There is now a considerable body of evidence that links HPV infection with anogenital squamous carcinoma, particularly for specific ‘high risk’ HPV types (HPV16 and 18) and invasive carcinoma of the cervix. Recent advances in the molecular study of these viruses have elucidated some potential mechanisms by which they may contribute to the development of these diseases.
In this review we concentrate on the interactions of 2 of the HPV encoded proteins, E6 and E7, with cellular tumour suppressor gene products. We provide a model of how these interactions may be important in tumourigenesis and draw together current knowledge of this exciting and rapidly evolving field.
BuckleyJDHarrisRWDollRVesseyMPWilliamsPT.Case-control study of the husbands of women with dysplasia or carcinoma of the cervix uteri. Lancet1981;ii:1010–15.
4.
VousdenKH.Human papillomaviruses and cervical cancer. Cancer Cells1989;1:43–9.
5.
zur HausenH.Human papillomaviruses in the pathogenesis of anogenital cancer. Virology1991;184:9–13.
6.
de VilliersE-M.Laboratory techniques in the investigation of human papillomavirus infection. Genitourin Med1992;68:50–4.
7.
YashumotoSBurkhardtALDoningerJDiPaoloJA.Human papillomavirus type 16-induced malignant transformation of NIH3T3 cells. J Virol1986;57:572–7.
8.
KandaTWatanabeSYoshiikoK.Immortalisation of primary rat cells by human papillomavirus type 16 subgenomic fragments controlled by the SV40 promoter. Virology1988;165:321–5.
9.
PirisiLYasumotoMFellerJDonigerJDiPaoloJA.Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol1987;61:1061–6.
10.
WoodworthCDDonigerJDiPaoloJA.Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical cancer. J Virol1989;63:159–64.
11.
McCanceDJKopanRFuchsELaiminsLA.Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci USA1988;85:7169–73.
12.
YeeCLKrishnan-HewlettIBakerCCSchlegelRHowleyPM.Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines. Am J Pathol1985;119:3261–6.
13.
BakerCCPhelpsWCLindgrenVStructural and transcriptional analysis of human papillomavirus type 16 sequences in cervical cancer cell lines. J Virol1987;61:962–71.
14.
MatsakuraTKandaTFurunoACloning of monomeric human papillomavirus type 16 integrated within cell DNA from a cervical carcinoma. J Virol1986;58:979–82.
15.
SchwarzEFreeseUKGissmanLStructure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature1985;314:111–14.
16.
CripeTPHaugenTHTurkJPTranscriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer and by viral E2 transactivator and repressor gene products: Implications for cervical carcinogenesis. EMBO J1987;6:3745–53.
17.
Schneider-GädickeASchwarzE.Different human cervical carcinoma cell lines show similar transcription patterns of human papillomavirus type 18 early genes. EMBO J1986;5:2285–92.
18.
SmotkinDWettsteinFO.Transcription of human papillomavirus type 16 early genes in a cervical cancer and a cancer-derived cell line and identification of the E7 protein. Proc Natl Acad Sci USA1986;83:4680–4.
19.
Hawley-NelsonPVousdenKHHubbertNLLowyDRSchillerJT.HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J1989;8:3905–10.
20.
MüngerKWernessBADysonNThe E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol1989;63:4417–21.
21.
BarbosaMSLowyDRSchillerJT.Papillomavirus polypeptides E6 and E7 are zinc-binding proteins. J Virol1989;63:1404–7.
22.
PhelpsWCYeeCLMüngerKHowleyPM.The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell1988;53:539–47.
23.
MoranE.A region of SV40 large T antigen can substitute for a transforming domain of the adenovirus El A products. Nature1988;334:168–70.
24.
DysonNHowleyPMMüngerKHarlowE.The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science1989;243:934–6.
25.
MüngerKWernessBADysonNHarlowEHowleyPM.Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J1989;8:4099–105.
26.
WernessBLevineAJHowleyPM.Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science1990;248:76–9.
27.
KnudsonAG.Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA1971:68:820–3.
28.
DryjaTPRapaportJMJoyceJMPetersenRA.Molecular detection of deletions involving band q14 and chromosome 13 in retinoblastoma. Proc Natl Acad Sci USA1986;83:7391–4.
29.
FriendSHBernardsRRogeljSA human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature1986;323:643–6.
30.
LeeW-HShewJ-YHongFDThe retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature1987;329:642–5.
31.
BuchkovichKDuffyLAHarlowE.The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell1989;58:1097–105.
32.
ChenP-LScullyPShewJ-YWangJYJLeeW-H.Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell1989;58:1193–8.
33.
LeesJABuchovichKJMarshakDRAndersonCWHarlowE.The retinoblastoma protein is phosphorylated on multiple sites by human cdc2. EMBO J1991;10:4279–90.
34.
ChellappanSPHiebertSMudryjMHorowitzJMNevinsJR.The E2F transcription factor is a cellular target for the RB protein. Cell1991;65:1053–61.
35.
CaoLFahaBDembskiMIndependent binding of the retinoblastoma protein and p107 to the transcription factor E2F. Nature1992;355:176–9.
36.
ShirodkarSEwenMDeCaprioJAThe transcription factor E2F interacts with the retinoblastoma product and a p107-Cyclin A complex in a cell cycle-regulated manner. Cell1992;68:157–66.
37.
WhytePBuchkovichKJHorowitzJMAssociation between an oncogene and an anti-oncogene: The adenovirus E1A proteins bind to the retinoblastoma gene product. Nature1988;334:124–9.
38.
DeCaprioJALudlowJWLynchDThe product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell1989;58:1085–95.
39.
BandaraLRLa ThangueNB.Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature1991;351:494–7.
40.
PaganoMDurstMJoswigSDraettaGJansen-DurrP.Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells. Oncogene1992;7:1681–6.
41.
ChellappanSKrausVBKrogerBAdenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA1992;89:4549–53.
42.
DysonNGuidaPMüngerKHarlowE.Homologous sequences in adenovirus E1A and HPV E7 proteins mediate interaction with the same set of cellular proteins. J Virol1992;66:6893–902.
43.
LaneDPCrawfordLV.T antigen is bound to a host protein in SV40-transformed cells. Nature1979;278:261–3.
44.
LambPCrawfordL.Characterisation of the human p53 gene. Mol Cell Biol1986;6:1379–85.
45.
FinlayCAHindsPWLevineAJ.The p53 protooncogene can act as a suppressor of transformation. Cell1989;57:1083–93.
DonehowerLAHarveyMSlagleBLMice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature1992;356:215–21.
48.
MalkinDLiFPStrongLCGerm line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science1990;250:1233–8.
49.
KuerbitzSJPlunkettBSWalshWVKastanMB.Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA1992;89:7491–5.
50.
El-DieryWSKernSEPietenpolJAKanzlerKWVogelsteinB.Definition of a consensus binding site for p53. Nature Genetics1992;1:45–50.
51.
FieldsSJangSK.Presence of a potent transcription activating sequence in the p53 protein. Science1990;249:1046–9.
52.
RaycroftLWuHLozanoG.Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science1990;249:1049–51.
53.
GannonJVLaneDP.P53 and DNA polymerase α compete for binding to SV40 T antigen. Nature1987;329:456–8.
54.
BraithwaiteAWSturzbecherHWAddisonCMouse p53 inhibits SV40 origin-dependent DNA replication. Nature1987;329:458–60.
55.
WangEHFriedmanPNPrivesC.The murine p53 protein blocks replication of SV40 in vitro by inhibiting the initiation functions of SV40 large T antigen. Cell1989;57:379–92.
56.
KernSEKinzlerKWBakerSJMutant p53 proteins bind DNA abnormally in vitro. Oncogene1991;6:131–6.
57.
KernSEPietenpolJAThiagalingamSOncogenic forms of p53 inhibit p53-regulated gene expression. Science1992;256:827–30.
58.
FarmerGBargonettiJZhuHWild-type p53 activates transcription in vitro. Nature1992;358:83–6.
59.
MilnerJMedcalfEA.Co-translation of activated mutant p53 with wild-type drives the wild-type p53 protein into the mutant conformation. Cell1991;65:765–74.
60.
HerskowitzI.Functional inactivation of genes by dominant negative mutations. Nature1987;329:219–22.
61.
MomandJZambettiGPOlsonDCGeorgeDLevineAJ.The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell1992;69:1237–45.
62.
OlinerJDKinzlerKWMeltzerPSGeorgeDLVolgelsteinB.Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature1992;358:80–4.
63.
ScheffnerMWernessBAHuibregtseJMLevineAJHowleyPM.The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell1990;63:1129–36.
64.
CrookTTidyJVousdenK.Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and transactivation. Cell1991;67:547–6.
65.
CrookTWredeDVousdenK.P53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene1991;6:873–5.
66.
CrookTWredeDTidyJAStatus of c-myc, p53 and retinoblastoma genes in human papillomavirus positive and negative squamous cell carcinomas of the anus. Oncogene1991;6:1251–7.
67.
WredeDTidyJACrookTLaneDVousdenKH.Expression of RB and p53 proteins in HPV-positive and HPV-negative cervical carcinoma cell lines. Mol Carcinogenesis1991;4:171–5.
68.
CrookTWredeDTidyJAClonal p53 mutation in primary cervical cancer: Association with human-papilloma-virus-negative tumours. Lancet1992;339:1070–3.
69.
ScheffnerMMüngerKByrneJCHowleyPM.The state of p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA1991;88:5523–7.
70.
FarrellPJAllanGJShanahanFVousdenKHCrookT.P53 is frequently mutated in Burkitt's lymphoma cell lines. EMBO J1991;10:2879–87.
