1887

Abstract

The early genes E6 and E7 from human papillomaviruses (HPVs) play a key role in the development of cervical cancer. Modulation of E6 and E7 gene expression may alter tumour progression; therefore, modifiers of viral transcription such as hormones or growth factors are potential risk factors in cancer development. We have analysed the effects of epidermal growth factor (EGF) on E6/E7 mRNA from human papillomavirus type 16 (HPV-16) by Northern blot in two cell lines, SiHa cervical carcinoma cells, and HPK IA, an HPV-16-immortalized keratinocyte cell line. E6/E7 mRNA is EGF-inducible in SiHa cells, with the earliest response after 2 h. In contrast, in HPK IA cells no increase in E6/E7 RNA is observed, suggesting a differential EGF response of viral transcription in tumour cells compared with keratinocytes. We demonstrate that the cell type-specific HPV-16 enhancer is a target of EGF-induced signals, as its activity is amplified by EGF in SiHa cell transfections. However, when transfected into HPK IA keratinocytes, the viral enhancer shows no EGF response. The enhancer contains two binding sites for the transcription factor AP-1, a potential mediator of the EGF signalling cascade. Enhancer subfragments with single AP-1 binding sites are also EGF-responsive in SiHa cells. Mutating either AP-1 site in the complete enhancer decreases the EGF response, whereas a double mutation causes a complete loss of EGF regulation, suggesting that the EGF induction of HPV-16 early transcription requires AP-1 activation. We conclude that alterations of EGF responsiveness that increase viral oncogene expression may contribute to cervical cancer progression.

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1995-08-01
2021-10-22
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References

  1. Ahn N. G., Weiel J. E., Chan C. P., Krebs E. G. 1990; Identification of multiple epidermal growth factor-stimulated protein serine/threonine kinases from Swiss 3T3 cells. Journal of Biological Chemistry 265:11487–11494
    [Google Scholar]
  2. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. 1987; Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49:729–739
    [Google Scholar]
  3. Anzai Y., Gong Y., Holinka C. F., Murphy L. J., Murphy L. C., Kuramoto H., Gurpide E. 1992; Effects of transforming growth factors and regulation of their mRNA levels in two human endometrial adenocarcinoma cell lines. Journal of Steroid Biochemistry and Molecular Biology 42:449–155
    [Google Scholar]
  4. Baker C. C., Phelps W. C., Lindgren V., Braun M. J., Gonda M. A., Howley P. M. 1987; Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. Journal of Virology 61:962–971
    [Google Scholar]
  5. Bellas R. E., Bendor R., Farmer S. R. 1991; Epidermal growth factor activation of vinculin and β l-Integrin gene transcription in quiescent swiss 3T3 cells. Journal of Biological Chemistry 266:12008–12014
    [Google Scholar]
  6. Ben-Ari E. T., Bernstein L. R., Colburn N. H. 1992; Differential c-jun expression in response to tumor promoters in JB6 cells sensitive or resistant to neoplastic transformation. Molecular Carcinogenesis 5:62–74
    [Google Scholar]
  7. Bernard B. A., Bailly C., Lenoir M. C., Darmon M., Thierry F., Yaniv M. 1989; The human papillomavirus type 18 (HPV 18) E2 gene product is a repressor of the HPV 18 regulatory region in human keratinocytes. Journal of Virology 63:4317–4324
    [Google Scholar]
  8. Bosch F. X., Schwarz E., Boukamp P., Fusenig N. E., Bartsch D., zur Hausen H. 1990; Suppression in vivo of human papillomavirus type 18 E6-E7 gene expression in nontumorigenic HeLa x fibroblast hybrid cells. Journal of Virology 64:4743–4754
    [Google Scholar]
  9. Boshart M., Kluppel M., Schmidt A., Schutz G., Luckow B. H. 1992; CAT reporter constructs with low background activity. Gene 110:129–130
    [Google Scholar]
  10. Bouvard V., Matlashewski G., Gu Z. M., Storey A., Banks L. 1994; The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression. Virology 203:73–80
    [Google Scholar]
  11. Bravo R. 1990; Growth factor-responsive genes in fibroblasts. Cell Growth and Differentiation 1:305–309
    [Google Scholar]
  12. Carpenter G., Cohen S. 1990; Epidermal growth factor. Journal of Biological Chemistry 265:7709–7712
    [Google Scholar]
  13. Chan W. K., Klock G., Bernard H. U. 1989; Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia. Journal of Virology 63:3261–3269
    [Google Scholar]
  14. Chan W. K., Chong T., Bernard H. U., Klock G. 1990; Transcription of the transforming genes of the oncogenic human papillomavirus-16 is stimulated by tumor promotors through API binding sites. Nucleic Acids Research 18:763–769
    [Google Scholar]
  15. Chomczynski P., Sacchi N. 1987; Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162:156–159
    [Google Scholar]
  16. Chong T., Chan W. K., Bernard H. U. 1990; Transcriptional activation of human papillomavirus 16 by nuclear factor I, API, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers. Nucleic Acids Research 18:465–170
    [Google Scholar]
  17. Chong T., Apt D., Gloss B., Isa M., Bernard H. U. 1991; The enhancer of human papillomavirus type 16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription. Journal of Virology 65:5933–5943
    [Google Scholar]
  18. Chung J., Pelech S. L., Blenis J. 1991; Mitogen-activated swiss mouse 3T3 RSK kinases I and II are related to pp44mpk from sea star oocytes and participate in the regulation of pp90rsk activity. Proceedings of the National Academy of Sciences, USA 88:4981–4985
    [Google Scholar]
  19. Colige A. C., Lambert C. A., Nusgens B. V., Lapiere C. M. 1992; Effect of cell–cell and cell–matrix interactions on the response of fibroblasts to epidermal growth factor in vitro. Expression of collagen type I, collagenase, stromelysin and tissue inhibitor of metalloproteinases. Biochemical Journal 285:215–221
    [Google Scholar]
  20. Cripe T. P., Haugen T. H., Turk J. P., Tabatabai F., Schmid P. G., Durst M., Gissmann L., Roman A., Turek L. 1987; Transcriptional regulation of the human papillomavirus-16 E6–E7-promoter by a keratinocyte-dependent enhancer, and by viral E2 transactivator and repressor gene products: implications for cervical carcinogenesis. EMBO Journal 6:3745–3753
    [Google Scholar]
  21. Cripe T. P., Alderborn A., Anderson R. D., Parkkinen S., Bergman P., Haugen T. H., Petterson U., Turek L. P. 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 Biologist 2:450–463
    [Google Scholar]
  22. Curran T., Franza B. R. 1988; Fos and Jun: the AP-1 connection. Cell 55:395–397
    [Google Scholar]
  23. Czech M. P. 1989; Signal transmission by the insulin-like growth factors. Cell 59:235–238
    [Google Scholar]
  24. Davis R. J. 1993; The mitogen-activated protein kinase signal transduction pathway. Journal of Biological Chemistry 268:14553–14556
    [Google Scholar]
  25. Derynck R. 1992; The physiology of transforming growth factor- alpha. Advances in Cancer Research 58:27–52
    [Google Scholar]
  26. Dürst M., Dzarlieva-Petrusevska R. T., Boukamp P., Fusenig N. E., Gissmann L. 1987; Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus 16 DNA. Oncogene 1:215–256
    [Google Scholar]
  27. Dyson N., Howley P. M., Munger 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]
  28. Fabricant R. N., De Larco J. E., Todaro G. J. 1977; Nerve growth factor receptors on human melanoma cells in culture. Proceedings of the National Academy of Sciences, USA 74:565–569
    [Google Scholar]
  29. Franchini G., Mulloy J. C., Koralnik I. J., Lo Monico A., Sparkowski J. J., Andresson T., Goldstein D. J., Schlegel R. 1993; The human T-cell leukemia/lymphotropic virus type I pl21 protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. Journal of Virology 67:7701–7704
    [Google Scholar]
  30. Franklin C. C., Kraft A. S. 1992; Protein kinase C-independent activation of c-jun and c-fos transcription by epidermal growth factor. Biochimica et Biophysica Acta 1134:137–142
    [Google Scholar]
  31. Fuchs P. G., Girardi F., Pfister H. 1989; Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases. International Journal of Cancer 43:41–44
    [Google Scholar]
  32. Galloway D. A., McDougall J. K. 1989; Human papillomaviruses and carcinomas. Advances in Virus Research 37:125–171
    [Google Scholar]
  33. Gardner D. P., Shimizu N. 1994; Loss of cytotoxic effect of epidermal growth factor (EGF) on EGF receptor overexpressing cells is associated with attenuation of EGF receptor tyrosine kinase activity. Journal of Cell Physiology 158:245–255
    [Google Scholar]
  34. Gille H., Sharrocks A. D., Shaw P. E. 1992; Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358:414–417
    [Google Scholar]
  35. Gloss B., Bernard H. U., Seedorf K., Klock G. 1987; The upstream regulatory region of the human papillomavirus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones. EM BO Journal 6:3735–3743
    [Google Scholar]
  36. Gloss B., Chong T., Bernard H. U. 1989; Numerous nuclear proteins bind the long control region of human papillomavirus-16: a subset of 6 out of 23 DNase I-protected segments coincides with the location of the cell type specific enhancer. Journal of Virology 63:1142–1152
    [Google Scholar]
  37. Godley J. M., Brand S. I. 1989; Regulation of the gastrin promoter by epidermal growth factor and neuropeptides. Proceedings of the National Academy of Sciences, USA 86:3036–3040
    [Google Scholar]
  38. Haigler H., Ash J. F., Singer S. J., Cohen S. 1978; Visualization by fluorescence of the binding and internalization of epidermal growth factor in human carcinoma cells A-431. Proceedings of the National Academy of Sciences, USA 75:3317–3321
    [Google Scholar]
  39. Hajnal A., Klemfnz R., Schafer R. 1994; Subtraction cloning of H-revl07, a gene specifically expressed in H-ras resistant fibroblasts. Oncogene 9:479–490
    [Google Scholar]
  40. Humbel R. E. 1990; Insulin-like growth factors I and II. European Journal of Biochemistry 190:445–462
    [Google Scholar]
  41. Ishiji T., Lace M. J., Parkkinen S., Anderson R. D., Haugen T. H., Cripe T. P., Xiao J.-H., Davidson I., Chambon P., Turek L. P. 1992; Transcriptional enhancer factor (TEF)-l and its cell-specific co-activator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells. EMBO Journal 11:2271–2281
    [Google Scholar]
  42. Katayama K., Seyer J. M., Raghow R., Kang A. H. 1991; Regulation of extracellular matrix production by chemically synthesized subfragments of type-I collagen carboxy propeptide. Biochemistry 30:7097–7104
    [Google Scholar]
  43. Klein S. B., Fisher G. J., Jensen T. C., Mendelsohn J., Voorhees J. J., Elder J. T. 1992; Regulation of TGF-alpha expression in human keratinocytes: PKC-dependent and -independent pathways. Journal of Cell Physiology 151:326–336
    [Google Scholar]
  44. Kolch W., Heidecker G., Kocks G., Hummel R., Vahidi H., Mischak H., Finkenzeller G., Marme D., Rapp U. R. 1993; Protein kinase Cα activates RAF-1 by direct phosphorylation. Nature 364:249–251
    [Google Scholar]
  45. Kumatori A., Nakamura T., Ichihara A. 1991; Cell-density dependent expression of the c-myc gene in primary cultured rat hepatocytes. Biochemical and Biophysical Research Communications 178:480–485
    [Google Scholar]
  46. Kunkel T. A., Roberts J. D., Zakour R. A. 1987; Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods in Enzymology 154:367–382
    [Google Scholar]
  47. Kyo S., Inoue M., Nishio Y., Nakanishi K., Akira S., Inoue H., Yutsodu M., Tanizawa O., Hakura A. 1993; NF-IL6 represses early gene expression of human papillomavirus type 16 through binding to the noncoding region. Journal of Virology 67:1058–1066
    [Google Scholar]
  48. Leechanachai P., Banks L., Moreau F., Matlashewski G. 1992; The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene 7:19–25
    [Google Scholar]
  49. Lenormand P., Pribnow D., Rodland K. D., Magun B. E. 1992; Identification of a novel enhancer element mediating calcium- dependent induction of gene expression in response to either epidermal growth factor or activation of protein kinase C. Molecular and Cellular Biology 12:2793–2803
    [Google Scholar]
  50. Li J., Beer D. G. 1993; Ki-ras mRNA regulation in untransformed mouse lung cells. Molecular Carcinogenesis 8:193–201
    [Google Scholar]
  51. List H. J., Patzel V., Zeidler U., Schopen A., Rühl G., Stollwerk J., Klock G. 1994; Methylation sensitivity of the enhancer from the human papillomavirus type 16. Journal of Biological Chemistry 269:11902–11911
    [Google Scholar]
  52. Martin P., Vass W. C., Schiller J. T., Lowy D. R., Velu T. J. 1989; The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors. Cell 59:21–32
    [Google Scholar]
  53. Matlashewski G., Schneider J., Banks L., Jones N., Murray A., Crawford L. 1987; Human papillomavirus type 16 DNA cooperates with activated ras in transforming primary cells. EMBO Journal 6:1741–1746
    [Google Scholar]
  54. 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
    [Google Scholar]
  55. Mcallister B. S., Leeb L. L., Javors M. A., Olson M. S. 1993; Bradykinin receptors and signal transduction pathways in human fibroblasts: integral role for extracellular calcium. Archives of Biochemistry and Biophysics 304:294–301
    [Google Scholar]
  56. McCormick F. 1993; How receptors turn ras on. Nature 363:15–16
    [Google Scholar]
  57. May M., Dong X. P., Beyer-Finkler E., Stubenrauch F., Fuchs P. G., Pfister H. 1994; The E6/E7 promoter of extrachromosomal HPV 16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. EMBO Journal 13:1460–1466
    [Google Scholar]
  58. Meyers C., Frattini M. G., Hudson J. B., Laimins L. A. 1992; Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation. Science 257:971–973
    [Google Scholar]
  59. Mitrani-Rosenbaum S., Tsvielli R., Tur-Kaspa R. 1989; Oestrogen stimulates differential transcription of human papillomavirus in SiHa cervical carcinoma cells. Journal of General Virology 70:2227–2232
    [Google Scholar]
  60. Murthy U., Basu A., Rodeck U., Herlyn M., Ross A. H., Das M. 1987; Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide. Archives of Biochemistry and Biophysics 252:549–560
    [Google Scholar]
  61. Niimi S., Hayakawa T., Tanaka A. 1991; Effect of cell density on induction of growth hormone receptors by dexamethasone in primary cultured rat hepatocytes. Biochemical and Biophysical Research Communications 174:928–933
    [Google Scholar]
  62. Offord E. A., Beard P. 1990; A member of the activator protein 1 family found in keratinocytes but not in fibroblasts required for transformation from a human papillomavirus type 18 promoter. Journal of Virology 64:4792–4798
    [Google Scholar]
  63. Pelech S. L., Sanghera J. S. 1992; MAP kinases: charting the regulatory pathways. Science 257:1355–1356
    [Google Scholar]
  64. Pim D., Collins M., Banks L. 1992; Human papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptor. Oncogene 7:27–32
    [Google Scholar]
  65. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. 1991; Phosphorylation of c-jun mediated by MAP kinases. Nature 353:670–674
    [Google Scholar]
  66. Quantin B., Breathnach R. 1988; Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. Nature 334:538–539
    [Google Scholar]
  67. Resing K. A., al Alawi N., Blomquist C., Fleckman P., Dale B. A. 1993; Independent regulation of two cytoplasmic processing stages of the intermediate filament-associated protein filaggrin and role of Ca2+ in the second stage. Journal of Biological Chemistry 268:25139–25145
    [Google Scholar]
  68. Romanczuk H., Thierry F., Howley P. M. 1990; Mutational analysis of cis elements in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoter. Journal of Virology 64:2849–2859
    [Google Scholar]
  69. Rose J. K., Buonocore L., Whitt M. A. 1991; A new cationic liposome reagent mediating nearly quantitative transfection of animal cells. BioTechniques 10:520–525
    [Google Scholar]
  70. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. 1990; The oncoprotein encoded by human papillomavirus types 16 and 18 promotes degradation of p53. Cell 63:1129–1136
    [Google Scholar]
  71. Schneider-Maunouri S., Croissant O., Orth G. 1987; Integration of human papillomavirus type 16 DNA sequences: a possible early event in the progression of genital tumours. Journal of Virology 61:3295–3298
    [Google Scholar]
  72. Schwarz E., Freese U. K., 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
    [Google Scholar]
  73. Sedman S. A., Barbosa M. S., Vass W. C., Hubbert N. L., Haas J. A., Lowy D. R., Schiller J. T. 1991; The full-length E6 protein of human papillomavirus type 6 has transforming and transactivating activities and cooperates with E7 to immortalize keratino-cytes in culture. Journal of Virology 65:4860–4866
    [Google Scholar]
  74. Sibbet G. J., Campo M. S. 1990; Multiple interactions between cellular factors and the non-coding region of human papillomavirus type 16. Journal of General Virology 71:2699–2707
    [Google Scholar]
  75. Smeal T., Binetruy B., Mercola D., Grover-Bardwick A., Heidecker G., Rapp U. R., Karin M. 1992; Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Molecular and Cellular Biology 12:3507–3513
    [Google Scholar]
  76. Smits P. H. M., Smits H. L., Jebbink M. F., ter Schegget J. 1990; The short arm of chromosome 11 likely is involved in the regulation of the human papillomavirus type 16 early enhancer- promoter and in the suppression of the transforming activity of the viral DNA. Virology 176:158–165
    [Google Scholar]
  77. Stewart A. F., Herrera R. E., Nordheim A. 1990; Rapid induction of c-fos transcription reveals quantitative linkage of RNA polymerase II and topoisomerase I. Cell 60:141–149
    [Google Scholar]
  78. Straight S. W., Hinkle P. M., Jewers R. J., McCance D. J. 1993; The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. Journal of Virology 67:4521–1532
    [Google Scholar]
  79. Teifel M., Friedl P. 1995; A new lipid mixture for efficient lipid- mediated transfection of BHK cells. BioTechniques (in press)
    [Google Scholar]
  80. Thierry F., Spyrou G., Yaniv M., Howley P. 1992; Two API sites binding JunB are essential for human papillomavirus type 18 transcription in keratinocytes. Journal of Virology 66:3740–3748
    [Google Scholar]
  81. Ullrich A., Schlessinger J. 1990; Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212
    [Google Scholar]
  82. Vambutas A., Di Lorenzo T. P., Steinberg B. M. 1993; Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. Cancer Research 53:910–914
    [Google Scholar]
  83. Williams G. T., Lau L. F. 1993; Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Molecular and Cellular Biology 13:6124–6136
    [Google Scholar]
  84. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. 1992; Ras mediates nerve growth factor receptor modulation of three signal- transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68:1041–1050
    [Google Scholar]
  85. Yasumoto S., Taniguchi A., Sohma K. 1991; Epidermal growth factor (EGF) elicits down-regulation 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. Journal of Virology 65:2000–2009
    [Google Scholar]
  86. Zur Hausen H. 1991; Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184:9–13
    [Google Scholar]
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