Molecular Pathogenesis of Cancer of the Cervix and Its Causation by Specific Human Papillomavirus Types

  • H. zur Hausen
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 186)


Less than 10 years after publication of the hypothesis of a papillomavirus etiology of cancer of the cervix (zur Hausen 1975, 1976, 1977), the DNAs of the first cervical cancer-associated human papillomavirus (HPV) types were cloned and characterized. These DNAs are regularly and frequently found in biopsies obtained from cervical cancer patients throughout the world (Dürst et al. 1983; Boshart et al. 1984).


Cervical Cancer Caski Cell Upstream Regulatory Region Early Gene Expression Malignant Conversion 
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  1. Arbeit JM, Münger K, Howley PM, Hanahan D. Neuroepithelial carcinomas in mice transgenic with human papillomavirus type 16 E6/E7 ORF’s. Am J Pathol (in press).Google Scholar
  2. Atkin NB, Baker MC (1984) Non-random chromosome changes in carcinoma of the cervix uteri. I. Nine near-diploid tumors. Cancer Genet Cytogenet 7:2209–2221.Google Scholar
  3. Atkin NB, Baker MC (1988) Deficiency of all or part of chromosome 11 in several types of cancer: significance of a reduction in the number of normal chromosomes 11. Cytogenet Cell Genet 47:106–107.PubMedCrossRefGoogle Scholar
  4. Auvinen E, Kujari H, Arstila P, Hukkanen V. Expression of α2 and E7 genes of the human papillomavirus type 16 in female genital dysplasias. Am J Pathol (in press).Google Scholar
  5. Band V, Zaychowski D, Kulesa V, Sager R (1990) Human papillomavirus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Nat Acad Sci USA 87:463–467.PubMedCrossRefGoogle Scholar
  6. Band V, Dalai S, Delmolino L, Androphy EJ (1993) Enhanced degradation of p53 protein in HPV-6 and BPV-1 immortalized human mammary epithelial cells. EMBO J 12:1847–1852.PubMedGoogle Scholar
  7. Barbosa MS, Edmonds C, Fisher C, Schiller JT, Lowy DR, Vousden KH (1990) 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 9:153–160.PubMedGoogle Scholar
  8. Bartsch D, Boye B, Baust C, zur Hausen H, Schwarz E (1992) Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor β gene in non-tumorigenic and tumorigenic HeLa hybrid cells. EMBO J 11: 2283–2291.PubMedGoogle Scholar
  9. Batova A, Danielpour D, Pirisi L, Creek KE (1992) Retinoic acid induces secretion of latent transforming growth factor beta 1 and beta 2 in normal and human papillomavirus type 16-immortalized human keratinocytes. Cell Growth Differ 3:763–772.PubMedGoogle Scholar
  10. Bauknecht T, Angel P, Royer H-D, zur Hausen H (1992) Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO J 11:4607–4617.PubMedGoogle Scholar
  11. Bosch F, Schwarz E, Boukamp P, Fusenig NE, Bartsch D, zur Hausen H (1990) Suppression in vivo of human papillomavirus type 18 E6–E7 gene expression in nontumorigenic HeLa-fibroblast hybrid cells. J Virol 64:4743–4754.PubMedGoogle Scholar
  12. Boshart M, zur Hausen H (1986) Human papillomaviruses in Buschke-Löwenstein tumors: physical state of DNA and identification of a tandem duplication in the non-coding region of a human papillomavirus 6 subtype. J Virol 58:963–966.PubMedGoogle Scholar
  13. Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H (1984) A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 3:1151–1157.PubMedGoogle Scholar
  14. Braun L, Dürst M, Mikumo R, Guipposo P (1990) Differential response of nontumorigenic and tumorigenic human papillomavirus type 16-positive epithelial cells to transforming growth factor β. Cancer Res 50:7324–7332.PubMedGoogle Scholar
  15. Burnett S, Ström AC, Jareborg N, Alderborn A, Dillner J, Moreno-Lopez J, Pettersson U, Kiessling N (1990) Induction of E2 gene expression and early region transcription by cell growth arrest: correlation with viral DNA amplification and evidence for differential promoter induction. J Virol 64:5529–5541.PubMedGoogle Scholar
  16. Chan WK, Klock G, Bernard HU (1989) Progesterone and glucocorticoid control elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia. J Virol 63:3261–3269.PubMedGoogle Scholar
  17. Chan WK, Chong T, Bernard HU, Klock G (1990) Transcription of the transforming genes of the oncogenic human papillomavirus-16 is stimulated by tumor promoters through AP-1 binding sites. Nucleic Acid Res 18:763–769.PubMedCrossRefGoogle Scholar
  18. Chellappan SP, Hieben S, Mudryj M, Horowitz JM, Nevins JR (1991) The E2F transcription factor is a cellular target of the RB protein. Cell 65, 1053–1061.PubMedCrossRefGoogle Scholar
  19. Chen T-M, Pecoraro G, Defendi V (1993) Genetic analysis of in vitro progression of human papillomavirus-transfected human cervical cells. Cancer Res 53:1167–1171.PubMedGoogle Scholar
  20. Chittenden T, Livingston DM, Kaelin WG Jr (1991) The T/E1 A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA binding protein. Cell 65:1073–1082.PubMedCrossRefGoogle Scholar
  21. Cid A, Auewarakul P, Garcia-Carranca A, Ovseiovich R, Gaissert H, Gissmann L (1993) Cell-type specific activity of the human papillomavirus (HPV) type 18 upstream regulatory region in transgenic mice and its modulation by TPA and glucocorticoids. J Virol 67:6742–6752.PubMedGoogle Scholar
  22. Cripe TP, Alderborn A, Anderson RD, Pakkinen S, Bergman T, Haugen H, Petterson V, Turek LP (1990) Transcriptional activation of the human papillomavirus-16 P97 promoter by an 88 nucleotide enhancer containing distinct cell-dependent and AP-1 responsive modules. New Biol 2:450–463.PubMedGoogle Scholar
  23. Crook T, Vousden KH (1992) Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. EMBO J 11:3935–3940.PubMedGoogle Scholar
  24. Crook T, Morgenstern JP, Crawford L, Banks L (1989) Continued expression of HPV16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV 16 plus EJ-ras. EMBO J 8:513–519.PubMedGoogle Scholar
  25. Crum CP, Nagai N, Milao M, Levine RU, Silverstein SJ (1985) Histological and molecular analysis of early neoplasia. J Cell Biochem [Suppl] 9c:70.Google Scholar
  26. Cullen AP, Reid R, Campion M, Lorincz AT (1991) Analysis of the physical state of different human papillomavirus DNA’s in intraepithelial and invasive cervical neoplasms. J Virol 65:606–612.PubMedGoogle Scholar
  27. Debiec-Rychter M, Zukowski K, Wang CY, Wen W-N (1991) Chromosomal characterizations of human nasal and nasopharyngeal cells immortalized by human papillomavirus type 16 DNA. Cancer Genet Cytogenet 52:51–61.PubMedCrossRefGoogle Scholar
  28. Defoe-Jones D, Vuocolo GA, Haskell KM, Hanobik MG, Kiefer DM, McAvoy EM, Ivey-Hoyle M, Brandsma JL, Oliff A, Jones RE (1993) Papillomavirus E7 protein binding to the retinoblastoma protein is not required for viral induction of warts. J Virol 67:716–725.Google Scholar
  29. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221.PubMedCrossRefGoogle Scholar
  30. Drews RE, Chan VT-W, Schnipper LE (1992) Oncogenes result in genomic alterations that activate a transcriptionally silent dominantly selectable reporter gene (neo). Mol Cell Biol 12:198–206.PubMedGoogle Scholar
  31. Dürst M, Gissmann L, Ikenberg H, zur Hausen H (1983) A new papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 80:3812–3815.PubMedCrossRefGoogle Scholar
  32. Dürst M, Kleinheinz A, Hotz M, Gissmann L (1985) The physical state of human papillomavirus type 16 DNA in benign and malignant genital tumors. J Gen Virol 66:1515–1522.PubMedCrossRefGoogle Scholar
  33. Dürst M, Dzarlieva-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L (1987) Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA. Oncogene 1:251–256.PubMedGoogle Scholar
  34. Dürst M, Bosch F, Glitz D, Schneider A, zur Hausen H (1991) Inverse relationship between HPV 16 early gene expression and cell differentiation in nude mice epithelial cysts and tumors induced by HPV positive human cell lines. J Virol 65:796–804.PubMedGoogle Scholar
  35. Dürst M, Glitz D, Schneider A, zur Hausen H (1992) Human papillomavirusestype 16 (HPV16) gene expression and DNA replication in cervical neoplasia: analysis by in situ hybridization. Virology 189:132–140.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. Evans AS (1976) Epidemiological concepts and methods. In: Evans AS (ed) Viral infections of humans, epidemiology and control. Wiley, London, pp 1–32.CrossRefGoogle Scholar
  38. Fu Y-S, Braun L, Shah KV, Lawrence WP, Robboy SJ (1983) Histologie, nuclear DNA and human papillomavirus studies of cervical condylomas. Cancer 52:1705–1711.PubMedCrossRefGoogle Scholar
  39. Garcia-Carranca A, Thierry F, Yaniv M (1988) Interplay of viral and cellular proteins along the long control region of human papillomavirus 18. J Virol 63:4321–4330.Google Scholar
  40. Gebert JF, Moghal N, Frangioni JV, Sugarbaker DJ, Neel BG (1991) High frequency of retinoic acid receptor β abnormalities in human lung cancer. Oncogene 6:1859–1868.PubMedGoogle Scholar
  41. Gloss B, Bernard HU (1990) The E6/E7 promoter of human papillomavirus type 16 is activated in the absence of E2 proteins by a sequence-aberrant SP I distal element. J Virol 64:5577–5584.PubMedGoogle Scholar
  42. Gloss B, Bernard HU, Seedorf K, Klock G (1987) The upstream regulatory region of human papillomavirus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones. EMBO J 6:3735–3743.PubMedGoogle Scholar
  43. Gloss B, Chong T, Bernard HU (1989) Numerous nuclear factors bind the long control region of human papillomavirus type 16: a subset of 6 out of 23 DNase l-protected segments coincides with the location of the cell-type-specific enhancer. J Virol 63:1142–1152.PubMedGoogle Scholar
  44. Griep AE, Herber R, Jeon S, Lohse JK, Dubielzig RR, Lambert P (1993) Tumorigenicity by HPV 16 E6 and E7 in transgenic mice correlates with alterations in epithelial cell growth and differentiation. J Virol 67:1373–1384.PubMedGoogle Scholar
  45. Gross L (1983) Oncogenic viruses, 3rd edn. Pergamon, Oxford.Google Scholar
  46. Halbert CL, Demers GW, Galloway DA (1991) The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human keratinocytes. J Virol 65:473–478.PubMedGoogle Scholar
  47. Han R, Breitburd F, Marche PN, Orth G (1992) Linkage of regression and malignant conversion of rabbit viral papillomas to MHC class II genes. Nature 356:66–68.PubMedCrossRefGoogle Scholar
  48. Hartwell L (1992) Defects in a cell cycle check point may be responsible for the genomic instability of cancer cells. Cell 71:543–546.PubMedCrossRefGoogle Scholar
  49. Hashida T, Yasumoto S (1991) Induction of chromosome abnormalities in mouse and human epidermal keratinocytes by the human papillomavirus type 16 E7 oncogene. J Gen Virol 72:1569–1577.PubMedCrossRefGoogle Scholar
  50. Haskell KM, Vuocolo GA, Defoe-Jones D, Jones RE, Ivey-Hoyle M (1993) Comparison of the binding of the human papillomavirus type 16 and cottontail rabbit papillomavirus E7 proteins to retinoblastoma gene product. J Gen Virol 74:115–119.PubMedCrossRefGoogle Scholar
  51. Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT (1989) HPV 16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 8:3905–3910.PubMedGoogle Scholar
  52. Heck DV, Yee CL, Howley PM, Münger K (1992) Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci USA 89:4442–4446.PubMedCrossRefGoogle Scholar
  53. Heiland A, Borresen AL, Kaern J, Ronningen KS, Thorsby E (1992) HLA antigens and cervical cancer. Nature 356:23.CrossRefGoogle Scholar
  54. Hoppe-Seyler F, Butz K (1992) Activation of human papillomavirus type 18 E6–E7 oncogene expression by transcription factor Sp1. Nucleic Acid Res 20:6701–6706.PubMedCrossRefGoogle Scholar
  55. Hoppe-Seyler F, Butz K, zur Hausen H (1991) Repression of the human papillomavirus type 18 enhancer by the cellular transcription factor Oct-1. J Virol 65:5613–5618.PubMedGoogle Scholar
  56. Houle B, Rochette-Egly C, Bradley WEC (1993) Tumor-suppressive effect of the retinoic acid receptor β in human epidermoid lung cancer cells. Proc Natl Acad Sci USA 90:985–989.PubMedCrossRefGoogle Scholar
  57. Howley PM (1991) Role of human papillomaviruses in human cancer. Cancer Res 51:5019–5022.Google Scholar
  58. Hubbert S, Schiller JT, Lowy DR, Androphy EJ (1988) Bovine papillomavirus transformed cells contain multiple E2 proteins. Proc Natl Acad Sci USA 85:5864–5868.PubMedCrossRefGoogle Scholar
  59. Hubbert NL, Sedman SA, Schiller JT (1992) Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol 66:6237–6241.PubMedGoogle Scholar
  60. Hudson JB, Bedell ML, McCance DJ, Laimins LA (1990) Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18. J Virol 64:519–529.PubMedGoogle Scholar
  61. Hurlin PJ, Kaur P, Smith P, Perez-Reyes N, Blanton RA, McDougall JK (1991) Progression of human papillomavirus type 18 immortalized human keratinocytes to a malignant phenotype. Proc Natl Acad Sci USA 88:570–574.PubMedCrossRefGoogle Scholar
  62. Iftner T, Oft M, Böhm S, Wolczynski SP, Pfister H (1992) Transcription of the E6 and E7 genes of human papillomavirus type 6 in anogenital condylomata is restricted to undifferentiated cell layers of the epithelium. J Virol 66:4639–4646.PubMedGoogle Scholar
  63. Ishiji T, Lace MJ, Parkhinen S, Anderson RD, Haugen TH, Cripe TP, Xiao J-H, Davidson I, Chambon P, Turek LP (1992) Transcriptional enhancer factor (TEF)-1 and its cell-specific co-activator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells. EMBO J 11:2271–2281.PubMedGoogle Scholar
  64. Jagella HP, Stegner HE (1974) Zur Dignität der Condylomata acuminata. Klinische, histopathologische und cytophotometrische Befunde. Arch Gynaekol 216:119–132.CrossRefGoogle Scholar
  65. 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 66:1329–1335.PubMedGoogle Scholar
  66. Kaebling M, Klinger HP (1986) Suppression of tumorigenicity in somatic cell hybrids. III. Co-segregation of human chromosome 11 of a normal cell and suppression of tumorigenicity in intraspecies hybrids of normal diploid-malignant cells. Cytogenet Cell Genet 41:65–70.CrossRefGoogle Scholar
  67. Kaelin WG, Pallas DC, DeCaprio JA, Kaye FJ, Livingston DM (1991) Identification of cellular proteins that can interact specifically with the T/E1 A-binding region of the retinoblastoma gene product. Cell 64, 521–532.PubMedCrossRefGoogle Scholar
  68. Karlen S, Beard P (1993) Identification and characterization of novel promoters in the genome of human papillomavirus type 18. J Virol 67:4296–4306.PubMedGoogle Scholar
  69. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51:6304–6311.PubMedGoogle Scholar
  70. Kessis TD, Slebos RJ, Nelson WG, Kastan MB, Plunkett BS, Hau SM, Lorincz AT, Hedrick L, Cho KR (1993) Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci USA 90:3988–3992.PubMedCrossRefGoogle Scholar
  71. Koch R (1891) Über bakteriologische Forschung. Verhandlungen des 10 Internationalen Medizinischen Congress, Berlin, Voll, p35.Google Scholar
  72. Koi M, Morita H, Yamada H, Saboh H, Barrett JC, Oshimura H (1989) Normal human chromosome 11 suppresses tumorigenicity of human cervical tumor cell line SiHa. Mol Carcinog 2:12–21.PubMedCrossRefGoogle Scholar
  73. Kondoh G, Murata Y, Aozasa K, Yutsudo M, Hakura A (1991) Very high incidence of germ cell tumorigenesis (seminomagenesis) in human papillomavirus type 16 transgenic mice. J Virol 65:3335–3339.PubMedGoogle Scholar
  74. Kyo S, Inoue M, Nishio Y, Nakanishi K, Akira S, Inoue H, Yutsudo M, Tanizawa O, Hakura A (1993) NF-IL 6 represses early gene expression of human papillomavirus type 16 through binding to the noncoding region. J Virol 67:1058–1066.PubMedGoogle Scholar
  75. Lambert PF, Spalholz BA, Howley PM (1987) A transcriptional repressor encoded by BPV-1 shares common carboxy-terminal domain with the E2 transactivator. Cell 50:69–78.PubMedCrossRefGoogle Scholar
  76. Lane DP (1992) p53, guardian of the genome. Nature 358:15–16.PubMedCrossRefGoogle Scholar
  77. Lechner MS, Mack DH, Finicle AB, Crook T, Vousden KH, Laimins LA (1992) Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO J 11:3045–3052.PubMedGoogle Scholar
  78. Lehn H, Villa LL, Marziona F, Hilgarth M, Hillemanns HG, Sauer G (1988) Physical state and biological activity of human papillomavirus genomes in precancerous lesions of the female genital tract. J Gen Virol 69:187–196.PubMedCrossRefGoogle Scholar
  79. Leid M, Kastner P, Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. TIBS 17:427–433.PubMedGoogle Scholar
  80. Mack DH, Laimins LA (1991) A keratinocyte-specific transcription factor, KRE-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells. Proc Natl Acad Sci USA 88:9102–9106.PubMedCrossRefGoogle Scholar
  81. Malejczyk J, Malejczyk M, Urbanski A, Köck A, Jablonska S, Orth G, Luger T (1991) Constitutive release of IL 6 by human papillomavirus type 16 (HPV 16)-harboring keratinocytes: a mechanism augmenting the NK-cell-mediated lysis of HPV-bearing neoplastic cells. Cell Immunol 136:155–164.PubMedCrossRefGoogle Scholar
  82. Malejczyk J, Malejczyk M, Köck A, Urbanski A, Majewski S, Hunzelmann N, Jablonska S, Orth G, Luger TA (1992) Autocrine growth limitation of human papillomavirus type 16— harboring keratinocytes by constitutively released tumor necrosis factor-α. J Immunol 149:2702–2708.PubMedGoogle Scholar
  83. Matsukura T, Koi S, Sugase M (1989) Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers. Virology 172:63–72.PubMedCrossRefGoogle Scholar
  84. McCance DJ, Kopan R, Fuchs E, Laimins LA (1988) Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci USA 85:7169–7173.PubMedCrossRefGoogle Scholar
  85. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of human papillomavirus type 16 are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421.PubMedGoogle Scholar
  86. Nevins JR (1992a) E2F: a link between Rb tumor suppressor protein and viral oncoproteins. Science 258, 424–429.PubMedCrossRefGoogle Scholar
  87. Nevins JR (1992b) Transcriptional regulation. A closer look at E2F. Nature 358,375–376.PubMedCrossRefGoogle Scholar
  88. Offord EA, Beard P (1990) A member of the activator protein 1 family found in keratinocytes but not in fibroblasts required for transcription from a human papillomavirus type 18 promoter. J Virol 64:4792–4798.PubMedGoogle Scholar
  89. Pagano M, Dürst M, Joswig S, Draetta G, Jansen-Dürr P (1992) Binding of human E2F transcription factor to the retinoblastoma protein but not cyclin A is abolished in HPV 16-immortalized cells. Oncogene 7:1681–1687.PubMedGoogle Scholar
  90. Park N-H, Min B-M, Li S-L, Huang MZ, Cherick HM, Doninger J (1991) Immortalization of normal human oral keratinocytes with type 16 human papillomavirus. Carcinogenesis 12:1627–1631.PubMedCrossRefGoogle Scholar
  91. Pater MM, Hughes GA, Hyslop DE, Nakshatri H, Pater A (1988) Glucocorticoid-dependent oncogenic transformation by type 16 and not type 11 human papillomavirus DNA. Nature 335:832–835.PubMedCrossRefGoogle Scholar
  92. Pecoraro G, Lee M, Morgan D, Defendi V (1991) Evolution of in vitro transformation and tumorigenesis of HPV 16 and HPV 18 immortalized primary cervical epithelial cells. Am J Pathol 138:1–8.PubMedGoogle Scholar
  93. Peng X, Olson RO, Christian CB, Lang CM, Kreider JW (1993) Papillomas and carcinomas in transgenic rabbits carrying EJ-ras and cottontail rabbit papillomavirus DNA. J Virol 67:1698–1701.PubMedGoogle Scholar
  94. Phelps WC, Baghi S, Barnes JA, Raychaudhuri P, Kraus V, Münger K, Howley PM, Nevius JR (1991) Analysis of transactivation by human papillomavirus type 16 E7 and adenovirus 12S E1A suggest a common mechanism J Virol 65:6922–8930.PubMedGoogle Scholar
  95. Phelps WC, Münger K, Yee CL, Barnes JA, Howley PM (1992) Structure-function analysis of the human papillomavirus type 16 E7 oncoprotein. J Virol 66:2418–2427.PubMedGoogle Scholar
  96. Pirisi L, Yasumoto S, Fellery M, Doninger JK, DiPaolo JA (1987) Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol 61:1061–1066.PubMedGoogle Scholar
  97. Pirisi L, Batova A, Jenkins GR, Hodam, JR, Creek KE (1992) Increased sensitivity of human keratinocytes immortalized by human papillomavirus type 16 DNA to growth control by retinoids. Cancer Res 52:187–193.PubMedGoogle Scholar
  98. Rösl F, Dürst M, zur Hausen H (1988) Selective suppression of human papillomavirus transcription in non-tumorigenic cells by 5-aza-cytidine. EMBO J 7:1321–1328.PubMedGoogle Scholar
  99. Rösl F, Westphal E-M, zur Hausen H (1989) Chromatin structure and transcriptional regulation of human papillomavirus type 18 DNA in HeLa cells. Mol Carcinog 2:72–80.PubMedCrossRefGoogle Scholar
  100. Rösl F, Achtstetter T, Hutter K-J, Bauknecht T, Futterman G, zur Hausen H (1991) Extinction of the HPV 18 upstream regulatory region in cervical carcinoma cells after fusion with nontumorigenic human keratinocytes under non-selective conditions. EMBO J 10:1337–1345.PubMedGoogle Scholar
  101. Rösl F, Arab A, Klevenz B, zur Hausen H (1993) The effect of DNA methylation on gene regulation of human papillomaviruses. J Gen Virol 74:791–801.PubMedCrossRefGoogle Scholar
  102. Rollins BJ, Sunday ME (1991) Suppression of tumor formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol 11:3125–3131.PubMedGoogle Scholar
  103. Romanczuk H, Thierry F, Howley PM (1990) Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and 18 P105 promoters. J Virol 64:2849–2859.PubMedGoogle Scholar
  104. Saxon PJ, Srivatsan ES, Stanbridge J (1986) Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression in HeLa cells. EMBO J 5:3461–3466.PubMedGoogle Scholar
  105. Scheffner M, Werness BA, Huibregtse JM, Levine JM, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136.PubMedCrossRefGoogle Scholar
  106. Scheffner M, Münger K, Byrne JC, Howley PM (1991) The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA 88:5523–5527.PubMedCrossRefGoogle Scholar
  107. Schwarz E (1987) Transcription of papillomavirus genomes. In: Syrjänen K, Gissmann L, Koss LG (eds) Papillomaviruses and human disease. Springer, Berlin Heidelberg New York, pp 443–466.CrossRefGoogle Scholar
  108. Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H (1985) Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314:111–114.PubMedCrossRefGoogle Scholar
  109. Searle PF, Thomas DP, Faulkner KB, Tinsley JM. Gastric carcinoma in transgenic mice expressing HPV 16 early region genes (submitted for publication).Google Scholar
  110. Sippola-Thiele M, Hanahan D, Howley PM (1989) Cell-heritable stages of tumor progression in transgenic mice harboring the bovine papillomavirus type 1 genome. Mol Cell Biol 9:925–934.PubMedGoogle Scholar
  111. Sircar S, Horvath J, Roberge D, Diouri M, Weber JM (1992) Adenovirus transformation revertant resistant to retransformation by E1 but not by SV40-T and HPV 16-E7 oncogenes. Virology 191:187–192.PubMedCrossRefGoogle Scholar
  112. Smith PP, Friedman CL, Bryand EM, McDougall JK (1992) Viral integration and fragile sites in human papillomavirus-immortalized human keratinocyte cell lines. Genes, Chrom Cancer 5:150–157.CrossRefGoogle Scholar
  113. Smits HL, Raadsheer E, Rood I, Mehendale S, Slater RM, van der Noordaa J, ter Schegget J (1988) Induction of anchorage-independent growth of human embryonic fibroblasts with a deletion in the short arm of chromosome 11 by human papillomavirus type 16 DNA. J Virol 62:4538–4543.PubMedGoogle Scholar
  114. Smits PHM, deRonde A, Smits HL, Minaar RP, van der Noordaa J, ter Schegget J (1992a) Modulation of the human papillomavirus type 16 induced transformation and transcription by deletion of loci on the short arm of chromosome 11 can be mimicked by SV 40 small t. Virology 190:40–44.PubMedCrossRefGoogle Scholar
  115. Smits PHM, Smits HL, Minnaar R, Hemmings BA, Mayer-Jaekel RE, Schuurman R, van der Noordaa J, ter Schegget J (1992b) The trans-activation of the HPV 16 long control region in human cells with a deletion in the short arm chromosome 11 is mediated by the 55kDa regulatory subunit of protein phosphatase 2A. EMBO J 11:4601–4606.PubMedGoogle Scholar
  116. Smits PHM, Smits HL, Minnaar RP, ter Schegget J (1993) Regulation of human papillomavirus type 16 (H PV-16) transcription by loci on the short arm of chromosome 11 is mediated by the TATAAAA motif of the HPV 16 promoter. J Gen Virol 74:121–124.PubMedCrossRefGoogle Scholar
  117. Smotkin D, Wettstein FO (1986) Transcription of human papillomavirus type 16 early genes in a cervical cancer and a cancer-derived cell line and identification of the E7 protein. Proc Natl Acad Sci USA 83:4680–4684.PubMedCrossRefGoogle Scholar
  118. Spalholz BA, Yang Y-C, Howley PM (1985) Transactivation of bovine papillomavirus transcriptional regulatory element by the E2 gene product. Cell 42:183–191.PubMedCrossRefGoogle Scholar
  119. Sreekantaiah C, de Braekeleer M, Haas O (1991) Cytogenetic findings in cervical carcinoma: a statistical approach. Cancer Genet Cytogenet 51:75–81.CrossRefGoogle Scholar
  120. Stoler MH, Rhodes CR, Whitbek A, Wolinsky SM, Chow LT, Broker TR (1992) Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Human Pathol 23:117–128.CrossRefGoogle Scholar
  121. Thierry F, Spyrou G, Yaniv M, Howley P (1992) Two AP-1 sites binding JunB are essential for human papillomavirus type 18 transcription in keratinocytes. J Virol 66:3740–3748.PubMedGoogle Scholar
  122. von Knebel Doeberitz M, Oltersdorf T, Schwarz E, Gissmann L (1988) Correlation of modified human papillomavirus early gene expression with altered growth properties in C4-1 cervical carcinoma cells. Cancer Res. 48:3780–3786.Google Scholar
  123. von Knebel Doeberitz M, Bauknecht T, Bartsch D, zur Hausen H (1991) Influence of chromosomal integration on glucocorticoid regulated transcription of growth-stimulating E6–E7 genes in cervical carcinoma cells. Proc Natl Acad Sci USA 88:1411–1415.CrossRefGoogle Scholar
  124. von Knebel Doeberitz M, Rittmüller C, zur Hausen H, Dürst M (1992) Inhibition of tumorigenicity of C4-1 cervical cancer cells in nude mice by HPV 18 E6–E7 antisense RNA. Int J Cancer 51:831–834.CrossRefGoogle Scholar
  125. Wank R, Thomssen C (1991) High risk of squamous cell carcinoma of the cervix for women with HLA-DQw3. Nature 352:723–725.PubMedCrossRefGoogle Scholar
  126. Wank R, Schendel DJ, Thomssen C (1992) HLA antigens and cervical carcinoma. Nature 356:22–23.PubMedCrossRefGoogle Scholar
  127. Watanabe S, Kanda T, Yoshiike K (1989) Human papillomavirus type 16 transformation of primary human embryonic fibroblasts requires expression of open reading frames E6 and E7. J Virol 63:965–969.PubMedGoogle Scholar
  128. Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79.PubMedCrossRefGoogle Scholar
  129. Willey JC, Broussoud A, Sleemi A, Bennett WP, Cerutti P, Harris, CC (1991) Immortalization of normal human bronchial epithelial cells by human papillomavirus 16 and 18. Cancer Res 51:5370–5377.PubMedGoogle Scholar
  130. Woodworth CD, Simpson S (1993) Comperative lymphokine secretion by cultured normal human cervical keratinocytes, papillomavirus-immortalized, and carcinoma cell lines. Am J Pathol 142:1544–1555.PubMedGoogle Scholar
  131. Woodworth CD, Waggoner S, Barnes W, Stoler MH, DiPaolo JA (1990a) Human cervical and foreskin epithelial cells immortalized by human papillomavirus DNAs exhibit dysplastic differentiation in vivo. Cancer Res 50:3709–3715.PubMedGoogle Scholar
  132. Woodworth CD, Notario V, DiPaolo JA (1990b) Transforming growth factor beta 1 and 2 transcriptionally regulate human papillomavirus (HPV) type 16 early gene expression in HPV-immortalized human genital epithelial cells. J Virol 64:4767–4775.PubMedGoogle Scholar
  133. Woodworth CD, Lichti U, Simpson S, Evans CH, DiPaolo JA (1992) Leukoregulin and gamma-interferon inhibit human papillomavirus type 16 gene transcription in human papil-lomavirus-immortalized human cervical cells. Cancer Res 52:456–463.PubMedGoogle Scholar
  134. Yang S, Lickteig RL, Estes R, Rundell K, Walter G, Mumby M (1991) Control of phosphatase 2A by simian virus 40 small t antigen. Mol Cell Biol 11:1988–1995.PubMedGoogle Scholar
  135. Yasumoto S, Taniguchi A, Sohma K (1991) Epidermal growth factor (EGF) elicits downregulation of human papillomavirus-type 16 (HPV-16) E6/E7 mRNA at the transcriptional level in an EGF-stimulated human keratinocyte cell line: functional role of EGF-responsive silencer in the HPV-16 long control region. J Virol 65:2000–2009.PubMedGoogle Scholar
  136. Yee C, Krishnan-Hewlatt I, Baker C, Schlegel R, Howley P (1985) Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines. Am J Pathol 119:361–366.PubMedGoogle Scholar
  137. zur Hausen H (1975) Oncogenic herpesviruses. Biochem Biophys Acta 417:25–53.PubMedGoogle Scholar
  138. zur Hausen H (1976) Condylomata acuminata and human genital cancer. Cancer Res 36:530.Google Scholar
  139. zur Hausen H (1977a) Human papillomaviruses and their possible role in squamous cell carcinomas. In: Compans RW, Cooper M, Koprowski H et al. (eds) Current topics in microbiology and immunology, vol 78. Springer, Berlin Heidelberg New York, pp1–30.CrossRefGoogle Scholar
  140. zur Hausen H (1977b) Cell-virus gene balance hypothesis of carcinogenesis. Behring Inst Mitt 61:23–30.Google Scholar
  141. zur Hausen H (1986) Human genital cancer: synergism between two virus infections or synergysm between a virus infection and initiating events. Lancet 2:1370–1372.Google Scholar
  142. zur Hausen H (1986a) Genital papillomavirus infections. In: Rigby PWJ, Wilkie NM (eds) Viruses and Cancer. Cambridge University Press, Cambridge, pp 83–90.Google Scholar
  143. zur Hausen H (1989) Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res 49:4677–4681.PubMedGoogle Scholar
  144. zur Hausen H (1991 a) Viruses in human cancers. Science 254:1167–1173.PubMedCrossRefGoogle Scholar
  145. zur Hausen H (1991b) Papillomavirus/host cell interactions in the pathogenesis of anogenital cancer. In: Brugge J, Curran T, Harlow E, McCormick F (eds) Origins of human cancer. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 685–705.Google Scholar
  146. zur Hausen H (1991c) Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184:9–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1994

Authors and Affiliations

  • H. zur Hausen
    • 1
  1. 1.Deutsches KrebsforschungszentrumHeidelbergGermany

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