Abstract
Human papillomavirus (HPV) infections play a crucial role in the pathogenesis of cervical neoplasia. Insights into the mechanisms by which HPV infection can, in a small numbers of cases, result in malignancy, comes from the observation that three proteins encoded by high-risk genital HPVs, E6, E7 and to a lesser extent E5, target factors that control the cell cycle and proliferation. These interactions result in abrogation of cell cycle control, chromosomal alterations, telomerase activation, and eventual cell immortalization. In this review, we discuss the functions of E6, E7, and E5 proteins that are most relevant to the malignant progression of HPV-transformed cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Allsopp RC and Harley CB . (1995). Exp. Cell Res., 219, 130–136.
Androphy EJ, Hubbert NL, Schiller JT and Lowy DR . (1987). EMBO J., 6, 989–992.
Baker CC, Phelps WC, Lindgren V, Braun MJ, Gonda MA and Howley PM . (1987). J. Virol., 61, 962–971.
Banks L, Spence P, Androphy E, Hubbert N, Matlashewski G, Murray A and Crawford L . (1987). J. Gen. Virol., 68(Pt 5), 1351–1359.
Bedell MA, Jones KH, Grossman SR and Laimins LA . (1989). J. Virol., 63, 1247–1255.
Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S and Wright WE . (1998). Science, 279, 349–352.
Boring CC, Squires TS, Tong T and Montgomery S . (1994). CA Cancer J. Clin., 44, 7–26.
Bouvard V, Matlashewski G, Gu ZM, Storey A and Banks L . (1994). Virology, 203, 73–80.
Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA and Reddel RR . (1997). Nat. Med., 3, 1271–1274.
Bubb V, McCance DJ and Schlegel R . (1988). Virology, 163, 243–246.
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM and Nevins JR . (1991). Cell, 65, 1053–1061.
Chiang CM, Ustav M, Stenlund A, Ho TF, Broker TR and Chow LT . (1992). Proc. Natl. Acad. Sci. USA, 89, 5799–5803.
Conrad M, Bubb VJ and Schlegel R . (1993). J. Virol., 67, 6170–6178.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S . (1992). EMBO J., 11, 1921–1929.
Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM and Weinberg RA . (1998). Proc. Natl. Acad. Sci. USA, 95, 14723–14728.
Craven SE and Bredt DS . (1998). Cell, 93, 495–498.
Crusius K, Auvinen E and Alonso A . (1997). Oncogene, 15, 1437–1444.
Crusius K, Auvinen E, Steuer B, Gaissert H and Alonso A . (1998). Exp. Cell Res., 241, 76–83.
Davies R, Hicks R, Crook T, Morris J and Vousden K . (1993). J. Virol., 67, 2521–2528.
de Villiers EM . (1994). Curr. Top. Microbiol. Immunol., 186, 1–12.
Demers GW, Foster SA, Halbert CL and Galloway DA . (1994a). Proc. Natl. Acad. Sci. USA, 91, 4382–4386.
Demers GW, Halbert CL and Galloway DA . (1994b). Virology, 198, 169–174.
Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP and Rheinwald JG . (2000). Mol. Cell. Biol., 20, 1436–1447.
DiPaolo JA, Woodworth CD, Popescu NC, Notario V and Doniger J . (1989). Oncogene, 4, 395–399.
Doorbar J, Ely S, Sterling J, McLean C and Crawford L . (1991). Nature, 352, 824–827.
Doorbar J, Foo C, Coleman N, Medcalf L, Hartley O, Prospero T, Napthine S, Sterling J, Winter G and Griffin H . (1997). Virology, 238, 40–52.
Durst M, Gallahan D, Jay G and Rhim JS . (1989). Virology, 173, 767–771.
Dyson N, Howley PM, Munger K and Harlow E . (1989). Science, 243, 934–937.
Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC and Weinberg RA . (2001). Genes Dev., 15, 50–65.
Fanning AS and Anderson JM . (1999). Curr. Opin. Cell Biol., 11, 432–439.
Fehrmann F, Klumpp DJ and Laimins LA . (2003). J Virol, 77, 2819–2831.
Frattini MG and Laimins LA . (1994). Virology, 204, 799–804.
Funk JO, Waga S, Harry JB, Espling E, Stillman B and Galloway DA . (1997). Genes Dev., 11, 2090–2100.
Gardiol D, Kuhne C, Glaunsinger B, Lee SS, Javier R and Banks L . (1999). Oncogene, 18, 5487–5496.
Gewin L and Galloway DA . (2001). J. Virol., 75, 7198–7201.
Giarre M, Caldeira S, Malanchi I, Ciccolini F, Leao MJ and Tommasino M . (2001). J. Virol., 75, 4705–4712.
Glaunsinger BA, Lee SS, Thomas M, Banks L and Javier R . (2000). Oncogene, 19, 5270–5280.
Gomperts SN . (1996). Cell, 84, 659–662.
Gu Z and Matlashewski G . (1995). J. Virol., 69, 8051–8056.
Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW and Weinberg RA . (1999). Nature, 400, 464–468.
Halbert CL, Demers GW and Galloway DA . (1991). J. Virol., 65, 473–478.
Halbert CL and Galloway DA . (1988). J. Virol., 62, 1071–1075.
Harley CB . (1991). Mutat. Res., 256, 271–282.
Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ . (1993). Cell, 75, 805–816.
Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR and Schiller JT . (1989). EMBO J., 8, 3905–3910.
Helt AM, Funk JO and Galloway DA . (2002). J. Virol., 76, 10559–10568.
Hickman ES, Picksley SM and Vousden KH . (1994). Oncogene, 9, 2177–2181.
Hildesheim A, Schiffman MH, Gravitt PE, Glass AG, Greer CE, Zhang T, Scott DR, Rush BB, Lawler P, Sherman ME, Kurman RJ and Manes MM . (1994). J. Infect. Dis., 169, 235–240.
Howley PM and Lowy DR . (2001). Virology, Vol. 2. Fields BN, Knipe JB, Howley PM (eds). Lippincott/The Williams & Wilkins Co: Philadelphia, PA, pp. 2197–2229.
Hudson JB, Bedell MA, McCance DJ and Laimins LA . (1990). J. Virol., 64, 519–526.
Huibregtse JM, Scheffner M and Howley PM . (1993). Mol. Cell. Biol., 13, 4918–4927.
Hurlin PJ, Kaur P, Smith PP, Perez-Reyes N, Blanton RA and McDougall JK . (1991). Proc. Natl. Acad. Sci. USA, 88, 570–574.
Jeon S, Allen-Hoffmann BL and Lambert PF . (1995). J. Virol., 69, 2989–2997.
Jones DL, Alani RM and Munger K . (1997). Genes Dev., 11, 2101–2111.
Jones DL and Munger K . (1997). J. Virol., 71, 2905–2912.
Jones DL, Thompson DA, Suh-Burgmann E, Grace M and Munger K . (1999). Virology, 258, 406–414.
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW . (1994). Science, 266, 2011–2015.
Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA and Klingelhutz AJ . (1998). Nature, 396, 84–88.
Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T and Ishibashi M . (1997). Proc. Natl. Acad. Sci. USA, 94, 11612–11616.
Klingelhutz AJ, Foster SA and McDougall JK . (1996). Nature, 380, 79–82.
La Thangue NB . (1994). Trends Biochem. Sci., 19, 108–114.
Laimins LA . (1993). Infect. Agents Dis., 2, 74–86.
Laimins LA . (1996). Semin. Virol., 305–313.
Lambert PF . (1991). J. Virol., 65, 3417–3420.
Lee SS, Glaunsinger B, Mantovani F, Banks L and Javier RT . (2000). J. Virol., 74, 9680–9693.
Lee SS, Weiss RS and Javier RT . (1997). Proc. Natl. Acad. Sci. USA, 94, 6670–6675.
Leechanachai P, Banks L, Moreau F and Matlashewski G . (1992). Oncogene, 7, 19–25.
Lepik D, Ilves I, Kristjuhan A, Maimets T and Ustav M . (1998). J. Virol., 72, 6822–6831.
Lepik D and Ustav M . (2000). J. Virol., 74, 4688–4697.
Leptak C, Ramon y Cajal S, Kulke R, Horwitz BH, Riese II DJ, Dotto GP and DiMaio D . (1991). J. Virol., 65, 7078–7083.
Liu JP . (1999). FASEB J., 13, 2091–2104.
Liu Y, Chen JJ, Gao Q, Dalal S, Hong Y, Mansur CP, Band V and Androphy EJ . (1999). J. Virol., 73, 7297–7307.
Lowe SW, Jacks T, Housman DE and Ruley HE . (1994). Proc. Natl. Acad. Sci. USA, 91, 2026–2030.
Martin P, Vass WC, Schiller JT, Lowy DR and Velu TJ . (1989). Cell, 59, 21–32.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA and Weinberg RA . (1997). Cell, 90, 785–795.
Mitic LL and Anderson JM . (1998). Annu. Rev. Physiol., 60, 121–142.
Mohr IJ, Clark R, Sun S, Androphy EJ, MacPherson P and Botchan MR . (1990). Science, 250, 1694–1699.
Munger K, Phelps WC, Bubb V, Howley PM and Schlegel R . (1989a). J. Virol., 63, 4417–4421.
Munger K, Werness BA, Dyson N, Phelps WC, Harlow E and Howley PM . (1989b). EMBO J., 8, 4099–4105.
Nakagawa S and Huibregtse JM . (2000). Mol. Cell. Biol., 20, 8244–8253.
Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Ide T and Ishikawa F . (1998). Nat. Genet., 18, 65–68.
Noya F, Chien WM, Broker TR and Chow LT . (2001). J. Virol., 75, 6121–6134.
Oh ST, Kyo S and Laimins LA . (2001). J. Virol., 75, 5559–5566.
Ozbun MA . (2002). J. Virol., 76, 11291–11300.
Parkin DM, Bray F, Ferlay J and Pisani P . (2001). Int. J. Cancer, 94, 153–156.
Petti L, Nilson LA and DiMaio D . (1991). EMBO J., 10, 845–855.
Phelps WC, Yee CL, Munger K and Howley PM . (1988). Cell, 53, 539–547.
Pim D, Collins M and Banks L . (1992). Oncogene, 7, 27–32.
Reddel RR . (1998). BioEssays, 20, 977–984.
Scheffner M, Huibregtse JM, Vierstra RD and Howley PM . (1993). Cell, 75, 495–505.
Scheffner M, Werness BA, Huibregtse JM, Levine AJ and Howley PM . (1990). Cell, 63, 1129–1136.
Schneider-Gadicke A and Schwarz E . (1986). EMBO J., 5, 2285–2292.
Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A and zur Hausen H . (1985). Nature, 314, 111–114.
Slansky JE and Farnham PJ . (1996). Curr. Top. Microbiol. Immunol., 208, 1–30.
Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB and Cho KR . (1994). Proc. Natl. Acad. Sci. USA, 91, 5320–5324.
Smotkin D and Wettstein FO . (1986). Proc. Natl. Acad. Sci. USA, 83, 4680–4684.
Stoler MH, Rhodes CR, Whitbeck A, Wolinsky SM, Chow LT and Broker TR . (1992). Hum. Pathol., 23, 117–128.
Straight SW, Herman B and McCance DJ . (1995). J. Virol., 69, 3185–3192.
Straight SW, Hinkle PM, Jewers RJ and McCance DJ . (1993). J. Virol., 67, 4521–4532.
Stubenrauch F, Colbert AM and Laimins LA . (1998). J. Virol., 72, 8115–8123.
Stubenrauch F and Laimins LA . (1999). Semin. Cancer Biol., 9, 379–386.
Thierry F and Yaniv M . (1987). EMBO J., 6, 3391–3397.
Thomas JT and Laimins LA . (1998). J. Virol., 72, 1131–1137.
Thomas JT, Oh ST, Terhune SS and Laimins LA . (2001). J. Virol., 75, 7564–7571.
Thomas M, Laura R, Hepner K, Guccione E, Sawyers C, Lasky L and Banks L . (2002). Oncogene, 21, 5088–5096.
Ustav M and Stenlund A . (1991). EMBO J., 10, 449–457.
Valle GF and Banks L . (1995). J. Gen. Virol., 76, 1239–1245.
van Oortmarssen GJ and Habbema JD . (1995). Int. J. Epidemiol., 24, 300–307.
Veldman T, Horikawa I, Barrett JC and Schlegel R . (2001). J. Virol., 75, 4467–4472.
Vousden KH . (1994). Adv. Cancer Res., 64, 1–24.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ and Munoz N . (1999). J. Pathol., 189, 12–19.
Wallin KL, Wiklund F, Angstrom T, Bergman F, Stendahl U, Wadell G, Hallmans G and Dillner J . (1999). N. Engl. J. Med., 341, 1633–1638.
Weinberg RA . (1995). Cell, 81, 323–330.
Werness BA, Levine AJ and Howley PM . (1990). Science, 248, 76–79.
Wu X and Levine AJ . (1994). Proc. Natl. Acad. Sci. USA, 91, 3602–3606.
Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW and Jansen-Durr P . (1996). Oncogene, 13, 2323–2330.
zur Hausen H . (1996). Biochim. Biophys. Acta, 1288, F55–F78.
zur Hausen H . (2002). Nat. Rev. Cancer, 2, 342–350.
zur Hausen H and de Villiers EM . (1994). Annu. Rev. Microbiol., 48, 427–447.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fehrmann, F., Laimins, L. Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation. Oncogene 22, 5201–5207 (2003). https://doi.org/10.1038/sj.onc.1206554
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206554
Keywords
This article is cited by
-
Molecular evaluation of human papillomavirus as an oncogenic biomarker in prostate cancer
Molecular Biology Reports (2023)
-
In silico design of a multi-epitope vaccine against HPV16/18
BMC Bioinformatics (2022)
-
The polymorphism analysis and epitope predicted of Alphapapillomavirus 9 E6 in Sichuan, China
Virology Journal (2022)
-
Drug repurposing approach for the identification and designing of potential E6 inhibitors against cervical cancer: an in silico investigation
Structural Chemistry (2020)
-
Investigating the aetiology of adverse events following HPV vaccination with systems vaccinology
Cellular and Molecular Life Sciences (2019)