Human papillomaviruses (HPV) are the aetiological agents of several types of anogenital tumours, particularly cervical carcinoma. Recent evidence also suggests a role for HPV in the development of squamous cell carcinomas of the skin, especially in immunocompromised individuals. HPV infection also produces a number of non-malignant, but nonetheless cosmetically unpleasant lesions. Therefore, any effective therapeutic treatment for HPV-induced diseases would be extremely beneficial both on humanitarian grounds as well as being economically very attractive. In this review, we will discuss the functions of the viral proteins that appear to be the most appropriate for the development of therapeutics aimed at the treatment of viral infection and virus-induced cancers.
References
1.
HowleyP.M., & LowyD.R.Papillomaviridae. In Virology, vol. 22001; pp. 2197–2264. Edited by FieldsB.N., KnipeJ.B., HowleyP.M.Philadelphia: Lippincott, Williams & Wilkins.
2.
zur HausenH., & SchneiderA.The Papillomaviruses. In The Papovaviridae: The Papillomaviruses, vol. 21987; pp. 245–263. Edited by SalzmanN.P., HowleyP.M.New York: Plenum Publishing.
3.
ParkinD.M., BrayF., FerlayJ., & PisaniP.Estimating the world cancer burden: Globocan 2000.International Journal of Cancer2001; 94: 153–156.
4.
WheelerC.M.Clinical aspects and epidemiology of HPV infection. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 1–29. Edited by McCanceD.J.Amsterdam: Elsevier Science B V.
5.
BoschF.X., ManosM.M., MunozN., ShermanM., JansenA.M., PetoJ., SchiffmanM.H., MorenoV., KurmanR., & ShahK. V.Prevalence of human papillomavirus in cervical cancer: a world-wide perspective. International biological study on cervical cancer (IBSCC) study group.Journal of the National Cancer Institute1995; 87: 796–801.
6.
BeckerT.M., WheelerC.M., McGoughN.S., ParmenterC.A., JordanS.W., StidleyC.A., McPhersonS., & DorinM.H.Sexually transmitted diseases and other risk factors for cervical dysplasia among southwestern Hispanic and Non-Hispanic white women.Journal of the American Medical Association1994; 271: 1181–1188.
7.
KoutskyL.A., HolmesK.K., CritchlowC.W., StevensC.E., PaavonenJ., BeckmannA.M., DeRouenT.A., GallowayD.A., VernonD., & KiviatN.B.A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.New England Journal of Medicine1992; 327: 1272–1278.
8.
SchiffmanM.H., BauerH.M., HooverR.N., GlassA.G., CadellD.M., RushB.B., ScottD.R., ShermanM.E., KurmanR.J., & WacholderS.Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia.Journal of the National Cancer Institute1993; 85: 1868–1870.
9.
MunozN., BoschF.X., de SanjoseS., HerreroR., CastellsagueX., ShahK. V., SnijdersP.J., & MeijerC.J.; International agency for research on cancer. Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer.New England Journal of Medicine2003; 348: 518–527.
10.
FuchsP.G., & PfisterH.Papillomavirus in epidermodysplasia verruciformis. In Papillomavirus Reviews: Current Research on Papillomaviruses, 1996; pp. 253–261. Edited by LaceyC.Leeds, UK: University of Leeds.
11.
BentonE.C., & ArendsM.J.Human papillomavirus in the immunosuppressed. In Papillomavirus Reviews: Current Research on Papillomaviruses, 1996; pp. 271–279. Edited by LaceyC. Leeds, UK: University of Leeds.
12.
zur HausenH.Oncogenic DNA viruses.Oncogene Reviews2001; 20: 7820–7823.
13.
StubenrauchF., & LaiminsL.A.Human papillomavirus life cycle: active and latent phases.Seminars in Cancer Biology1999; 9: 379–386.
DoorbarJ., FooC., ColemanN., MedcalfL., HartleyO., ProsperoT., NapthineS., SterlingJ., WinterG., & GriffinH.Characterisation of events during the late stages of HPV16 infection in vivo using high affinity synthetic Fabs to E4.Virology1997; 238: 40–52.
16.
MungerK., PhelpsW.C., BubbV., HowleyP.M., & SchlegelR.The E6 and E7 genes of human papillomavirus type 16 are necessary and sufficient for transformation of primary human keratinocytes.Journal of Virology1989; 63: 4417–4423.
17.
Hawley-NelsonP., VousdenK.H., HubbertN.L., LowyD.R., & SchillerJ.T.HPV 16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes.EMBO Journal1989; 8: 3905–3910.
18.
BarbosaM.S., & SchlegelR.The E6 and E7 genes of HPV-18 are sufficient for inducing two-stage in vitro transformation of human keratinocytes.Oncogene1989; 4: 1529–1532.
19.
YeeC., Krishnan-HewlettI., BakerC.C., SchlegelR., & HowleyP.M.Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines.American Journal of Pathology1985; 119: 361–366.
20.
SchwarzE., FreeseU., GissmannL., MayerW., RoggenbuckB., StremlauA., & zur HausenH.Structure and transcription of human papillomavirus sequences in cervical carcinoma cells.Nature1985; 314: 111–114.
21.
BakerC.C., PhelpsW.C., LindgrenV., BraunM.J., GondaM.A., & HowleyP.M.Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines.Journal of Virology1987; 61: 962–971.
22.
SteeleJ.C.Immunity to human papillomaviruses: implications for vaccine design. In Viruses, Cell Transformation and Cancer, 2001; pp. 451–478. Edited by GrandR.J.A.Amsterdam: Elsevier Science B V.
23.
BreitburdF., & CoursagetP.Human papillomavirus vaccines.Seminars in Cancer Biology1999; 9: 431–445.
24.
LiuJ-S, & MelendyT.Human papillomavirus DNA replication. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 53–70. Edited by McCanceD.J.Amsterdam: Elsevier Science BV.
25.
YangL., LiR., MohrI., ClarkR., & BotchanM.R.Activation of BPV-1 replication in vitro by the transcription factor E2.Nature1991; 353: 628–633.
26.
SeoY-S, MullerF., LuskyM., GibbsE., KimH-Y, PhillipsB. & HurwitzJ.Bovine papilloma virus (BPV)-encoded E2 protein enhances binding of E1 protein to the BPV replication origin.Proceedings of the National Academy of Sciences, USA1993; 90: 2865–2869.
27.
SedmanJ., & StenlundA.Co-operative interaction between the initiator E1 and the transcriptional activator E2 is required for replicator specific DNA replication of bovine papillomvirus in vivo and in vitro.EMBO Journal1995; 14: 6218–6228.
28.
SedmanT., SedmanJ., & StenlundA.Binding of the E1 and E2 proteins to the origin of replication of bovine papillomavirus.Journal of Virology1997; 71: 2887–2896.
29.
FaucherA.M., WhiteP.W., BrochuC., Grand-MaitreC., RancourtJ., & FazalG.Discovery of small-molecule inhibitors of the ATPase activity of human papillomavirus E1 helicase.Journal of Medicinal Chemistry2004; 47: 18–21.
30.
del Mar PenaL., & LaiminsL.A.Regulation of human papillomavirus gene expression in the vegetative life cycle. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 31–51. Edited by McCanceD.J.Amsterdam: Elsevier Science BV.
31.
CowsertL.M., FoxM.C., ZonG., & MirabelliK.In vitro evaluation of phosphorothioate oligonucleotides targeted to the E2 mRNA of papillomavirus: potential treatment for genital warts.Antimicrobial Agents & Chemotherapy1993; 37: 171–177.
32.
ClarkP.R., RobertsM.L., & CowsertL.M.A novel drug screening assay for papillomavirus specific antiviral activity.Antiviral Research1998; 37: 97–106.
33.
KurgR., LangelU., & UstavM.Inhibition of the bovine papillomavirus E2 protein activity by peptide nucleic acid.Virus Research2000; 66: 39–50.
34.
HajdukP.J., DingesJ., MiknisG.F., MerlokM., MiddletonT., KempfD.J., EganD.A., WalterK.A., RobinsT.S., ShukerS.B., HolzmanT.F., & FesikS.W.NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.Journal of Medicinal Chemistry1997; 40: 3144–3150.
35.
SchaalT.D., MalletW.G., McMinnD.L., NguyenN.V., SopkoM.M., JohnS., & ParekhB.S.Inhibition of human papilloma virus E2 DNA binding protein by covalently linked polyamides.Nucleic Acids Research2003; 31: 1282–1291.
36.
KasukawaH., HowleyP.M., & BensonJ.D.A fifteen-amino-acid peptide inhibits human papillomavirus E1-E2 interaction and human papillomavirus DNA replication in vitro.Journal of Virology1998; 72: 8166–8173.
37.
YoakimC., OgilvieW.W., GoudreauN., NaudJ., HacheB., O'MearaJ.A., CordingleyM.G., ArchambaultJ., & WhiteP.W.Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the E1-E2-origin DNA complex.Bioorganic & Medicinal Chemistry Letters Symposia-in-Print2003; 13: 2539–2541.
38.
WhiteP. W., TitoloS., BraultK., ThauvetteL., PelletierA., WelchnerE., BurgonL., DoyonL., OgilvieW.W., YoakimC., CordingleyM.G., & ArchambaultJ.Inhibition of human papillomavirus DNA replication by small molecule antagonists of the E1-E2 protein interaction.Journal of Biological Chemistry2003; 278: 26765–26772.
39.
WangY., CoulombeR., CameronD.R., ThauvetteL., MassariolM-J, AmonL.M., FinkD., TitoloS., WelchnerE., YoakimC., ArchambaultJ., & WhiteP.W.Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor.Journal of Biological Chemistry2004; 279: 6976–6985.
40.
DengS-J, PearceK.H., DixonE. P., HartleyK.A., StanleyT.B., LobeD.C., GarveyE.P., KostT.A., PettyR.L., RocqueW.J., AlexanderK.A., & UnderwoodM.R.Identification of peptides that inhibit the DNA binding, trans-activator, and DNA replication functions of the human papillomavirus type 11 E2 protein.Journal of Virology2004; 78: 2637–2641.
41.
FujiiT., AustinD., GuoD., SrimatkandadaS., WangT., KubushiroK., MasumotoN., TsukazakiK., NozawaS., & DeisserothA.B.Peptides inhibitory for the transcriptional regulatory function of human papillomavirus E2.Clinical Cancer Research2003; 9: 5423–5428.
42.
ChiandC-M, UstavM., StenlundA., HoT.F., BrokerT.R., & ChowL.T.Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.Proceedings of the National Academy of Sciences, USA1992; 89: 5799–5803.
43.
BoshartM., GissmannL., IkenbergH., KleinheinzA., ScheurlenW., & zur HausenH.A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer.EMBO Journal1984; 3: 1151–1157.
44.
PaterM.M., & PaterA.Human papillomavirus types 16 and 18 sequences in carcinoma cell lines of the cervix.Virology1985; 145: 313–318.
45.
MatsukuraT., KandaT., FurunoA., YoshikawaH., KawanaT., & YoshiikeK.Cloning of monomeric human papillomavirus type 16 DNA integrated within cell DNA from a cervical carcinoma.Journal of Virology1986; 58: 979–982.
46.
RomanczukH., & HowleyP.M.Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity.Proceedings of the National Academy of Sciences, USA1992; 89: 3159–3163.
47.
DoorbarJ.The E4 proteins and their role in the viral life cycle. In Papillomavirus Reviews: Current Research on Papillomaviruses, 1996; pp. 31–38. Edited by LaceyC.Leeds, UK: University of Leeds.
48.
RobertsS.Biology of the E4 protein. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 119–142. Edited by McCanceD.J.Amsterdam: Elsevier Science B V.
49.
DavyC.E., JacksonD.J., WangQ., RajK., MastersonP.J., FennerN.F., SouthernS., CythillS., MillarB.A., & DoorbarJ.Identification of a G2 arrest domain in the E1^E4 protein of human papillomavirus type 16.Journal of Virology2002; 76: 9806–9818.
50.
RobertsS., HillmanM.L., KnightG.L., & GallimoreP.H.The ND10 component promyelocytic leukemia protein relocates to human papillomavirus type 1 E4 intranuclear inclusion bodies in cultured keratinocytes and in warts.Journal of Virology2003; 77: 673–684.
51.
PehW.L., BrandsmaJ.L., ChristensenN.D., CladelN.M., WuX., & DoorbarJ.The viral E4 protein is required for the completion of the cottontail rabbit papillomavirus productive cycle in vivo.Journal of Virology2004; 78: 2142–2151.
52.
DoorbarJ., ElyS., SterlingJ., McLeanC., & CrawfordL.Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network.Nature1991; 352: 824–827.
53.
WangQ., GriffinH., SouthernS., JacksonD., MartinA., McIntoshP., DavyC., MastersonP.J., WalkerP.A., LaskeyP., OmaryM.B., & DoorbarJ.Functional analysis of the human papillomavirus type 16 E1^E4 protein provides a mechanism for in vivo and in vitro keratin filament reorganization.Journal of Virology2004; 78: 821–833.
54.
NakaharaT., NishimuraA., TanakaM., UenoT., IshimotoA., & SakaiH.Modulation of the cell division cycle by human papillomavirus type 18 E4.Journal of Virology2002; 76: 10914–10920.
55.
LeechanachaiP., BanksL., MoreauF., & MatlashewskiG.The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus.Oncogene1992; 7: 19–25.
56.
LeptakC., CajalR., KulkeS.R., HorwitzB.H., de RieseD., DottoG.P., & DiMaioD.Tumorigenic transformation of murine keratinocytes by the E5 genes of bovine papillo-mavirus type 1 and human papillomavirus type 16.Journal of Virology1991; 65: 7078–7083.
57.
PimD., CollinsM., & BanksL.Human papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptor.Oncogene1992; 7: 27–32.
58.
StraightS.W., HinkleP.M., JewersR.J., & McCanceD.J.The E5 oncoprotein of human papillomavirus type 16 transform fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes.Journal of Virology1993; 67: 4521–4532.
59.
BouvardV., MatlashewskiG., GuZ.M., StoreyA., & BanksL.The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression.Virology1994; 203: 73–80.
60.
ConradM., BubbV.J., & SchlegelR.The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein.Journal of Virology1993; 67: 6170–6178.
61.
SchlegelR., Wade-GlassM., RabsonM.S., & YangY.C.The E5 transforming gene of bovine papillomavirus encodes a small, hydrophobic polypeptide.Science1986; 233: 464–467.
62.
MartinP., VassW.C., SchillerJ.T., LowyD.R., & VeluT.J.The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors.Cell1989; 59: 21–32.
63.
BanksL., & MatlashewskiG.Biochemical and biological activities of the HPV E5 proteins. In Papillomavirus Reviews: Current Research on Papillomaviruses, 1996; pp. 39–45. Edited by LaceyC.Leeds, UK: University of Leeds.
64.
VenutiA., & CampoM.S.The E5 protein papillomaviruses. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 143–164. Edited by McCanceD.J.Amsterdam: Elsevier Science BV.
65.
PimD., ThomasM., & BanksL.The function of the human papillomavirus oncogenes. In Viruses, Cell Transformation and Cancer, 2001; pp. 145–192. Edited by GrandR.J.A.Amsterdam: Elsevier Science BV.
66.
DiMaioD., & MattoonD.Mechanisms of cell transformation by papillomavirus E5 proteins.Oncogene Reviews2001; 20: 7866–7873.
67.
PettiL., NilsonL.A., & DiMaioD.Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein.EMBO Journal1991; 10: 845–855.
68.
PettiL., & DiMaioD.Stable association between the bovine papillomavirus E5 transforming protein and activated platelet-derived growth factor receptor in transformed mouse cells.Proceedings of the National Academy of Sciences, USA1992; 89: 6736–6740.
69.
CrusiusK., KaszkinM., KinzelV., & AlonsoA.The human papillomavirus type 16 E5 protein modulated phospholipase C-gamma-1 activity and phosphatidyl inositol turnover in mouse fibroblasts.Oncogene1999; 18: 6714–6718.
70.
FehrmannF., KlumppD.J., & LaiminsL.A.Human papillomavirus type 31 E5 protein supports cell cycle progression and activated late viral functions upon epithelial differentiation.Journal of Virology2003; 77: 2819–2831.
71.
GentherS.M., SterlingS., DuensingS., MungerK., SattlerC., & LambertP.Quantitative role of the human papillomavirus type 16 E5 gene during the productive stage of the viral life cycle.Journal of Virology2003; 77: 2832–2842.
72.
BauknechtT., KohlerM., JanzL., & PfleidererA.The occurrence of epidermal growth factor receptors and the characterization of EGF-like factors in human ovarian, endometrial, cervical and breast cancer.Journal of Cancer Research & Clinical Oncology1989; 115: 193–199.
73.
KohlerM., JanzI., WintzerH.O., WagnerE., & BauknechtT.The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance.Antiviral Research1989; 9: 15371547.
74.
SmotkinD., & WettsteinF.O.Transcription of human papillomavirus type 16 early genes in a cervical cancer and a cancer-derived cell line and identification of the E7 protein.Proceedings of the National Academy of Sciences, USA1986; 83: 4680–4684.
75.
AndrophyE.J., HubbertN.L., SchillerJ.T., & LowyD.R.Identification of the HPV-16 E6 protein from transformed mouse cells and human cervical carcinoma cell lines.EMBO Journal1987; 6: 989–992.
76.
BanksL., SpenceP., AndrophyE., HubbertN., MatlashewskiG., MurrayA., & CrawfordL.Identification of human papillomavirus type 18 E6 polypeptide in cells derived from human cervical carcinomas.Journal of General Virology1987; 68: 1351–1359.
77.
von Knebel-DoeberitzM., OltersdorfT., SchwarzE., & GissmannL.Correlation of modified human papilloma virus early gene expression with altered growth properties in C4-1 cervical carcinoma cells.Cancer Research1988; 48: 3780–3786.
78.
CrookT., MorgensternJ.P., CrawfordL., & BanksL.Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV-16 plus EJ-ras.EMBO Journal1989; 8: 513–519.
79.
StoreyA., MassimiP., DawsonK., & BanksL.Conditional immortalization of primary cells by human papillomavirus type 18 E6 and EJ-ras defines an E6 activity in G0/G1 phase which can be substituted for mutations in p53.Oncogene1995; 11: 653–661.
80.
GoodwinE.C., & DiMaioD.Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways.Proceedings of the National Academy of Sciences, USA2000; 97: 12513–12518.
81.
HamadaK., SakaueM., AlemanyR., ZhangW., HorioY., RothJ., & MitchellM.Adenovirus-mediated transfer of HPV 16 E6/E7 antisense RNA to human cervical cancer cells.Gynecologic Oncology1996; 63: 219–227.
82.
von Knebel DoeberitzM., RittmullerC., zur HausenH., & DurstM.Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV E6-E7 anti-sense RNA.International Journal of Cancer1992; 51: 831–834.
83.
Alvarez-SalasL., CullinanA., SiwkowskiA., HampelA., & DiPaoloD.Inhibition of HPV-16 E6/E7 immortalization of normal keratinocytes by hairpin ribozymes.Proceedings of the National Academy of Sciences, USA1998; 95: 1189–1194.
84.
HallA.H.S., & AlexsanderK.A.RNA interference of human papillomavirus type 18 E6 and E7 induces senescence in HeLa cells.Journal of Virology2003; 77: 6066–6069.
85.
ButzK., RistrianiT., HengstermannA., DenkC., ScheffnerM., & Hoppe-SeylerF.siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells.Oncogene2003; 22: 5938–5945.
86.
YoshinouchiM., YamadaT., KizakiM., FenJ., KosekiT., IkedaY., NishiharaT., & YamatoK.In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA.Molecular Therapy2003; 8: 762–768.
87.
FloresE.R., Allen-HoffmannB.L., LeeD., & LambertP.F.The human papillomavirus type 16 E7 oncogene is required for the productive stage of the viral life cycle.Journal of Virology2000; 74: 6622–6631.
88.
ThomasJ.T., HubertW.G., RueschM.N., & LaiminsL.A.Human papillomavirus type 31 oncoproteins E6 and E7 are required for the maintenance of episomes during the viral life cycle in normal human keratinocytes.Proceedings of the National Academy of Sciences, USA1999; 96: 8449–8454.
89.
ParkR.B., & AndrophyE.J.Genetic analysis of high-risk E6 in episomal maintenance of human papillomavirus genomes in primary human keratinocytes.Journal of Virology2002; 76: 11359–11364.
90.
OhS.T., LongworthM.S., & LaiminsL.A.Roles of the E6 and E7 proteins in the life cycle of low-risk human papillomavirus type 11.Journal of Virology2004; 78: 2620–2626.
91.
ThomasM., PimD., & BanksL.Human papillomavirus E6 protein interactions. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 71–99. Edited by McCanceD.J.Amsterdam: Elsevier Science BV.
92.
McDougallJ.K.HPV immortalisation and transformation. In Papillomavirus Reviews: Current Research on Papillomaviruses, 1996; pp. 47–53. Edited by LaceyC.Leeds, UK: University of Leeds.
93.
HerberR., LiemA., PitotH., & LambertP.F.Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene.Journal of Virology1996; 70: 1873–1881.
94.
SongS., PitotH.C., & LambertP.F.The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals.Journal of Virology1999; 73: 5887–5893.
95.
DemersG.W., HalbertC.L., & GallowayD.A.Elevated wild-type p53 protein levels in human epithelial cell lines immortalized by the human papillomavirus type 16 E7 gene.Virology1994; 198: 169–174.
96.
SongS., GulliverG.A., & LambertP.F.Human papillo-mavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways.Proceedings of the National Academy of Sciences, USA1998; 95: 2290–2295.
97.
WhiteA.E., LivanosE.M., & TlstyT.D.Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins.Genes & Development1994; 8: 666–677.
98.
ReznikoffC.A., BelairC., SavelievaE., ZhaiY., PfeiferK., YeagerT., ThompsonK.J., DeVriesS., BindleyC., NewtonM.A., SekhonG., & WaldmanF.Long-term genome stability and minimal genotypic and phenotypic alterations in HPV16 E7-, but not E6-, immortalized human uroepithelial cells.Genes & Development1994; 8: 2227–2240.
99.
SchaefferA.J., NguyenM., LiemA., LeeD., MontagnaC., LambertP.F., RiedT., & DifilippantonioM.J.E6 and E7 oncoproteins induce distinct patterns of chromosomal aneuploidy in skin tumors from transgenic mice.Cancer Research2004; 64: 538–546.
100.
SongS., LiemA., MillerJ.A., & LambertP.F.Human papillo-mavirus types 16 E6 and E7 contribute differently to carcinogenesis.Virology2000; 267: 141–150.
101.
RileyR.R., DuensingS., BrakeT., MungerK., LambertP.F., & ArbeitJ.M.Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.Cancer Research2003; 63: 4862–4871.
102.
CaldeiraS., ZehbeI., AccardiR., MalanchiI., DongW., GiarreM., de VilliersE.M., FiloticoR., BoukampP., & TommasinoM.The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties.Journal of Virology2003; 77: 2195–2206.
103.
MantovaniF., & BanksL.The human papillomavirus E6 protein and its contribution to malignant progression.Oncogene Reviews2001; 20: 7874–7887.
104.
MantovaniF., & BanksL.The interaction between p53 and papillomaviruses.Seminars in Cancer Biology1999; 9: 387–395.
105.
LevineA.J.p53, the cellular gatekeeper for growth and division.Cell1997; 88: 323–331.
106.
HansenR., & OrenM.p53; from inductive signal to cellular effect.Current Opinion in Genetics & Development1997; 7: 46–51.
107.
CrookT., WredeD., & VousdenK.H.p53 point mutation in HPV negative human cervical carcinoma cell lines.Oncogene1991; 6: 873–875.
108.
ScheffnerM., MungerK., ByrneJ.C., & HowleyP.M.The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines.Proceedings of the National Academy of Sciences, USA1991; 88: 5523–5527.
109.
HuibregtseJ.M., ScheffnerM., & HowleyP.M.Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins.Molecular & Cellular Biology1993; 13: 4918–4927.
110.
HuibregtseJ.M., ScheffnerM., & HowleyP.M.Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53.Molecular & Cellular Biology1993; 13: 775–784.
111.
ScheffnerM., HuibregtseJ.M., VierstraR.D., & HowleyP.M.The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.Cell1993; 75: 495–505.
112.
HengstermannA., LinaresL.K., CiechanoverA., WhitakerN.J., & ScheffnerM.Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells.Proceedings of the National Academy of Sciences, USA2001; 98: 1218–1223.
113.
Beer-RomeroP., GlassS., & RolfeM.Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells.Oncogene1997; 14: 595–602.
114.
ButzK., DenkC., UllmannA., ScheffnerM., & Hoppe-SeylerF.Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein.Proceedings of the National Academy of Sciences, USA2000; 97: 6693–6697.
115.
LiuY., ChenJ.J., GaoQ., DalalS., HongY., MansurC.P., BandV., & AndrophyE.J.Multiple functions of human papillomavirus type 16 E6 contribute to the immortalization of mammary epithelial cells.Journal of Virology1999; 73: 7297–7307.
116.
NakagawaS., WatanabeS., YoshikawaH., TaketaniY., YoshiikeK., & KandaT.Mutational analysis of human papillomavirus type 16 E6 protein: transforming function for human cells and degradation of p53 in vitro.Virology1995; 212: 535–542.
117.
PanH., & GriepA.E.Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development.Genes & Development1995; 9: 2157–2169.
118.
PimD., StoreyA., ThomasM., MassimiP., & BanksL.Mutational analysis of HPV-18 E6 identifies domains required for p53 degradation in vitro, abolition of p53 transactivation in vivo and immortalisation of primary BMK cells.Oncogene1994; 9: 1869–1876.
119.
KiyonoT., FosterS.A., KoopJ.I., McDougallJ.K., GallowayD.A., & KlingelhutzA.J.Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.Nature1998; 396: 84–88.
120.
KiyonoT., HiraiwaA., FujitaM., HayashiY., AkiyamaT., & IshibashiM.Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein.Proceedings of the National Academy of Sciences, USA1997; 94: 11612–11616.
121.
ElbelM., CarlS., SpadernaS., & IftnerT.A comparative analysis of the interactions of the E6 proteins from cutaneous and genital papillomaviruses with p53 and E6AP in correlation to their transforming potential.Virology1997; 239: 132–149.
122.
KempC.J., DonehowerL.A., BradleyA., & BalmainA.Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors.Cell1993; 74: 813–822.
123.
ChenJ.J., ReidC.E., BandV., & AndrophyE.J.Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein.Science1995; 269: 529–531.
124.
GaoQ., SrinivasanS., BoyerS.N., WazerD.E., & BandV.The E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation.Molecular & Cellular Biology1999; 19: 733–744.
125.
RoncoL.V., KarpovaA.Y., VidalM., & HowleyP.M.Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity.Genes & Development1998; 12: 2061–2072.
126.
TongX., & HowleyP.M.The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton.Proceedings of the National Academy of Sciences, USA1997; 94: 4412–4417.
127.
Vande PolS.B., BrownM.C., & TurnerC.E.Association of bovine papillomavirus type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif.Oncogene1998; 16: 43–52.
128.
BeX., HongY., WeiJ., AndrophyE.J., ChenJ.J., & BalejaJ.D.Solution structure determination and mutational analysis of the papillomavirus E6 interacting peptide of E6AP.Biochemistry2001; 40: 1293–1299.
129.
ChenJ.J., HongY., RustamzadehE., BalejaJ.D., & AndrophyE.J.Identification of an alpha helical motif sufficient for association with papillomavirus E6.Journal of Biological Chemistry1998; 273: 13537–13544.
130.
ElstonR.C., NapthineS., & DoorbarJ.The identification of a conserved binding motif within human papillomavirus type 16 E6 binding peptides, E6AP and E6BP.Journal of General Virology1998; 79: 371–374.
131.
NguyenM., SongS., LiemA., AndrophyE., LiuY., & LambertP.F.A mutant of human papillomavirus type 16 E6 deficient in binding alpha-helix partners displays reduced oncogenic potential in vivo.Journal of Virology2002; 76: 13039–13048.
132.
CrookT., TidyJ.A., & VousdenK.H.Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation.Cell1991; 67: 547–556.
133.
NguyenM.L., NguyenM.M., LeeD., GriepA.E., & LambertP. F.The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo.Journal of Virology2003; 77: 6957–6964.
134.
LeeS.S., WeissR.S., & JavierR.T.Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein.Proceedings of the National Academy of Sciences, USA1997; 94: 6670–6675.
135.
NakagawaS., & HuibregtseJ.M.Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase.Molecular & Cellular Biology2000; 20: 8244–8253.
136.
LeeS.S., GlaunsingerB., MantovaniF., BanksL., & JavierR.T.Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high-risk papillo-mavirus type 18 E6 oncoproteins.Journal of Virology2000; 74: 9680–9693.
137.
GlaunsingerB.A., LeeS.S., ThomasM., BanksL., & JavierR.Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins.Oncogene2000; 19: 5270–5280.
138.
GardiolD., KuhneC., GlaunsingerB., LeeS.S., JavierR., & BanksL.Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation.Oncogene1999; 18: 5487–5496.
139.
Morais CabralJ.H., PetosaC., SutcliffeM.J., RazaS., ByronO., PoyF., MarfatiaS.M., ChishtiA.H., & LiddingtonR.C.Crystal structure of a PDZ domain.Nature1996; 382: 649–652.
140.
DoyleD.A., LeeA., LewisJ., KimE., ShengM., & MacKinnonR.Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ.Cell1996; 85: 1067–1076.
141.
HillierB.J., ChristophersonK.S., PrehodaK.E., BredtD.S., & LimW.A.Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex.Science1999; 284: 812–815.
142.
Sterlinko GrmH., WeberM., ElstonR., McIntoshP., GriffinH., BanksL., & DoorbarJ.Inhibition of E6-induced degradation of its cellular substrates by novel blocking peptides.Journal of Molecular Biology2004; 335: 971–985.
143.
GrossA., McDonnellJ.M., & KorsmeyerS.J.BCL-2 family members and the mitochondria in apoptosis.Genes & Development1999; 13: 1899–1911.
144.
BergerS.L.Gene activation by histone and factor acetyl-transferases.Current Opinion in Cell Biology1999; 11: 336–341.
145.
GoodmanR.H., & SmolikS.CBP/p300 in cell growth, transformation, and development.Genes & Development2000; 14: 1553–1577.
146.
PatelD., HuangS.M., BagliaL.A., & McCanceD.J.The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300.EMBO Journal1999; 18: 5061–5072.
147.
ZimmermannH., DegenkolbeR., BernardH.U., & O'ConnorM.J.The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300.Journal of Virology1999; 73: 6209–6219.
148.
ZimmermannH., KohC.H., DegenkolbeR., O'ConnorM.J., MullerA., StegerG., ChenJ.J., LuiY., AndrophyE., & BernardH.U.Interaction with CBP/p300 enables the bovine papillomavirus type 1 E6 oncoprotein to downregulate CBP/p300-mediated transactivation by p53.Journal of General Virology2000; 81: 2617–2623.
149.
BernatA., MassimiP., & BanksL.Complementation of a p300/CBP defective-binding mutant of adenovirus E1a by human papillomavirus E6 proteins.Journal of General Virology2002; 83: 829–833.
150.
ThomasM., & BanksL.Inhibition of Bak-induced apoptosis by HPV-18 E6.Oncogene1998; 17: 2943–2954.
151.
ThomasM., & BanksL.Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types.Journal of General Virology1999; 80: 1513–1517.
152.
KrajewskiS., KrajewskaM., ShabaikA., MiyashitaT., WangH.G., & ReedJ.C.Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2.American Journal of Pathology1994; 145: 1323–1336.
153.
KrajewskiS., KrajewskaM., & ReedJ.C.Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family.Cancer Research1996; 56: 2849–2855.
154.
ChengS., Schmidt-GrimmingerD.C., MurantT., BrokerT.R., & ChowL.T.Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes.Genes & Development1995; 9: 2335–2349.
155.
PanH., & GriepA.E.Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development.Genes & Development1994; 8: 1285–1299.
156.
DysonN.The regulation of E2F by pRB-family proteins.Genes & Development1998; 12: 2245–2262.
157.
ZwerschkeW., & Jansen-DurrP.Cell transformation by the E7 oncoprotein of human papillomavirus type 16: interactions with nuclear and cytoplasmic target proteins.Advances in Cancer Research2000; 78: 1–29.
158.
MungerK., BasileJ.R., DuensingS., EichtenA., GonzalezS.L., GraceM., & ZacnyV.L.Biological activities and molecular targets of the human papillomavirus E7 oncoprotein.Oncogene Reviews2001; 20: 7888–7898.
159.
McCanceD.The biology of E7. In Perspectives in Medical Virology, 8: Human Papilloma Viruses, 2002; pp. 101–118. Edited by McCanceD.J.Amsterdam: Elsevier Science BV.
160.
GiarreM., CaldeiraS., MalanchiI., CiccoliniF., LeaoM.J., & TommasinoM.Induction of pRb degradation by the human papillomavirus type 16 E7 protein is essential to efficiently overcome p16INK4a-imposed G1 cell cycle arrest.Journal of Virology2001; 75: 4705–4712.
161.
GonzalezS.L., StremlauM., HeX., BasileJ.R., & MungerK.Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7.Journal of Virology2001; 75: 7583–7591.
162.
LeeJ.O., RussoA.A., & PavletichN. P.Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7.Nature1998; 391: 859–865.
163.
SchmittA., HarryJ.B., RappB., WettsteinF.O., & IftnerT.Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1.Journal of Virology1994; 68: 7051–7059.
164.
MungerK., WernessB.A., DysonN., PhelpsW.C., HarlowE., & HowleyP.M.Complex formation of human papillo-mavirus E7 proteins with the retinoblastoma tumor suppressor gene product.EMBO Journal1989; 8: 4099–4105.
165.
DickF.A., SailhamerE., & DysonN.J.Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins.Molecular & Cellular Biology2000; 20: 3715–3727.
166.
SellersW.R., NovitchB.G., MiyakeS., HeithA., OttersonG.A., KayeF.J., LassarA.B., & KaelinW.G.Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth.Genes & Development1998; 12: 95–106.
167.
JewersR.J., HildebrandtP., LudlowJ.W., KellB., & McCanceD.J.Regions of human papillomavirus type 16 E7 oncoprotein required for immortalization of human keratinocytes.Journal of Virology1992; 66: 1329–1335.
168.
FunkJ.O., WagaS., HarryJ.B., EsplingE., StillmanB., & GallowayD.A.Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein.Genes & Development1997; 11: 2090–2100.
169.
JonesD.L., AlaniR.M., & MungerK.The human papillo-mavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2.Genes & Development1997; 11: 2101–2111.
170.
Zerfass-ThomeK., ZwerschkeW., MannhardtB., TindleR., BotzJ.W., & Jansen-DurrP.Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein.Oncogene1996; 13: 2323–2330.
171.
MisseroC., CalauttiE., EcknerR., ChinJ., TsaiL.H., LivingstonD.M., & DottoG.P.Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation.Proceedings of the National Academy of Sciences, USA1995; 92: 5451–5455.
172.
HeltA.M., FunkJ.O., & GallowayD.A.Inactivation of both the retinoblastoma tumor suppressor and p21 by the human papillomavirus type 16 E7 oncoprotein is necessary to inhibit cell cycle arrest in human epithelial cells.Journal of Virology2002; 76: 10559–10568.
173.
SmotkinD., & WettsteinF.O.The major human papillo-mavirus protein in cervical cancers is a cytoplasmic phosphoprotein.Journal of Virology1987; 61: 1686–1689.
174.
FirzlaffJ.M., LuscherB., & EisenmanR.N.Negative charge at the casein kinase II phosphorylation site is important for transformation but not for Rb protein binding by the E7 protein of human papillomavirus type 16.Proceedings of the National Academy of Sciences, USA1991; 88: 5187–5191.
175.
FirzlaffJ.M., GallowayD.A., EisenmanR.N., & LuscherB.The E7 protein of human papillomavirus type 16 is phosphorylated by casein kinase II.New Biologist1989; 1: 44–53.
176.
BarbosaM.S., EdmondsC., FisherC., SchillerJ.T., LowyD.R., & VousdenK.H.The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation.EMBO Journal1990; 9: 153–160.
177.
MassimiP., PimD., KuhneC., & BanksL.Regulation of the human papillomavirus oncoproteins by differential phosphorylation.Molecular & Cellular Biochemistry2001; 227: 137–144.
178.
MassimiP., & BanksL.Differential phosphorylation of the HPV-16 E7 oncoprotein during the cell cycle.Virology2000; 276: 388–394.
179.
MassimiP., PimD., StoreyA., & BanksL.HPV-16 E7 and adenovirus E1a complex formation with TATA box binding protein is enhanced by casein kinase II phosphorylation.Oncogene1996; 12: 2325–2330.
180.
ChienW.M., ParkerJ.N., Schmidt-GrimmingerD.C., BrokerT.R., & ChowL.T.Casein kinase II phosphorylation of the human papillomavirus-18 E7 protein is critical for promoting S-phase entry.Cell Growth & Differentiation2000; 11: 425–435.
181.
BanksL., EdmondsC., & VousdenK.H.Ability of the HPV16 E7 protein to bind RB and induce DNA synthesis is not sufficient for efficient transforming activity in NIH3T3 cells.Oncogene1990; 5: 1383–1389.
182.
WatanabeS., KandaT., SatoH., FurunoA., & YoshiikeK.Mutational analysis of human papillomavirus type 16 E7 functions.Journal of Virology1990; 64: 207–214.
183.
ReinsteinE., ScheffnerM., OrenM., CiechanoverA., & SchwartzA.Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue.Oncogene2000; 19: 5944–5950.
