Skip to main content
SpringerLink
Log in

Molecular mechanisms of virus-induced carcinogenesis: the interaction of viral factors with cellular tumor suppressor proteins

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Accumulating evidence indicates that tumor viruses represent a major etiological factor in a significant portion of human cancers. These cancers include human papillomavirus induced anogenital cancers, hepatitis B and C virus associated hepatocellular carcinomas, nasopharyngeal carcinomas and lymphomas linked to Epstein-Barr virus infection, and human T cell leukemia virus associated adult T cell leukemias. This review summarizes the recent progress made in understanding the molecular mechanisms of viral carcinogenesis, with a particular focus on the interaction of viral factors with cellular tumor suppressor proteins. The functional inactivation of tumor suppressor proteins may represent a common strategy by which several tumor viruses contribute to malignant cell transformation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

EBV :

Epstein-Barr virus

E6AP :

E6-associated protein

HBV :

Hepatitis B virus

HCC :

Hepatocellular carcinoma

HPV :

Human papillomavirus

HTLV :

Human T cell leukemia virus

pRb :

Retinoblastoma protein

RB :

Retinoblastoma

SV40 :

Simian virus 40

References

  1. Allday MJ, Sinclair A, Parker G., Crawford DH, Farrell PJ (1995) Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. EMBO J 7:1382–1391

    Google Scholar 

  2. Beasley, RP (1988) Hepatitis B virus. The major etiology of hepatocellular carcinoma Cancer 61:1942–1956

    Google Scholar 

  3. Blattner, WA (1991) Human retroviruses and malignancy. In: Brugge J, Curran T, Harlow E, McCormick F (eds) Origins of human cancer: a comprehensive review. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 199–209

    Google Scholar 

  4. Butz K, Shahabeddin L, Geisen C, Spitkovsky D, Ullmann A, Hoppe-Seyler F (1995) Functional p53 protein in human papillomavirus-positive cancer cells. Oncogene 10:927–936

    Google Scholar 

  5. Caelles C, Helmberg A, Karin M (1994) p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370:220–223

    Google Scholar 

  6. Chellapan S, Kraus VB, Kroger B, Münger K, Howley PM, Phelps WC, Nevins JR (1992) Adeno virus 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 USA 89:4549–4553

    Google Scholar 

  7. Chen JJ, Reid CE, Band V, Androphy EJ (1995) Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science 269:529–531

    Google Scholar 

  8. Cochet C, Martel-Renoir D, Grunewald V, Bosq J, Cochet G, Schwaab G, Bernaudin J-F, Joab I (1993) Expression of the Epstein-Barr virus immediate-early gene, BZLF1, in nasopharyngeal carcinoma tumor cells. Virology 197:358–365

    Google Scholar 

  9. Cross, SM, Sanchez CA, Morgan CA, Schimke MK, Ramel S, Idzerda RL, Raskind WH, Reid BJ (1995) A p53-dependent mouse spindle checkpoint. Science 267:1353–1355

    Google Scholar 

  10. Culver KW, Blaese, RM (1994) Gene therapy for cancer. Trends Genet 10:174–178

    Google Scholar 

  11. de The G, Zeng Y (1986) Population screening for EBV markers: towards improvement of nasopharyngeal carcinoma control. In: Epstein MA, Achog BG (eds) The Epstein-Barr virus. Wiley, New York, pp 237–248

    Google Scholar 

  12. de Villiers EM (1991) Heterogeneity of the human papillomavirus group. J Virol 63:4898–4903

    Google Scholar 

  13. Debbas M, White E (1993) Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 7:546–554

    CAS  PubMed  Google Scholar 

  14. 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 243:934–937

    Google Scholar 

  15. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer E, Kinzler KW, Vogelstein B (1993) WAF-1, a potential mediator of p53 tumor suppression. Cell 75:817–825

    Google Scholar 

  16. Ellermann V, Bang O (1908) Experimentelle Leukämie bei Hühnern. Zentralbl Bakteriol 46:595–609

    Google Scholar 

  17. Feitelson MA, Zhu M, Duan X-L, London WT (1993) Hepatitis X-antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:1109–1117

    Google Scholar 

  18. Fritsche M, Haessler C, Brandner G (1993) Induction of nuclear accumulation of the tumor suppressor protein p53 by DNA-damaging agents. Oncogene 8:307–318

    Google Scholar 

  19. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878

    CAS  PubMed  Google Scholar 

  20. Greene WC, Leonard WJ, Wano Y, Svetlik PB, Peffer NJ, Sodrosky JG, Rosen CA, Goh WC, Haseltine WA (1986) Transactivator gene of HTLV II induces IL-2 receptor and IL-2 cellular gene expression. Science 232:877–881

    Google Scholar 

  21. Hilger C, Velhagen I, Zentgraf H, Schröder CH (1991) Diversity of hepatitis B virus X gene-related transcripts in hepatocellular carcinoma: a novel polyadenylation site on viral DNA. J Virol 65:4284–4291

    Google Scholar 

  22. Höhne M, Schäfer S, Seifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalised transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9:137–1145

    Google Scholar 

  23. Hoppe-Seyler F, Butz K (1993) Repression of endogenous p53 transactivation function in HeLa cervical carcinoma cells by human papillomavirus type 16 E6, human mdm-2, and mutant p53. J Virol 67:3111–3111

    Google Scholar 

  24. Hoppe-Seyler F, Butz K (1994) Tumor suppressor genes in molecular medicine. Clin Investig 72:619–630

    Google Scholar 

  25. Howes KA, Ransom N, Papermaster DS, Lasudry JGH, Albert DM, Windle JJ (1994) Apoptosis or retinoblastoma: alternative fates of photoreceptors expressing the HPV-16 E7 gene in the presence or absence of p53. Genes Dev 8:1300–1310

    Google Scholar 

  26. Huang PS, Patrick DR, Edwards G, Goodhart PJ, Huber HE, Miles L, Garsky VM, Oliff A, Heimbrook DC (1993) Protein domains governing interactions between E2F, the retinoblastoma gene product, and human papillomavirus type 16 E7 protein. Mol Cell Biol 13:953–960

    Google Scholar 

  27. Jablonska S, Majewski S (1994) Epidermodysplasia verruciformis: immunological and clinical aspects. Curr Top Microbiol Immunol 186:157–175

    CAS  PubMed  Google Scholar 

  28. Jewers RJ, Hildebrandt P, Ludlow JW, Kell B, McCance DJ (1992) Regions of human papillomavirus type 16 E7 oncoprotein required for immortalization of human keratinocytes. J Virol 66:1229–1235

    Google Scholar 

  29. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of the p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311

    CAS  PubMed  Google Scholar 

  30. Kekulé AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R (1990) The pre S2/S region of integrated hepatitis B virus DNA encodes a transcriptional activator. Nature 343:457–461

    Google Scholar 

  31. Kim S, Koike K, Saito I, Myamura F, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320

    Google Scholar 

  32. Kiyono T, Hiraiwa A, Ishii S, Takahashi T, Ishibashi M (1994) Inhibition of p53-mediated transactivation by E6 of type 1, but not type 5, 8, or 47, human papillomavirus of cutaneous origin. J Virol 68:4656–4661

    Google Scholar 

  33. Lam EW-F, Morris JDH, Davies R, Crook T, Watson RJ, Vousden KH (1994) HPV16 E7 oncoprotein deregulates B-myb expression: correlation with targeting of p107/E2F complexes. EMBO J 13:871–878

    Google Scholar 

  34. Lane DP (1992) p53, guardian of the genome. Nature 358:15–16

    Article  CAS  PubMed  Google Scholar 

  35. LaThangue NB (1994) DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell cycle control. Trends Biochem Sci 19:108–114

    Google Scholar 

  36. Lee JM, Bernstein A (1993) p53-mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 90:5742–5746

    Google Scholar 

  37. Levine AJ (1992) The p53 tumor-suppressor gene. N Engl J Med 326:1350–1352

    Google Scholar 

  38. Lowe SW, Ruley HE, Jacks T, Housman D (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967

    Google Scholar 

  39. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T. (1994) p53 status and the efficiency of cancer therapy in vivo. Science 266:807–810

    CAS  PubMed  Google Scholar 

  40. Ludlow JW (1993) Interactions between SV40 large tumor antigen and the growth suppressor proteins pRb and p53. FASEB J 7:866–871

    Google Scholar 

  41. Mannick JB, Cohen JI, Birkenbach M, Marchini A, Kieff E (1991) The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important for B-lymphocyte transformation. J Virol 65:6826–6837

    Google Scholar 

  42. Maruyama M, Shibuya H, Harada H, Hatakeyama M, Seiki M, Fujita T, Inoue J, Yoshida M, Taniguchi T (1987) Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-I-encoded p40x and T3/Ti complex triggering. Cell 48:343–350

    Google Scholar 

  43. Mietz JA, Unger T, Huibregtse J, Howley PM (1992) The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J 11:5013–5020

    Google Scholar 

  44. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299

    CAS  PubMed  Google Scholar 

  45. Moran E. (1993) Interaction of adenoviral proteins with pRb and p53. FASEB J 7:880–885

    Google Scholar 

  46. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421

    Google Scholar 

  47. Münger K, Yee CL, Pietenpol JA, Moses HL, Howley PM (1991) Biochemical and biological differences between E7 oncoproteins of the high- and low risk human papillomaviruses are determined by amino-terminal sequences. J Virol 65:3943–3948

    Google Scholar 

  48. Pallesen G, Hamilton-Dutoit S, Rowe M, Lisse I, Ralfkiaer E, Sandvej K, Young L (1990) Expression of Epstein-Barr virus replicative proteins in AIDS-related non-Hodgkin's lymphoma cells. J Pathol 165:289–299

    Google Scholar 

  49. Pallesen G, Hamilton-Dutoit SJ, Zhou X (1993) The association of Epstein-Barr virus (EBV) with T-cell lymphoproliferations and Hodgkin's disease: two new developments in the EBV field. Adv Cancer Res 62:179–239

    Google Scholar 

  50. Pallesen G, Sandvej K, Hamilton-Dutoit S, Rowe M, Young L (1991) Activation of Epstein-Barr virus replication in Hodgkin and Reed-Sternberg cells. Blood 78:1162–1165

    Google Scholar 

  51. Pan H, Griep AE (1994) Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. Genes Dev 8:1285–1299

    Google Scholar 

  52. Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594–606

    Google Scholar 

  53. Pietenpol JA, Tokino T, Thiagalingam S, El-Deiry WS, Kinzler KW, Vogelstein B (1994) Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc Natl Acad Sci USA 91:1998–2002

    Google Scholar 

  54. Pim D, Storey A, Thomas M, Massimi P, Banks L (1994) 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. Oncogene 9:1869–1876

    Google Scholar 

  55. Popovic M, Lange-Wantzin G, Sarin PS, Mann D, Gallo RC (1983) Transformation of human umbilical cord blood T cells by human T cell leukemia/lymphoma virus. Proc Natl Acad Sci USA 80:5402–5406

    Google Scholar 

  56. Puisieux A, Ji J, Guillot C, Legros Y, Soussi T, Isselbacher K, Ozturk M (1995) p53-mediated cellular response to DNA damage in cells with replicative hepatitis B virus. Proc Natl Acad Sci USA 92:1342–1346

    Google Scholar 

  57. Reid RL, Lindholm PF, Mireskandari A, Dittmer J, Brady JN (1993) Stabilization of wild-type p53 in human T-lymphocytes transformed by HTLV-I. Oncogene 8:3029–3036

    Google Scholar 

  58. Robinson WS (1994) Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma. Annu Rev Med 45:297–323

    Google Scholar 

  59. Rous P (1911) A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med 13:397–411

    Google Scholar 

  60. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136

    Google Scholar 

  61. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitinprotein ligase in the ubiquitination of p53. Cell 75:495–505

    Google Scholar 

  62. Scheffner M, Romanczuk H, Miinger K, Huibregtse JM, Mietz JA, Howley PM (1994) Functions of human papillomavirus proteins. Curr Top Microbiol Immunol 186:83–99

    Google Scholar 

  63. Schlüter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH (1994) Integrated hepatitis B virus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 9:3335–3344

    Google Scholar 

  64. Schmitt A, Harry JB, Rapp B, Wettstein FO, Iftner T (1994) 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. J Virol 68:7051–7059

    Google Scholar 

  65. Sedman SA, Hubbert NL, Vass WC, Lowy DR, Schiller JT (1992) Mutant p53 can substitute for human papillomavirus type 16 E6 in immortalization of human keratinocytes but does not have E6-associated trans-activation or transforming activity. J Virol 66:4201–4208

    Google Scholar 

  66. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163

    CAS  PubMed  Google Scholar 

  67. Shibata D (1994) Biologic aspects of AIDS-related lymphoma. Curr Opin Oncol 6:503–507

    Google Scholar 

  68. Snijders PJF, van den Brule AJC, Meijer CJLM, Walboomers JMM (1994) Papillomaviruses and cancer of the upper digestive and respiratory tracts. Curr Top Microbiol Immunol 186:177–198

    Google Scholar 

  69. Stewart N, Hicks GG, Paraskevas F, Mowat M (1995) Evidence for a second cell cycle block at G2/M by p53. Oncogene 10:109–115

    Google Scholar 

  70. Strasser A, Harris AW, Jacks T, Cory S (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by bcl-2. Cell 79:329–339

    Google Scholar 

  71. Szekely L, Selivanova G, Magnusson KP, Klein G, Wiman KG (1993) EBNA-5, an Epstein-Barr virus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. Proc Natl Acad Sci USA 90:5455–5459

    Google Scholar 

  72. Takada S, Gotoh Y, Hayashi M, Koike K (1990) Structural rearrangements of integrated hepatitis B virus DNA as well as flanking DNA is present in chronically infected hepatic tissues. J Virol 64:822–828

    Google Scholar 

  73. Tiemann F, Deppert W (1994) Stabilization of the tumor suppressor p53 during cellular transformation by simian virus 40: influence of viral and cellular factors and biological consequences. J Virol 68:2869–2878

    Google Scholar 

  74. Truant R, Antunovic J, Greenblatt J, Prives C, Cromlish JA (1995) Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. J Virol 69:1851–1859

    Google Scholar 

  75. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, Kawashima T (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. New Engl J Med 328:1797–1801

    Google Scholar 

  76. Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G (1995) Functional inactivation but not structural mutation of p53 causes liver cancer. Nature Genet 9:41–47

    Google Scholar 

  77. Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70:523–526

    Google Scholar 

  78. Von Knebel Doeberitz M (1992) Papillomaviruses in human disease. II. Molecular biology and immunology of papillomavirus infections and carcinogenesis. Eur J Med 1:485–491

    Google Scholar 

  79. Vousden K (1994) Interactions between papillomavirus proteins and tumor suppressor gene products. Adv Cancer Res 64:1–24

    Google Scholar 

  80. Wands JR, Blum HE (1991) Primary hepatocellular carcinoma. New Engl J Med 325:729–731

    Google Scholar 

  81. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu J-R, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234

    Google Scholar 

  82. Wano Y, Feinberg M, Hoskin JB, Bogerd H, Green WC (1988) Stable expression of the tax gene of type I human T cell leukemia virus in human T-cells activates specific cellular genes involved in growth. Proc Natl Acad Sci USA 85:9733–9737

    Google Scholar 

  83. Weinberg RA (1991) Tumor suppressor genes. Science 254:1138–1146

    Google Scholar 

  84. Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81:323–330

    CAS  PubMed  Google Scholar 

  85. Weiss LM, Mohaved LA, Warnke RA, Sklar J (1989) Detection of Epstein-Barr virus genomes in Reed-Sternberg cells of Hodgkin's disease. New Engl J Med 320:502–506

    Google Scholar 

  86. Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79

    Google Scholar 

  87. White AE, Livanos EM, Tlsty T (1994) Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8:666–677

    Google Scholar 

  88. Yamamoto N, Okada M, Koyanagi Y, Kannagi Y, Kannagi M, Hinuma Y (1982) Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science 217:737–739

    Google Scholar 

  89. Yamato K, Oka T, Hiroi M, Iwahara Y, Sugito S, Tsuchida N, Miyoshi I (1993) Aberrant expression of the p53 tumor suppressor gene in adult T-cell leukemia and HTLV-I-infected cells. Jpn J Cancer Res 84:4–8

    Google Scholar 

  90. Yamato K, Yamamoto M, Hirano Y, Tsuchida N (1995) A human temperature-sensitive p53 mutant p53Val-138: modulation of the cell cycle, viability and expression of p53-responsive genes. Oncogene 11:1–6

    Google Scholar 

  91. Yokota J, Sugimura T (1993) Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes. FASEB J 7:920–925

    Google Scholar 

  92. Zahm P, Hofschneider PH, Koshy R (1988) The HBV X-ORF encodes a transactivator: a potential factor in hepatocarcinogenesis. Oncogene 3:169–177

    Google Scholar 

  93. Zhang Q, Gutsch D, Kenney S (1994) Functional and physical interactions between p53 and BZLF1: implications for Epstein-Barr virus latency. Mol Cell Biol 14:1929–1938

    Google Scholar 

  94. zur Hausen H (1991) Viruses in human cancers. Science 254:1167–1173

    Google Scholar 

  95. zur Hausen H (1994) Molecular pathogenesis of cancer of the cervix and its causation by specific HPV types. Curr Top Microbiol Immunol 186:131–156

    Google Scholar 

  96. zur Hausen H, Schulte-Holthausen H, Klein G, Henle W, Henle G, Clifford P, Santesson L (1970) EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature 228:1056–1058

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120, Heidelberg, Germany

    F. Hoppe-Seyler & K. Butz

Authors
  1. F. Hoppe-Seyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Butz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoppe-Seyler, F., Butz, K. Molecular mechanisms of virus-induced carcinogenesis: the interaction of viral factors with cellular tumor suppressor proteins. J Mol Med 73, 529–538 (1995). https://doi.org/10.1007/BF00195138

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00195138

Key words

Search

Navigation