Gene expression isaccomplished using the cellular transcription apparatusand, in fact, the SV40 early promoter is used to driveexpression of transgenes in a number of eucaryoticexpression vectors. The functions of the viral Tantigens are discussed below.The SV40 transcript initiated from the viral latepromoter is di•erentially spliced to result in mRNAsencoding the major capsid protein VP1, the minorcapsid proteins VP2 and VP3, or the viral agnoprotein. VP1, VP2, and VP3 are the only virus-encodedproteins found in mature virions. The agno proteinseems to function at some stage of virion assembly orvirus exit from infected cells.All polyomaviruses share the same basic genomestructure, a circular DNA with the T antigens and thecapsid proteins expressed from separate transcriptionunits, and an approximately 400 bp noncoding reg-ulatory region containing the origin of viral DNAreplication and the early and late promoters. Allpolyomaviruses encode LT, ST, VP1, VP2, and VP3.Murine polyomavirus and hamster polyomavirus bothencode a middle T antigen (MT) as well. Like LT andST, MT is produced by di•erential splicing of the earlyregion primary transcript.SV40 is one of 14 characterized polyomaviruses, ofwhich 12 have been fully sequenced. These include twohuman viruses, JCV and BKV, and the well-character-ized murine polyomavirus (PyV). Some of these virusessuch as SV40 and BKV are rarely pathogenic in theirnatural hosts, while others such as BFDV, PyV, ormurine K virus are deadly (Pipas, 1992).The host of SV40 is the Rhesus macaque and manyof these animals harbor apparently harmless lifelongpersistent infections of SV40. The kidney is thought tobe the primary target organ of SV40 infection. Thevirus undergoes productive infection in terminallydi•erentiated epithelial cells. This presents a problemfor the virus in that because of its small genome size it