Revista de Oncología

, Volume 6, Issue 5, pp 263–271 | Cite as

Elementos víricos y celulares que intervienen en el proceso de replicación del virus del papiloma humano

  • Erick de la Cruz Hernández
  • Alejandro Mohar Betancourt
  • Marcela Lizano SoberónEmail author


La infección del virus del papiloma humano (VPH) es el principal factor de riesgo para el desarrollo del cáncer cervicouterino. El ciclo de vida del VPH está ligado al proceso de diferenciación epitelial. Cuando estos virus infectan las células basales se mantienen como elementos autorreplicativos con bajos niveles de expresión génica. A medida que los estratos celulares se van differenciando, los niveles de replicación del genoma vírico aumentan y se sintelizan las proteínas víricas tardías, con lo que se inicia la formación de partículas infecciosas. Aun cuando las proteínas E1 y E2 son los elementos principales en la replicación, otras proteínas víricas también contribuyen promoviendo o replrimiendo la transcripción de ciertos genes víricos. Sin embargo, no está claro cómo es que estos factores de replicación son regulados durante el ciclo de vida del VPH. Por lo tanto, resulta importante entender estos mecanismos de regulación, además de las interacciones de las proteínas víricas con múltiples dianas celulares, que promueven la transformación celular.

Palabras clave

VPH cáncer cérvico-uterino replicación viral 

Cellular and viral elements involved in the replication of human papilloma virus


Infection by the human papilloma virus (HPV) is the main risk factor in the development of cancer of the cervix and uterus (CaCU). The life cycle of the HPV is linked to the epithelial differentiation process. When the virus infects the basal cells they remain as self-replicating elements with low levels of gene expression. While the cell layer differentiates, the levels of the viral genome increase, late viral proteins are synthesised and begin to form infectious particles. Even when the E1 and E2 proteins are the principal elements in the replication, there are other viral proteins that, as well, contribute to promoting or suppressing the transcription of certain viral genes. However, it is still unclear as to how these replication factors are regulated during the life cycle of the HPV. As such, it is important to identify these regulatory mechanisms, apart from the interactions of the viral proteins with multiple cell targets, which promote cellular transformation.

Key words

HPV cervical cancer viral replication 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Villiers EM. Human papillomavirus. Introduction. Semin Cancer Biol 1999;9(6):377.CrossRefGoogle Scholar
  2. 2.
    Evander M, Frazer H, Payne E, et al. Identification of the alfa-6 integrin as a candidate receptor for papillomaviruses. J Virol 1997;71:2449–56.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Joyce G, Tung S, Przysiecky T, et al. The L1 major capside protein of human papillomavirus type 11 recombinant-virus like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes. J Biol Chem 1999;274:5810–22.CrossRefGoogle Scholar
  4. 4.
    Stubenrauch F, Hummel M, Laimins L, et al. The E8^E2C protein, a negative regulator of viral transcription and replication, is required for extrachromosomal maintenance of human papillomavirus type 31 in keratinocytes. J Virol 2000;74(3):1178–86.CrossRefGoogle Scholar
  5. 5.
    Barbosa S, Lowy R, Schiller T. Papillomavirus polypeptides E6 and E7 are zinc-binding proteins. J Virol 1989;63:1404–7.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kühne C, Gardiol D, Banks L, et al. Differential regulation of human papillomavirus E6 by protein kinase A: Conditional degradation of human dish large by oncogenic E6. Oncogene 2000;19:5884–91.CrossRefGoogle Scholar
  7. 7.
    Werness BA, Levine AJ, Howley PM. Association of human papillomavirus type 16 and 18, E6 proteins with p55. Science 1990;24876–9.CrossRefGoogle Scholar
  8. 8.
    Hengstermann A, Linares L, Scheffner M, et al. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci USA 2001;98(3):1218–23.CrossRefGoogle Scholar
  9. 9.
    Mantovani F, Lawrence B. Inhibition of E6 induced degradation of p53 is not sufficient for stabilization of p53 protein in cervical tumour derived cell lines. Oncogene 1999;18:3309–15.CrossRefGoogle Scholar
  10. 10.
    Butz K, Shahabeddin L, Geisen C, et al. Functional p53 protein in human papillomavirus-positive cancer cells. Oncogene 1995;10:927–36.PubMedGoogle Scholar
  11. 11.
    Pim D, Massimi P, Banks L. Alternatively spliced HPV-18 E6* protein inhibits E6 mediated degradation of p53 and suppresses transformed cell growth. Oncogene 1997;15:257–64.CrossRefGoogle Scholar
  12. 12.
    Pim D, Banks L. HPV-18 E6*I protein modulates the E6-direct degradation of p53 by binding to full length HPV-18E6. Oncogene 1999;18:7403–8.CrossRefGoogle Scholar
  13. 13.
    Patel D, Huang S, McCance, J. et al. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J 1999;18:5061–72.CrossRefGoogle Scholar
  14. 14.
    Sheppard HM, Corneilie S, Espiritu C. et al. New insights into the mechanism of inhibition of p53 by simian virus 40 large T antigen. Mol Cell Biol 1999;19:2746–53.CrossRefGoogle Scholar
  15. 15.
    Sedman SA, Barbosa MS, Vass WC. et al. The full-length E6 protein of human papillomavirus type 16 has transforming and trans-activating activities and cooperates with E7 to immortalize keratinocytes in culture. J Virol 1991;65:4860–6.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Mantovani F, Banks L. The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 2001;20:7874–87.CrossRefGoogle Scholar
  17. 17.
    Thomas M, Banks L. Inhibition of Bak-induced apoptosis by HPV-18E6. Oncogene 1998;17:2943–54.CrossRefGoogle Scholar
  18. 18.
    Thomas M, Banks L. Human papillomavirus (HPV) E6 interactions with bak are conserved among E6 proteins from high and low risk HPV types. J Gen Virol 1999; 80:1513–7.CrossRefGoogle Scholar
  19. 19.
    Gross-Mesilaty S, Reinstein E, Bercovich B, et al. Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Natl Acad Sci USA 1998:95:8058–63.CrossRefGoogle Scholar
  20. 20.
    Chen J, Reid E, Band V, et al. Interaction of papillomavirus E6 oncoprotein with a putative calcium-binding protein. Science 1995;269:529–31.CrossRefGoogle Scholar
  21. 21.
    Tong X, Howley M. The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton. PNAS USA 1997;94:4412–7.CrossRefGoogle Scholar
  22. 22.
    Kühne C, Banks L. E3 ubiquitin ligase/E6 AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, The L2G box. J Biol Chem 1998;273:34302–9.CrossRefGoogle Scholar
  23. 23.
    Saras J, Heldin C. PDZ domains bind carboxy-terminal sequences of target proteins. Trends Biochem Sci 1996;21:455–8.CrossRefGoogle Scholar
  24. 24.
    Doyle D, Lee A, Lewis J, et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 1996;85:1067–76.CrossRefGoogle Scholar
  25. 25.
    Kiyono T, Hiraiwa A, Fujita M, et al. Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. PNAS USA 1997;94:11612–6.CrossRefGoogle Scholar
  26. 26.
    Glausinger B, Thomas M, Banks L, et al. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 2000;19:1093–8.Google Scholar
  27. 27.
    Nakagawa S, Huibregtse M. Hunan Scribble (vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol Cell Biol 2000;20:8244–53.CrossRefGoogle Scholar
  28. 28.
    McIntyre C, Frattini G, Grossman R, et al. Human papillomavirus type 18, E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization and transformation but not for RB binding. J Virol 1993;67:3142–50.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Barbosa S, Edmonds C, Fisher C, et al. 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 J 1990;9:153–60.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Guccione E, Massimi P, Bernat A, et al. Comparative analysis of the intracellular location of the high- and low-risk human papillomavirus oncoproteins. Virol 2002;293:20–5.CrossRefGoogle Scholar
  31. 31.
    Dyson N, Howley M, Munger K, et al. The human papillomavirus type 16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;243:934–7.CrossRefGoogle Scholar
  32. 32.
    Antinore J, Birrer J, Patel D, et al. The human papillomavirus type 16, E7 gene product interacts with and trans-activates the AP1 family of transcription factor. EMBO J 1996;15:1950–60.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Cheng S, Schmidt-Grimminger C, Murant T, et al. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 1995;9:2335–49.CrossRefGoogle Scholar
  34. 34.
    Morris D, Crook T, Bandara R, et al. Human papillomavirus type 16 E7 regulates E2F and contributes to mitogenic signaling. Oncogene 1993;8:893–8.PubMedGoogle Scholar
  35. 35.
    Jones DL, Thompson A, Munger K. Destabilization of the RB tumor suppressor protein and stabilization of p53 contribute to HPV type 16 E7-induced apoptosis. Virol 1997;239:97–107.CrossRefGoogle Scholar
  36. 36.
    Adams D, Kaelin G, WG Jr. Transcriptional control by E2F. Semin Cancer Biol 1995;6:99–108.CrossRefGoogle Scholar
  37. 37.
    Jones DL, Alani RM, Münger K. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21c1pl-mediated inhibition of cdk2. Genes Dev 1997;11:2101–11.CrossRefGoogle Scholar
  38. 38.
    Zerfass-Thome K, Zwerschke W, Mannhardt B, et al. Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 1996;13:2323–30.PubMedGoogle Scholar
  39. 39.
    Conrad M, Bubb BJ, Schlegel R. The human papillomavirus type 6 and 16, E5 proteins are membrane-associated proteins which associate with the 16-Kilodalton pore-forming protein. J Virol 1993;67:6170–8.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hwang S, Nottoli T, Dimaio D. The HPV-16, E5 protein: expression, detection and stable complex formation with transmembrane proteins in COS cells. Virol 1995;211:227–33.CrossRefGoogle Scholar
  41. 41.
    Straight SW, Hinkle M, Jewers J, et al. The E5 oncoprotein of human papillomavirus type 16 transforms fribroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. J Virol 1993;67:4521–32.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Straight SW, Herman B, McCance DJ. The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes. J Virol 1995;69:3185–92.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Gu Z, Matlashewski G. Effect of human papillomavirus type 16 oncogenes on MAP kinase activity. J Virol 1995;69:8051–6.PubMedPubMedCentralGoogle Scholar
  44. 44.
    DiMaio D, Lai C, Mattoon D. The platelet-derived growth factor b receptor as a target of the bovine papillomavirus E5 protein. Cytokine Growth Factor Rev 2000;11:283–93.CrossRefGoogle Scholar
  45. 45.
    Hummel M, Lim HB, Laimins L. Human papillomavirus type 31b late gene expression is regulated through protein kinase C-mediated changes in RNA processing. J Virol 1995;69:3381–8.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Pray R, Laimins L. Differentiation-dependent expression of E1^E4 proteins in cell lines maintaining episomes of human papillomavirus type 31b. Virol 1995;206:679–85.CrossRefGoogle Scholar
  47. 47.
    Nakahara T, Nishimura A, Tanaka M, et al. Modulation of the cell division cycle by human papillomavirus type 18 E4. J Virol 2002;76(21):10914–20.CrossRefGoogle Scholar
  48. 48.
    Yukawa K, Butz K, Yasui T, et al. Regulation of human papillomavirus transcription by the differentiation-dependent epithelial factor Epoc-1/skn-1a. J Virol 1996;70(1):10–6.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Narahari A, Roman A. Ying yang 1 negatively regulates the differentiation-specific E1 promoter of human papillomavirus type 6. J Virol 2000;74:5198–205.CrossRefGoogle Scholar
  50. 50.
    O'Connor J, Stunkel H, Zimmermann H, et al. The differentiation-specific factor CDP/cut represses transcription and replication of human papillomaviruses through a conserved silencing element. J Virol 2000;74:401–10.CrossRefGoogle Scholar
  51. 51.
    Demeret C, Desaintes C, Yaniv M, et al. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol 1997;71(12):9343–9.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Hubert W, Laimins L. Human papillomavirus type 31 replication modes during the early phases of the viral life cycle depend on transcriptional and posttranscriptional regulation of E1 and E2 expression. J Virol 2002;76(5):2263–73.CrossRefGoogle Scholar
  53. 53.
    Smotkin D, Prokoph H, Wettstein O. Oncogenic an nooncogenic human genital papillomaviruses generate the E7 mRNA by different mechanisms. J Virol 1989;63:1441–7.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Kaufman R, Murtha P, Davies M. Translational efficiency of polycistronic mRNAs and their utilization to express heterologous genes in mammalian cells. EMBO 1987;6:187–93.Google Scholar

Copyright information

© FESEO 2004

Authors and Affiliations

  • Erick de la Cruz Hernández
    • 1
  • Alejandro Mohar Betancourt
    • 1
  • Marcela Lizano Soberón
    • 1
    Email author
  1. 1.Subdirección de Investigación Básica, Servicio de Oncología MédicaInstituto Nacional de CancerologíaMéxico

Personalised recommendations