Pathology & Oncology Research

, Volume 14, Issue 4, pp 345–354 | Cite as

Human Papilloma Virus (HPV) and Host Cellular Interactions

  • Ioannis N. Mammas
  • George Sourvinos
  • Athena Giannoudis
  • Demetrios A. SpandidosEmail author
Original Paper


Viral-induced carcinogenesis has been attributed to the ability of viral oncoproteins to target and interact with the host cellular proteins. It is generally accepted that Human papilloma virus (HPV) E6 and E7 function as the dominant oncoproteins of ‘high-risk’ HPVs by altering the function of critical cellular proteins. Initially it was shown that HPV E6 enhances the degradation of p53, while HPV E7 inactivates the function of the retinoblastoma tumor suppressor protein Rb. However, recent studies during the last decade have identified a number of additional host cellular targets of both HPV E6 and E7 that may also play an important role in malignant cellular transformation. In this review we present the interactions of HPV E6 and E7 with the host cellular target proteins. We also present the role of DNA integration in the malignant transformation of the epithelial cell.


Human papilloma virus HPV E6 E7 Host cellular proteins DNA integration 



human papilloma virus


retinoblastoma protein


E6-associated protein


E6-binding protein


human Drosophila discs large protein


human Scribble tumor suppressor protein


membrane-associated guanylate kinases

IRF-1 and -3

interferon regulatory factor 1 and 3


multicopy maintenance protein 7


human telomerase reverse transcriptase


human E6-targeted protein 1


G-protein pathway suppressor 2


interferon-alpha receptor 1


multi-PDZ-domain protein 1


cyclin-dependent kinases


TATA box-binding protein

CKI and II

casein kinase I and II


subunit 4


M2 pyruvate kinase


interferon-stimulated gene factor 3




  1. 1.
    zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350PubMedGoogle Scholar
  2. 2.
    zur Hausen H (1996) Papillomavirus infections—a major cause of human cancers. Biochim Biophys Acta 1288:F55–F78PubMedGoogle Scholar
  3. 3.
    Steben M, Duarte-Franco E (2007) Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol 107:S2–S5PubMedGoogle Scholar
  4. 4.
    Fehrmann F, Laimins LA (2003) Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation. Oncogene 22:5201–5207PubMedGoogle Scholar
  5. 5.
    Huibregtse JM, Scheffner M, Howley PM (1991) A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 10:4129–4135PubMedGoogle Scholar
  6. 6.
    Huibregtse JM, Scheffner M, Howley PM (1993) Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 13:4918–4927PubMedGoogle Scholar
  7. 7.
    Kuballa P, Matentzoglu K, Scheffner M (2007) The role of the ubiquitin ligase E6-AP in human papillomavirus E6-mediated degradation of PDZ domain-containing proteins. J Biol Chem 282:65–71PubMedGoogle Scholar
  8. 8.
    Handa K, Yugawa T, Narisawa-Saito M et al (2007) E6AP-dependent degradation of DLG4/PSD95 by high-risk human papillomavirus type 18 E6 protein. J Virol 81:1379–1389PubMedGoogle Scholar
  9. 9.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p 53. Cell 75:495–505PubMedGoogle Scholar
  10. 10.
    Dalal S, Gao Q, Androphy EJ, Band V (1996) Mutational analysis of human papillomavirus type 16 E6 demonstrates that p53 degradation is necessary for immortalization of mammary epithelial cells. J Virol 70:683–688PubMedGoogle Scholar
  11. 11.
    Kiyono T, Foster SA, Koop JI et al (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88PubMedGoogle Scholar
  12. 12.
    Liu Y, Chen JJ, Gao Q et al (1999) Multiple functions of human papillomavirus type 16 E6 contribute to the immortalization of mammary epithelial cells. J Virol 73:7297–7307PubMedGoogle Scholar
  13. 13.
    Chen JJ, Reid CE, Band V, Androphy EJ (1995) Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science 269:529–531PubMedGoogle Scholar
  14. 14.
    Sherman L, Itzhaki H, Jackman A et al (2002) Inhibition of serum- and calcium-induced terminal differentiation of human keratinocytes by HPV 16 E6: study of the association with p53 degradation, inhibition of p53 transactivation, and binding to E6BP. Virology 292:309–320PubMedGoogle Scholar
  15. 15.
    Thomas M, Banks L (1998) Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17:2943–2954PubMedGoogle Scholar
  16. 16.
    Thomas M, Banks L (1999) Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 80:1513–1517PubMedGoogle Scholar
  17. 17.
    Nagata S (1997) Apoptosis by death factor. Cell 88:355–365PubMedGoogle Scholar
  18. 18.
    Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337PubMedGoogle Scholar
  19. 19.
    Turner CE (2000) Paxillin interactions. J Cell Sci 113:4139–4140PubMedGoogle Scholar
  20. 20.
    Tong X, Howley PM (1997) The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton. Proc Natl Acad Sci USA 94:4412–4417PubMedGoogle Scholar
  21. 21.
    Vande Pol SB, Brown MC, Turner CE (1998) Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif. Oncogene 16:43–52PubMedGoogle Scholar
  22. 22.
    Kiyono T, Hiraiwa A, Fujita M et al (1997) Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 94:11612–11616PubMedGoogle Scholar
  23. 23.
    Lee SS, Weiss RS, Javier RT (1997) Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 94:6670–6675PubMedGoogle Scholar
  24. 24.
    Nakagawa S, Huibregtse JM (2000) Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol Cell Biol 20:8244–8253PubMedGoogle Scholar
  25. 25.
    Liu Y, Herny GD, Hegde RS, Bleja JD (2007) Solution structure of the hDlg/SAP97PDZ2 domain and its mechanism of interaction with HPV-18 papillomavirus E6 protein. Biochemistry 46:10864–10874PubMedGoogle Scholar
  26. 26.
    Glaunsinger BA, Lee SS, Thomas M et al (2000) Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 19:5270–5280PubMedGoogle Scholar
  27. 27.
    Thomas M, Laura R, Hepner K et al (2002) Oncogenic human papillomavirus E6 proteins target the MAGI-2 and MAGI-3 proteins for degradation. Oncogene 21:5088–5096PubMedGoogle Scholar
  28. 28.
    Zhang Y, Dasgupta J, Ma RZ et al (2007) Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J Virol 81:3618–3626PubMedGoogle Scholar
  29. 29.
    Thomas M, Glaunsinger B, Pim D et al (2001) HPV E6 and MAGUK protein interactions: determination of the molecular basis for specific protein recognition and degradation. Oncogene 20:5431–5439PubMedGoogle Scholar
  30. 30.
    Ronco L, Karpova A, Vidal M, Howley PM (1998) Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072PubMedGoogle Scholar
  31. 31.
    Lee SH, Kim JW, Lee HW et al (2003) Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression. Oncogene 22:381–391PubMedGoogle Scholar
  32. 32.
    Kuhne C, Banks L (1998) E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box. J Biol Chem 273:34302–34309PubMedGoogle Scholar
  33. 33.
    Zimmermann H, Degenkolbe R, Bernard HU, O’Connor MJ (1999) The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300. J Virol 73:6209–6219PubMedGoogle Scholar
  34. 34.
    Janknecht R, Hunter T (1996) Transcription. A growing coactivator network. Nature 383:22–23PubMedGoogle Scholar
  35. 35.
    Giles RH, Peters DJ, Breuning MH (1998) Conjunction dysfunction: CBP/p300 in human disease. Trends Genet 14:178–183PubMedGoogle Scholar
  36. 36.
    Gu W, Shi XL, Roeder RG (1997) Synergistic activation of transcription by CBP and p53. Nature 387:819–823PubMedGoogle Scholar
  37. 37.
    Avantaggiati ML, Ogryzko V, Gardner K et al (1997) Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89:1175–1184PubMedGoogle Scholar
  38. 38.
    Bernat A, Avvakumov N, Mymryk JS, Banks L (2003) Interaction between the HPV E7 oncoprotein and the transcriptional coactivator p300. Oncogene 22:7871–7881PubMedGoogle Scholar
  39. 39.
    Klingelhutz AJ, Foster SA, McDougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380:79–82PubMedGoogle Scholar
  40. 40.
    James MA, Lee JH, Klingelhutz AZ (2006) HPV 16-E6 associated hTERT promoter acetylation is E6AP dependent, increased in later passage cells and enhanced by loss of p300. Int J Cancer 119:1878–1885PubMedGoogle Scholar
  41. 41.
    Zhang H, Jin Y, Chen X et al (2007) Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation. Cancer Lett 245:184–194PubMedGoogle Scholar
  42. 42.
    Greider CW (1998) Telomerase activity, cell proliferation, and cancer. Proc Natl Acad Sci USA 5:90–92Google Scholar
  43. 43.
    Holt SE, Shay JW, Wright WE (1996) Refining the telomere–telomerase hypothesis of aging and cancer. Nat Biotechnol 4:836–839Google Scholar
  44. 44.
    Altschuler DL, Ribeiro-Neto F (1998) Mitogenic and oncogenic properties of the small G protein Rap1b. Proc Natl Acad Sci USA 95:7475–7479PubMedGoogle Scholar
  45. 45.
    Gao Q, Singh L, Kumar A et al (2001) Human papillomavirus type 16 E6-induced degradation of E6TP1 correlates with its ability to immortalize human mammary epithelial cells. Virology 75:4459–4466Google Scholar
  46. 46.
    Gao Q, Srinivasan S, Boyer S et al (1999) The E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation. Mol Cell Biol 19:733–744PubMedGoogle Scholar
  47. 47.
    Singh L, Gao Q, Kumar A et al (2003) The high-risk human papillomavirus type 16 E6 counters the GAP function of E6TP1 toward small Rap G proteins. J Virol 77:1614–1620PubMedGoogle Scholar
  48. 48.
    Lee C, Wooldridge TR, Laimins LA (2007) Analysis of the roles of E6 binding to E6TP1 and nuclear localization in the human papillomavirus type 31 life cycle. Virology 358:201–210PubMedGoogle Scholar
  49. 49.
    Gao Q, Kumar A, Singh L et al (2002) Human papillomavirus E6-induced degradation of E6TP1 is mediated by E6AP ubiquitin ligase. Cancer Res 62:3315–3321PubMedGoogle Scholar
  50. 50.
    Gao Q, Kumar A, Srinivasan S et al (2000) PKN binds and phosphorylates human papillomavirus E6 oncoprotein. J Biol Chem 275:14824–14830PubMedGoogle Scholar
  51. 51.
    Degenhardt YY, Silverstein J (2001) Gps2, a protein partner for human papillomavirus E6 proteins. J Virol 75:151–160PubMedGoogle Scholar
  52. 52.
    Gross-Mesilaty S, Reinstein E, Bercovich B et al (1998) Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Natl Acad Sci USA 95:8058–8063PubMedGoogle Scholar
  53. 53.
    Wang YW, Chang HS, Lin CH, Yu WC (2007) HPV-18 E7 conjugates to c-Myc and mediates its transcriptional activity. Int J Biochem Cell Biol 39:401–412Google Scholar
  54. 54.
    Liu X, Disbrow GL, Yuan H et al (2007) Myc and human papillomavirus type 16 E7 genes cooperate to immortalize human keratinocytes. J Virol 81:12689–12695PubMedGoogle Scholar
  55. 55.
    McMurray HR, McCance DJ (2003) Human papiloomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. J Virol 77:9852–9861PubMedGoogle Scholar
  56. 56.
    Li S, Labrecque S, Gauzzi MC et al (1999) The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-a. Oncogene 18:5727–5737PubMedGoogle Scholar
  57. 57.
    Lee SS, Glaunsinger B, Mantovani F et al (2000) Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high-risk papillomavirus type 18 E6 oncoproteins. J Virol 74:9680–9693PubMedGoogle Scholar
  58. 58.
    Tsutsui T, Kumakura S, Yamamoto A et al (2002) Association of p16(INK4a) and pRb inactivation with immortalization of human cells. Carcinogenesis 23:2111–2117PubMedGoogle Scholar
  59. 59.
    Mammas IN, Zafiropoulos A, Sifakis S et al (2005) Human papillomavirus (HPV) typing in relation to ras oncogene mRNA expression in HPV-associated human squamous cervical neoplasia. Int J Biol Markers 20:257–263PubMedGoogle Scholar
  60. 60.
    Schreiber K, Cannon RE, Karrison RE et al (2004) Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors. Oncogene 23:3972–3979PubMedGoogle Scholar
  61. 61.
    Felsani A, Mileo AM, Paggi MG (2006) Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene 25:5277–5285PubMedGoogle Scholar
  62. 62.
    Lavia P, Jansen-Durr P (1999) E2F target genes and cell-cycle checkpoint control. Bioessays 21:221–230PubMedGoogle Scholar
  63. 63.
    Caldeira S, de Villiers EM, Tommasino M (2000) Human papillomavirus E7 proteins stimulate proliferation independently of their ability to associate with retinoblastoma protein. Oncogene 19:821–826PubMedGoogle Scholar
  64. 64.
    Dyson N, Howley PM, Münger K, Harlow E (1989) The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937PubMedGoogle Scholar
  65. 65.
    Gonzalez SL, Stremlau M, He X et al (2001) 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. J Virol 75:7583–7591PubMedGoogle Scholar
  66. 66.
    Heck DV, Yee CL, Howley PM, Münger K (1992) Efficiency of binding to the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci USA 89:4442–4446PubMedGoogle Scholar
  67. 67.
    Chellappan S, Kraus VB, Kroger B et al (1992) Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between the transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA 89:4549–4553PubMedGoogle Scholar
  68. 68.
    Edmonds C, Vousden KH (1989) A point mutational analysis of human papillomavirus type 16 E7 protein. J Virol 63:2650–2656PubMedGoogle Scholar
  69. 69.
    Strati K, Lambert PF (2007) Role of Rb-dependent and Rb-independent functions of papillomavirus E7 oncogene in head and neck cancer. Cancer Res 67:11585–11593PubMedGoogle Scholar
  70. 70.
    Zerfass K, Levy LM, Cremonesi C et al (1995) Cell cycle-dependent disruption of E2F-p107 complexes by human papillomavirus type 16 E7. J Gen Virol 76:1815–1820PubMedGoogle Scholar
  71. 71.
    Davies R, Hicks R, Crook T et al (1993) Human papillomavirus type 16 E7 associates with a histone H1 kinase and with p107 through sequences necessary for transformation. J Virol 67:2521–2528PubMedGoogle Scholar
  72. 72.
    Roman A (2006) The human papillomavirus E7 protein shines a spotlight on the pRB family member, p130. Cell Cycle 5:567–568PubMedGoogle Scholar
  73. 73.
    Zhang B, Chen W, Roman A (2006) The E7 proteins of low- and high-risk human papillomaviruses share the ability to target the pRB family member p130 for degradation. Proc Natl Acad Sci USA 103:437–442PubMedGoogle Scholar
  74. 74.
    Grana X, Garriga J, Mayol X (1998) Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 17:3365–3383PubMedGoogle Scholar
  75. 75.
    Stubdal H, Zalvide J, Campbell KS et al (1997) Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen. Mol Cell Biol 17:4979–4990PubMedGoogle Scholar
  76. 76.
    Bruce JL, Hurford RK, Classon J et al (2000) Requirements for cell cycle arrest by p16ink4a. Mol Cell 6:737–742PubMedGoogle Scholar
  77. 77.
    Dyson N, Dembski M, Fattaey A et al (1993) Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1. J Virol 67:7641–7647PubMedGoogle Scholar
  78. 78.
    Arroyo M, Bagchi S, Raychaudhuri P (1993) Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F–cyclin A complex. Mol Cell Biol 13:6537–6546PubMedGoogle Scholar
  79. 79.
    Tommasino M, Adamczewski JP, Carlotti F et al (1993) HPV16 E7 protein associates with the protein kinase p33CDK2 and cyclin A. Oncogene 8:195–202PubMedGoogle Scholar
  80. 80.
    McIntyre MC, Ruesch MN, Laimins LA (1996) Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107. Virology 215:73–82PubMedGoogle Scholar
  81. 81.
    Vogt B, Zerfass-Thome K, Schulze A et al (1999) Regulation of cyclin E gene expression by the human papillomavirus type 16 E7 oncoprotein. J Gen Virol 80:2103–2113PubMedGoogle Scholar
  82. 82.
    Balsitis S, Dick F, Dyson N, Lambert PF (2006) Critical roles for non-pRB targets of human papillomavirus type 16 E7 in cervical carcinogenesis. Cancer Res 66:9393–9400PubMedGoogle Scholar
  83. 83.
    Zerfass K, Schulze A, Spitkovsky D et al (1995) Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol 69:6389–6399PubMedGoogle Scholar
  84. 84.
    He W, Staples D, Smith C, Fisher C (2003) Direct activation of cyclin-dependent kinase 2 by human papillomavirus E7. J Virol 77:10566–10574PubMedGoogle Scholar
  85. 85.
    Duensing S, Duensing A, Lee DC et al (2004) Cyclin-dependent kinase inhibitor indirubin-3¢-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies. Oncogene 23:8206–8215PubMedGoogle Scholar
  86. 86.
    Massimi P, Pim D, Storey A, Banks L (1996) HPV-16 E7 and adenovirus E1a complex formation with TATA box binding protein is enhanced by casein kinase II phosphorylation. Oncogene 12:2325–2330PubMedGoogle Scholar
  87. 87.
    Maldonado E, Cabrejos ME, Banks L, Allende JE (2002) Human papillomavirus-16 E7 protein inhibits the DNA interaction of the TATA binding transcription factor. J Cell Biochem 85:663–669PubMedGoogle Scholar
  88. 88.
    Berezutskaya E, Bagchi S (1997) The human papillomavirus E7 oncoprotein functionally interacts with the S4 subunit of the 26 S proteasome. J Biol Chem 272:30135–30140PubMedGoogle Scholar
  89. 89.
    Coux O, Tanaka K, Goldberg AL (1996) Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem 65:801–847PubMedGoogle Scholar
  90. 90.
    Nead MA, Baglia LA, Antimore MJ et al (1998) Rb binds c-Jun and activates transcription. EMBO J 17:2342–2352PubMedGoogle Scholar
  91. 91.
    Nishitani J, Nishinaka T, Cheng CH et al (1999) Recruitment of the retinoblastoma protein to c-Jun enhances transcription activity mediated through the AP-1 binding site. J Biol Chem 274:5454–5461PubMedGoogle Scholar
  92. 92.
    Schilling B, De-Medine T, Syken J et al (1998) A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein. Virology 247:74–85PubMedGoogle Scholar
  93. 93.
    Zwerschke W, Mazurek S, Massimi P et al (1999) Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc Natl Acad Sci USA 96:1291–1296PubMedGoogle Scholar
  94. 94.
    Mazurek S, Zwerschke W, Jansen-Durr P, Eigenbrodt E (2001) Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7. Oncogene 20:6891–6898PubMedGoogle Scholar
  95. 95.
    Barnard P, McMillan NA (1999) The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferon-alpha. Virology 259:305–313PubMedGoogle Scholar
  96. 96.
    Jones DL, Alani RM, Munger K (1997) The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev 11:2101–2111PubMedGoogle Scholar
  97. 97.
    Funk JO, Waga S, Harry J et al (1997) Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev 11:2090–2100PubMedGoogle Scholar
  98. 98.
    Zehbe I, Ratsch A, Alumni-Fabbroni M et al (1999) Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions. Oncogene 18:2201–2211PubMedGoogle Scholar
  99. 99.
    Charette ST, McCance DJ (2007) The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner. Oncogene 26:7386–7390PubMedGoogle Scholar
  100. 100.
    Westbrook TF, Nguyen DX, Trash BR, McCance DJ (2002) E7 abolishes raf-induced arrest via mislocalization of p21(Cip1). Mol Cell Biol 22:7041–7052PubMedGoogle Scholar
  101. 101.
    Um SJ, Rhyu JW, Kim EJ et al (2002) Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo. Cancer Lett 179:205–212PubMedGoogle Scholar
  102. 102.
    Alazawi W, Pett M, Arch B et al (2002) Changes in cervical keratinocyte gene expression associated with integration of human papillomavirus 16. Cancer Res 62:6959–6965PubMedGoogle Scholar
  103. 103.
    Klaes R, Woerner SM, Ridder R et al (1999) Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59:6132–6136PubMedGoogle Scholar
  104. 104.
    Giannoudis A, van Duin M, Snijder PJF, Herrington CS (2001) Variation in the E2-binding domain of HPV 16 is associated with high-grade squamous intraepithelial lesions of the cervix. Br J Cancer 84:1058–1063PubMedGoogle Scholar
  105. 105.
    Pett M, Coleman N (2007) Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 212:356–367PubMedGoogle Scholar
  106. 106.
    Jeon S, Lambert PF (1995) Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA 92:1654–1658PubMedGoogle Scholar
  107. 107.
    Durst M, Croce CM, Gissmann L et al (1987) Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. Proc Natl Acad Sci USA 84:1070–1074PubMedGoogle Scholar
  108. 108.
    Ferber MJ, Thorland EC, Brink AA et al (2003) Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene 22:7233–7242PubMedGoogle Scholar
  109. 109.
    Peter M, Rosty C, Couturier J et al (2006) MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors. Oncogene 25:5985–5993PubMedGoogle Scholar
  110. 110.
    Ferber MJ, Montoya DP, Yu C et al (2003) Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene 22:3813–3820PubMedGoogle Scholar
  111. 111.
    Ziegert C, Wentzensen N, Vinokurova S et al (2003) A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques. Oncogene 22:3977–3398PubMedGoogle Scholar
  112. 112.
    Wentzensen N, Vinokurova S, von Knebel DM (2004) Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 64:3878–3884PubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2008

Authors and Affiliations

  • Ioannis N. Mammas
    • 1
  • George Sourvinos
    • 1
  • Athena Giannoudis
    • 2
  • Demetrios A. Spandidos
    • 1
    Email author
  1. 1.Department of Virology, School of MedicineUniversity of CreteHeraklionGreece
  2. 2.Faculty of MedicineUniversity of LiverpoolLiverpoolUK

Personalised recommendations