Papillomavirus Transformation

  • Peter M. Howley
  • Richard Schlegel
Part of the The Viruses book series (VIRS)


The papillomaviruses have been studied extensively since the early 1930s when Shope initiated his studies on CRPV (Shope, 1933). Detailed studies on the biology and molecular genetics of this group of viruses have been severely hampered, however, due in large part to the lack of a tissue culture system for the in vitro propagation of these viruses. Cellular transformation of rodent cells by some papillomaviruses has provided cell culture systems for investigators to study the viral functions involved in cellular proliferation, cellular transformation, and plasmid maintenance. Although a few studies have now demonstrated transformation with certain of the HPV types, the analysis of papillomavirus-transforming functions has largely been performed with a subgroup of papillomaviruses which are able to induce fibroblastic tumors in hamsters. These viruses are listed in Table I. Of these, BPV-1 is the best studied. BPV-1 can induce fibroblastic tumors in a variety of heterologous hosts other than hamsters, including horses (Olson et al., 1969; Lancaster et al., 1977), mice (Boiron et al., 1964), and pika (Puget et al., 1975). One characteristic of the viruses listed in Table I is that each induces fibropapillomas consisting of a proliferative fibroblastic component as well as a proliferative squamous epithelial component. Thus, the ability to induce fibroblastic tumors in heterologous hosts would appear to correlate with the ability of an individual papillomavirus to induce fibroblastic proliferation as a part of the normal benign lesion induced in its natural host.


C127 Cell Long Control Region Plasmid Maintenance Hamster Embryo Cell Fibroblastic Tumor 
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  1. Ahola, H., Stenlund, A., Moreno-López, J., and Pettersson, U., 1983, Sequences of bovine papillomavirus type 1 DNA—Functional and evolutionary implications, Nucleic Acids Res. 11: 2639–2650.PubMedCrossRefGoogle Scholar
  2. Allshire, R. C., and Bostock, C. J., 1986, Structure of bovine papillomavirus type 1 DNA in a transformed mouse cell line, j. Mol. Biol. 188: 1–13.PubMedCrossRefGoogle Scholar
  3. Amtmann, E., and Sauer, G., 1982, Bovine papillomavirus transcription: Polyadenylated RNA species and assessment of the direction of transcription, J. Virol. 43: 59–66.PubMedGoogle Scholar
  4. Androphy, E., Schiller, J. T., and Lowy, D., 1985, Identification of the protein encoded by the E6 transforming gene of bovine papillomavirus, Science 230: 442–445.PubMedCrossRefGoogle Scholar
  5. Babiss, L. E., and Fisher, P. B., 1986, Characterization of Fischer rat embryo (CREF) cells transformed by bovine papillomavirus type 1, Virology 154: 180–194.PubMedCrossRefGoogle Scholar
  6. Benjamin, T. L., 1970, Host range mutants of polyoma virus, Proc. Natl. Acad. Sci. USA 67: 394–399.PubMedCrossRefGoogle Scholar
  7. Berg, L. J., Singh, K., and Botchan, M., 1986, Complementation of a bovine papillomavirus low-copy-number mutant: Evidience for a temporal requirement of the complementing gene, Mol. Cell. Biol 6: 859–869.PubMedGoogle Scholar
  8. Binetruy, B., Meneguzzi, G., Breathnach, R., and Cuzin, F., 1982, Recombinant DNA molecules comprising bovine papilloma virus type 1 DNA linked to plasmid DNA are maintained in a plasmidial state both in rodent fibroblasts and in bacterial cells, EMBO J. 1: 621–628.PubMedGoogle Scholar
  9. Black, P. H., Hartley, J. W., Rowe, W. P., and Huebner, R. J., 1963, Transformation of bovine tissue culture cells by bovine papilloma virus, Nature 199: 1016–1018.PubMedCrossRefGoogle Scholar
  10. Boiron, M., Levy, J. P., Thomas, M., Friedman, J. C., and Bernard, J., 1964, Some properties of bovine papillomavirus, Nature 201: 423–424.PubMedCrossRefGoogle Scholar
  11. Botchan, M., Berg, L., Reynolds, J., and Lusky, M., 1986, The bovine papillomavirus replicon, Ciba Symp. 120: 53–64.Google Scholar
  12. Campo, M. S., and Spandidos, D. A., 1983, Molecularly cloned bovine papillomavirus DNA transforms mouse fibroblasts in vitro, J. Gen. Virol 64: 549–557.PubMedCrossRefGoogle Scholar
  13. Campo, M. S., Spandidos, D. A., Lang, J., and Wilkie, N. M., 1983, Transcriptional control signals in the genome of bovine papillomavirus type 1, Nature 303: 77–80.PubMedCrossRefGoogle Scholar
  14. Chen, E. Y., Howley, P. M., Levinson, A. D., and Seeburg, P. H., 1982, The primary structure and genetic organization of the bovine papillomavirus (BPV) type 1, Nature 299: 529–534.PubMedCrossRefGoogle Scholar
  15. Danos, O., Georges, E., Orth, G., and Yaniv, M., 1985, Fine structure of the cottontail rabbit papillomavirus mRNAs expressed in the transplantable VX2 carcinoma, J. Virol 53: 735–741.PubMedGoogle Scholar
  16. DiMaio, D., Corbin, V., Sibley, E., and Maniatis, T., 1984, High-level expression of a cloned HLA heavy chain gene introduced into mouse cells on a bovine papillomavirus vector, Mol. Cell. Biol 4: 340–350.PubMedGoogle Scholar
  17. DiMaio, D., Metherall, J., Neary, K., and Guralski, D., 1986a, Nonsense mutation in open reading frame E2 of bovine papillomavirus DNA, J. Virol 57: 475–480.PubMedGoogle Scholar
  18. DiMaio, D., Guralski, D., and Schiller, J. T., 1986b, Translation of open reading frame E5 of bovine papillomavirus is required for its transforming activity, Proc. Natl. Acad. Sci. USA 83: 1797–1801.PubMedCrossRefGoogle Scholar
  19. Dvoretzky, I., Shober, R., Chattopadhyay, S., and Lowy, D. R., 1980, A quantitative in vitro focus forming assay for bovine papilloma virus, Virology 103: 369–375.PubMedCrossRefGoogle Scholar
  20. Engel, L. W., Heilman, C. A., and Howley, P. M., 1983, Transcriptional organization of the bovine papillomavirus type 1, J. Virol 47: 516–528.PubMedGoogle Scholar
  21. Friedman, J. C., Levy, J. P., Lasneret, J., Thomas, M., Boiron, M., and Bernard, J., 1963, Induction de fibromes sous-cutanés chez le hamster doré par inoculation d’extraits à cellulaires de papillomes bovins, C.R. Acad. Sci 257: 2328–2331.Google Scholar
  22. Geraldes, A., 1969, Malignant transformation of hamster cells by cell-free extracts of bovine papilloma (in vitro). Nature 222: 1283–1285.PubMedCrossRefGoogle Scholar
  23. Gibbs, E. P. J., Smale, C. J., and Lawman, M. J. P., 1975, Warts in sheep, J. Comp. Pathol 85: 327–334.PubMedCrossRefGoogle Scholar
  24. Grisoni, M., Meneguzzi, G., DeLapeyriere, O., Binetruy, B., Rassoulzadegan, M., and Cuzin, F., 1984, The transformed phenotype in culture and tumorigenicity of Fischer rat fibroblast cells (FR3T3) transformed with bovine papillomavirus type 1, Virology 135: 406–416.PubMedCrossRefGoogle Scholar
  25. Groff, D. E., and Lancaster, W. D., 1986, Genetic analysis of the 3’ early region transformation and replication functions of bovine papillomavirus type 1, Virology 150: 221–230.PubMedCrossRefGoogle Scholar
  26. Groff, D. E., Sundberg, J. P., and Lancaster, W. D., 1983, Extrachromosomal deer fibromavirus DNA in deer fibromas and virus transformed mouse cells, Virology 131: 546–550.PubMedCrossRefGoogle Scholar
  27. Heilman, C. A., Engel, L., Lowy, D. R., and Howley, P. M., 1982, Virus-specific transcription in bovine papillomavirus transformed mouse cells, Virology 119: 22–34.PubMedCrossRefGoogle Scholar
  28. Howley, P. M., 1983, The molecular biology of papillomavirus transformation, Am. J. Pathol 113: 414–421.PubMedGoogle Scholar
  29. Howley, P. M., Law, M.-F., Heilman, C. A., Engel, L. W., Alonso, M. C., Lancaster, W. D., Israel, M. A., and Lowy, D. R., 1980, Molecular characterization of papillomavirus genomes, in: Viruses in Naturally Occurring Cancers ( M. Essex, G. Todaro, and H. zur Hausen, eds.), pp. 233–247, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.Google Scholar
  30. Howley, P. M., Schenborn, E. T., Lund, E., Byrne, J. C., and Dahlberg, J. E., 1985, The bovine papillomavirus distal “enhancer” is not cis-essential for transformation or for plasmid maintenance, Mol. Cell. Biol 5: 3310–3315.PubMedGoogle Scholar
  31. Jarrett, W. F. H., McNeil, P. E., Grimshaw, W. T. R., Selman, I. E., and McIntyre, W. I. M., 1978, High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and papilloma virus, Nature 274: 215–217.PubMedCrossRefGoogle Scholar
  32. Koller, L. D., and Olson, C., 1972, Attempted transmission of warts from man, cattle, and horses, and of deer fibroma, to selected hosts, J. Invest. Dermatol 58: 366–368.PubMedCrossRefGoogle Scholar
  33. Kyte, J., and Doolittle, R., 1982, A simple method for displaying the hydrophobic character of a protein, J. Mol. Biol 157: 105–132.PubMedCrossRefGoogle Scholar
  34. Lancaster, W. D., 1981, Apparent lack of integration of bovine papillomavirus DNA in virus-induced equine and bovine tumor cells and virus-transformed mouse cells, Virology 108: 251–255.PubMedCrossRefGoogle Scholar
  35. Lancaster, W. D., and Olson, C., 1980, State of bovine papillomavirus DNA in connective-tissue tumors, Cold Spring Harbor Conf. Cell Prolif. 7: 223–232.Google Scholar
  36. Lancaster, W. D., Olson, C., and Meinke, W., 1977, Bovine papilloma virus: Presence of virus-specific DNA sequences in naturally occurring equine tumors, Proc. Natl. Acad. Sci. USA 74: 524–528.PubMedCrossRefGoogle Scholar
  37. Law, M.-F., Lowy, D. R., Dvoretzky, I., and Howley, P. M., 1981, Mouse cells transformed by bovine papillomavirus contain only extrachromosomal viral DNA sequences, Proc. Natl. Acad. Sci. USA 78: 2727–2731.PubMedCrossRefGoogle Scholar
  38. Law, M.-F., Byrne, J. C., and Howley, P. M., 1983, A stable bovine papillomavirus hybrid plasmid that expresses a dominant selective trait, Mol. Cell. Biol 3: 2110–2115.PubMedGoogle Scholar
  39. Lowy, D. R., Dvoretzky, I., Shober, R., Law, M.-F., Engel, L., and Howley, P. M., 1980, In vitro tumorigenic transformation by a defined subgenomic fragment of bovine papillomavirus DNA, Nature 287: 72–74.PubMedCrossRefGoogle Scholar
  40. Lusky, M., and Botchan, M., 1984, Characterization of the bovine papilloma virus plasmid maintenance sequences, Cell 36: 391–401.PubMedCrossRefGoogle Scholar
  41. Lusky, M., and Botchan, M. R., 1985, Genetic analysis of the bovine papillomavirus type 1 trans-acting replication factors, J. Virol 53: 955–965.PubMedGoogle Scholar
  42. Lusky, M., and Botchan, M. R., 1986, Transient replication of BPV-1 plasmids: Cis and trans requirements, Proc. Natl. Acad. Sci. USA 83: 3609–3613.PubMedCrossRefGoogle Scholar
  43. Lusky, M., Berg, L., Weiher, H., and Botchan, M., 1983, The bovine papillomavirus contains an activator of gene expression at the distal end of the transcriptional unit, Mol. Cell. Biol 3: 1108–1122.PubMedGoogle Scholar
  44. Matthias, D. D., Bernard, H. U., Scott, A., Brody, G., Hashimoto-Gotoh, T., and Schutz, G., 1983, A bovine papillomavirus vector with a dominant resistance marker replicates extrachromosomally in mouse cells and E. coli cells, EMBO J. 2: 1487–1492.PubMedGoogle Scholar
  45. Meischke, H. R. C., 1979, In vitro transformation by bovine papilloma virus, J. Gen. Virol 43: 473–487.PubMedCrossRefGoogle Scholar
  46. Meneguzzi, G., Binetruy, B., Grisoni, M., and Cuzin, F., 1984, Plasmidial maintenance in rodent fibroblasts of a BPV-1—pBR322 shuttle vector without immediately apparent oncogenic transformation of the recipient cells, EMBO I. 3: 365–371.Google Scholar
  47. Moar, M. H., Campo, M. S., Laird, H., and Jarrett, W. F. H., 1981, Persistence of nonintegrated viral DNA in bovine cells transformed in vitro by bovine papillomavirus type 2, Nature 293: 749–751.PubMedCrossRefGoogle Scholar
  48. Morgan, D. M., and Meinke, W., 1980, Isolation of clones of hamster embryo cells transformed by the bovine papilloma virus, Curr. Microbial 3: 247–251.CrossRefGoogle Scholar
  49. Nakabayashi, Y., Chattopadhyay, S. K., and Lowy, D. R., 1983, The transforming function of bovine papillomavirus DNA, Proc. Natl. Acad. Sci. USA 80: 5832–5836.PubMedCrossRefGoogle Scholar
  50. Nassen, M., and Wettstein, F. O., 1984., Differences exist between viral transcripts in cottontail rabbit papillomavirus-induced benign and malignant tumors as well as nonvirus-producing and virus-producing tumors, J. Viral 51: 706–712.Google Scholar
  51. Okayama, H., and Berg, P., 1983, A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells, Mol. Cell. Biol 3: 280–289.PubMedGoogle Scholar
  52. Olson, C., Gordon, D. C., Robl, M. G., and Lee, K. P., 1969, Oncogenicity of bovine papillomavirus, Arch. Environ. Health 19: 827–837.PubMedGoogle Scholar
  53. Pettersson, U., Ahola, H., Stenlund, A., Bergman, P., Ustav, M., and Moreno-López, J., 1986, Organization and expression of the genome of bovine papillomavirus type 1, Ciba Symp. 120: 23–34.Google Scholar
  54. Puget, A., Favre, M., and Orth, G., 1975, Induction de tumeurs fibroblastiques cutanées où sous-custanées chez l’Ochotone afghan (Ochotono rufescens rufescens) par inoculation du virus du papillome bovin, C.R. Acad. Sci 280: 2813–2816.Google Scholar
  55. Rabson, M. S., Yee, C., Yang, Y.-C., and Howley, P. M., 1986, Analysis of the bovine papillomavirus type 1 3’ early region transformation and plasmid maintenance function, J. Viral 60: 626–634.Google Scholar
  56. Rösl, R., Waldeck, W., and Sauer, G., 1983, Isolation of episomal bovine papillomavirus chromatin and identification of a DNase I-hypersensitive region, J. Viral 46: 567–574.Google Scholar
  57. Rösl, R., Waldeck, W., Zentgraf, H., and Sauer, G., 1986, Properties of intracellular bovine papillomavirus chromatin, J. Viral 58: 500–507.Google Scholar
  58. Sarver, N., Byrne, J. C., and Howley, P. M., 1982, Transformation and replication in mouse cells of a bovine papillomavirus/pML2 plasmid vector that can be rescued in bacteria, Proc. Natl. Acad. Sci. USA 79: 7147–7151.PubMedCrossRefGoogle Scholar
  59. Sarver, N., Rabson, M. S., Yang, Y.-C., Byrne, J. C., and Howley, P. M., 1984, Localization and analysis of bovine papillomavirus type 1 transforming functions, J. Viral 52: 377–388.Google Scholar
  60. Sarver, N., Muschel, R., Byrne, J. C., Khoury, G., and Howley, P. M., 1985, Enhancer dependent expression of the rat preproinsulin genes in BPV-1 vectors, Mol. Cell. Bio1. 5: 3507–3516.Google Scholar
  61. Schiller, J., Vass, W. C., and Lowy, D. R., 1984, Identification of a second transforming region of bovine papillomavirus, Proc. Natl. Acad. Sci. USA 81: 7880–7884.PubMedCrossRefGoogle Scholar
  62. Schiller, J., Vousden, K., Vass, W. C., and Lowy, D. R., 1986, The E5 open reading frame of bovine papillomavirus type 1 encodes a transforming gene, J. Virol 57: 1–6.PubMedGoogle Scholar
  63. Schlegel, R., Wade-Glass, M., Rabson, M. S., and Yang, Y.-C., 1986, The E5 transforming gene of bovine papillomavirus encodes a small hydrophobic polypeptide, Science 233: 464–466.PubMedCrossRefGoogle Scholar
  64. Schwarz, E., Freese, U. K., Gissmann, L., Mayer, W., Roggenback, B., Stremlau, A., and zur Hausen, H., 1985, Structure and transcription of human papillomavirus sequences in cervical carcinoma cells, Nature 314: 111–114.PubMedCrossRefGoogle Scholar
  65. Shope, R. E., 1933, Infectious papillomatosis of rabbits, with a note on the histopathology, J. Exp. Med 58: 607–624.PubMedCrossRefGoogle Scholar
  66. Spalholz, B. A., Yang, Y.-C., and Howley, P. M., 1985, Transactivation of a bovine papillomavirus transcriptional regulatory element by the E2 gene product, Cell 42: 183–191.PubMedCrossRefGoogle Scholar
  67. Stenlund, A., Moreno-López, J., Ahola, H., and Pettersson, U., 1983, European elk papillomavirus: Characterization of the genome, induction of tumors in animals, and transformation in vitro, J. Virol 48: 370–376.PubMedGoogle Scholar
  68. Stenlund, A., Zabielski, J., Ahola, H., Moreno-López, J., and Pettersson, U., 1985, The messenger RNAs from the transforming region of bovine papillomavirus type 1, J. Mol. Biol 182: 541–544.PubMedCrossRefGoogle Scholar
  69. Thomas, M., Boiron, M., Tanzer, J., Levy, J. P., and Bernard, J., 1964, In vitro transformation of mice cells by bovine papilloma virus, Nature 202: 709–710.PubMedCrossRefGoogle Scholar
  70. Turek, L. P., Byrne, J. C., Lowy, D. R., Dvoretzky, I., Friedman, R. M., and Howley, P. M., 1982, Interferon induces morphologic reversion with elimination of extrachromosomal viral genomes in bovine papillomavirus transformed mouse cells, Proc. Natl. Acad. Sci. USA 79: 7914–7918.PubMedCrossRefGoogle Scholar
  71. Waldeck, W., Rösl, F., and Zentgraf, H., 1984, Origin of replication in episomal bovine papilloma virus type 1 DNA isolated from transformed cells, EMBO J. 3: 2173–2178.PubMedGoogle Scholar
  72. Watts, S. L., Ostrow, R. S., Phelps, W. C., Prince, J. T., and Faras, A. J., 1983, Free cottontail rabbit papillomavirus DNA persists in warts and carcinomas of infected rabbits and in cells in culture transformed with virus or viral DNA, Virology 125: 127–138.PubMedCrossRefGoogle Scholar
  73. Watts, S. L., Phelps, W. C., Ostrow, R. S., Zachow, K. R., and Faras, A. J., 1984, Cellular transformation of human papillomavirus DNA in vitro, Science 225: 634–636.PubMedCrossRefGoogle Scholar
  74. Weiher, H., and Botchan, M. R., 1984, An enhancer sequence from bovine papillomavirus DNA consists of two essential regions, Nucleic Acids Res. 12: 2901–2916.PubMedCrossRefGoogle Scholar
  75. Yang,Y.-C., Okayama, H., and Howley, P. M., 1985a, Bovine papillomavirus contains multiple transforming genes, Proc. Natl. Acad. Sci. USA 82: 1030–1033.PubMedCrossRefGoogle Scholar
  76. Yang, Y.-C., Spalholz, B. A., Rabson, M. S., and Howley, P. M., 1985b, Dissociation of transforming and transactivation functions for bovine papillomavirus type 1, Nature 318: 575–577.PubMedCrossRefGoogle Scholar
  77. Yasumoto, S., Burkhardt, A. L., Doniger, J., and DiPaolo, J. A., 1986, Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells, J. Virol. 57: 572–577.PubMedGoogle Scholar
  78. Yee, C., Krishnan-Hewlett, I., Baker, C. C., Schlegel, R., and Howley, P. M., 1985, Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines, Am. J. Pathol 119: 361–366.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Peter M. Howley
    • 1
  • Richard Schlegel
    • 1
  1. 1.Laboratory of Tumor Virus BiologyNational Cancer InstituteBethesdaUSA

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