1887

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Volume 84, Issue 12

A promoter within the E6 ORF of human papillomavirus type 16 contributes to the expression of the E7 oncoprotein from a monocistronic mRNA Free

Abstract

Human papillomavirus type 16 (HPV-16) has the capacity to transform human primary keratinocytes. Maintenance of the transformed phenotype requires constitutive expression of the oncoproteins E6 and E7. The low-risk HPV types express E7 from monocistronic mRNA, but for the high-risk types, no mRNA that encodes E7 as the first open reading frame (ORF) has been identified. We recently identified a transcription initiation site within the E6 ORF of HPV-16 at nt 542. In the present study we have characterized the P542 promoter, which putatively controls monocistronic expression of E7. The monocistronic mRNA is not very abundant, but we have shown that an E7–luciferase fusion protein can be expressed in SiHa cells from a monocistronic HPV-16 transcript initiated at nt 542. The monocistronic mRNA expresses E7–luciferase more efficiently than the most abundant -like mRNA E6*IE7, initiated by P97 and spliced from nt 226 to 409. Furthermore, the translation initiation of E7 is most abundant from the monocistronic mRNA. We have also shown that the P542 promoter is downregulated by the transcription factor activator protein 4 (AP-4) and the differentiation-dependent factor hSkn-1a, both binding downstream of the transcription initiation site. In conclusion, we have found that P542 is a relatively weak promoter compared with P97 and may be downregulated in differentiated epithelial cells.

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2003-12-01
2024-04-24
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References

  1. Andersen B., Schonemann M. D., Flynn S. E., Pearse R. V., Singh H., Rosenfeld M. G. 1993; Skn-1a and Skn-1i: two functionally distinct Oct-2-related factors expressed in epidermis. Science 260:78–82
     [Google Scholar]
  2. Andersen B., Weinberg W. C., Rennekampff O. 8 other authors 1997; Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes Dev 11:1873–1884
     [Google Scholar]
  3. Baker C., Calef C. 1995 Human Papillomaviruses: a Compilation and Analysis of Nucleic Acid and Amino Acid Sequences Los Alamos, NM: Los Alamos National Library;
     [Google Scholar]
  4. Bohm S., Wilczynski S. P., Pfister H., Iftner T. 1993; The predominant mRNA class in HPV16-infected genital neoplasias does not encode the E6 or the E7 protein. Int J Cancer 55:791–798
     [Google Scholar]
  5. Braunstein T. H., Madsen B. S., Gavnholt B., Rosenstierne M. W., Koefoed J. C., Norrild B. 1999; Identification of a new promoter in the early region of the human papillomavirus type 16 genome. J Gen Virol 80:3241–3250
     [Google Scholar]
  6. de Villiers E. M. 1994; Human pathogenic papillomavirus types: an update. Curr Top Microbiol Immunol 186:1–12
     [Google Scholar]
  7. Dignam J. D., Lebovitz R. M., Roeder R. G. 1983; Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489
     [Google Scholar]
  8. Doorbar J., Parton A., Hartley K., Banks L., Crook T., Stanley M., Crawford L. 1990; Detection of novel splicing patterns in a HPV16-containing keratinocyte cell line. Virology 178:254–262
     [Google Scholar]
  9. 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]
  10. Ellenberger T., Fass D., Arnaud M., Harrison S. C. 1994; Crystal structure of transcription factor E47: E-box recognition by a basic region helix–loop–helix dimer. Genes Dev 8:970–980
     [Google Scholar]
  11. Gloss B., Bernard H. U. 1990; The E6/E7 promoter of human papillomavirus type 16 is activated in the absence of E2 proteins by a sequence-aberrant Sp1 distal element. J Virol 64:5577–5584
     [Google Scholar]
  12. Grassmann K., Rapp B., Maschek H., Petry K. U., Iftner T. 1996; Identification of a differentiation-inducible promoter in the E7 open reading frame of human papillomavirus type 16 (HPV-16) in raft cultures of a new cell line containing high copy numbers of episomal HPV-16 DNA. J Virol 70:2339–2349
     [Google Scholar]
  13. Higgins G. D., Uzelin D. M., Phillips G. E., McEvoy P., Marin R., Burrell C. J. 1992; Transcription patterns of human papillomavirus type 16 in genital intraepithelial neoplasia: evidence for promoter usage within the E7 open reading frame during epithelial differentiation. J Gen Virol 73:2047–2057
     [Google Scholar]
  14. Hu Y. F., Luscher B., Admon A., Mermod N., Tjian R. 1990; Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev 4:1741–1752
     [Google Scholar]
  15. International Agency for Research on Cancer 1995; Human Papillomaviruses . IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, WHO vol 64
     [Google Scholar]
  16. Ishiji T. 2000; Molecular mechanism of carcinogenesis by human papillomavirus-16. J Dermatol 27:73–86
     [Google Scholar]
  17. Kozak M. 1989; Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol Cell Biol 9:5134–5142
     [Google Scholar]
  18. Kukimoto I., Kanda T. 2001; Displacement of YY1 by differentiation-specific transcription factor hSkn-1a activates the P(670) promoter of human papillomavirus type 16. J Virol 75:9302–9311
     [Google Scholar]
  19. Lawrenz-Smith S. C., Thomas C. Y. 1995; The E47 transcription factor binds to the enhancer sequences of recombinant murine leukemia viruses and influences enhancer function. J Virol 69:4142–4148
     [Google Scholar]
  20. Leach K. M., Vieira K. F., Kang S. H., Aslanian A., Teichmann M., Roeder R. G., Bungert J. 2003; Characterization of the human beta-globin downstream promoter region. Nucleic Acids Res 31:1292–1301
     [Google Scholar]
  21. Lo K., Smale S. T. 1996; Generality of a functional initiator consensus sequence. Gene 182:13–22
     [Google Scholar]
  22. McGlennen R. C. 2000; Human papillomavirus oncogenesis. Clin Lab Med 20:383–406
     [Google Scholar]
  23. Mermod N., Williams T. J., Tjian R. 1988; Enhancer binding factors AP-4 and AP-1 act in concert to activate SV40 late transcription in vitro. Nature 332:557–561
     [Google Scholar]
  24. Munoz N. 2000; Human papillomavirus and cancer: the epidemiological evidence. J Clin Virol 19:1–5
     [Google Scholar]
  25. Murre C., McCaw P. S., Baltimore D. 1989a; A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56:777–783
     [Google Scholar]
  26. Murre C., McCaw P. S., Vaessin H. & 7 other authors (1989b). Interactions between heterologous helix–loop–helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58:537–544
     [Google Scholar]
  27. O'Connor M. J., Tan S. H., Tan C. H., Bernard H. U. 1996; YY1 represses human papillomavirus type 16 transcription by quenching AP-1 activity. J Virol 70:6529–6539
     [Google Scholar]
  28. O'Connor M. J., Stunkel W., Zimmermann H., Koh C. H., Bernard H. U. 1998; A novel YY1-independent silencer represses the activity of the human papillomavirus type 16 enhancer. J Virol 72:10083–10092
     [Google Scholar]
  29. Ou S. H., Garcia-Martinez L. F., Paulssen E. J., Gaynor R. B. 1994; Role of flanking E box motifs in human immunodeficiency virus type 1 TATA element function. J Virol 68:7188–7199
     [Google Scholar]
  30. Phelps W. C., Barnes J. A., Lobe D. C. 1998; Molecular targets for human papillomaviruses: prospects for antiviral therapy. Antivir Chem Chemother 9:359–377
     [Google Scholar]
  31. Rohlfs M., Winkenbach S., Meyer S., Rupp T., Durst M. 1991; Viral transcription in human keratinocyte cell lines immortalized by human papillomavirus type-16. Virology 183:331–342
     [Google Scholar]
  32. Rosenstierne M. W., Vinther J., Hansen C. N., Prydsoe M., Norrild B. 2003; Identification and characterization of a cluster of transcription start sites located in the E6 ORF of human papillomavirus type 16. J Gen Virol 84:2909–2920
     [Google Scholar]
  33. Rösl F., Das B. C., Lengert M., Geletneky K., zur Hausen H. 1997; Antioxidant-induced changes of the AP-1 transcription complex are paralleled by a selective suppression of human papillomavirus transcription. J Virol 71:362–370
     [Google Scholar]
  34. Scheffner M., Huibregtse J. M., Vierstra R. D., Howley P. M. 1993; The HPV-16 E6 and E6–AP complex functions as a ubiquitin–protein ligase in the ubiquitination of p53. Cell 75:495–505
     [Google Scholar]
  35. Smotkin D., Wettstein F. O. 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 U S A 83:4680–4684
     [Google Scholar]
  36. Smotkin D., Prokoph H., Wettstein F. O. 1989; Oncogenic and nononcogenic human genital papillomaviruses generate the E7 mRNA by different mechanisms. J Virol 63:1441–1447
     [Google Scholar]
  37. Stacey S. N., Jordan D., Snijders P. J., Mackett M., Walboomers J. M., Arrand J. R. 1995; Translation of the human papillomavirus type 16 E7 oncoprotein from bicistronic mRNA is independent of splicing events within the E6 open reading frame. J Virol 69:7023–7031
     [Google Scholar]
  38. Stacey S. N., Jordan D., Williamson A. J., Brown M., Coote J. H., Arrand J. R. 2000; Leaky scanning is the predominant mechanism for translation of human papillomavirus type 16 E7 oncoprotein from E6/E7 bicistronic mRNA. J Virol 74:7284–7297
     [Google Scholar]
  39. Stoppler H., Stoppler M. C., Johnson E., Simbulan-Rosenthal C. M., Smulson M. E., Iyer S., Rosenthal D. S., Schlegel R. 1998; The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis. Oncogene 17:1207–1214
     [Google Scholar]
  40. Stunkel W., Huang Z., Tan S. H., O'Connor M. J., Bernard H. U. 2000; Nuclear matrix attachment regions of human papillomavirus type 16 repress or activate the E6 promoter, depending on the physical state of the viral DNA. J Virol 74:2489–2501
     [Google Scholar]
  41. Tan S. H., Leong L. E., Walker P. A., Bernard H. U. 1994a; The human papillomavirus type 16 E2 transcription factor binds with low cooperativity to two flanking sites and represses the E6 promoter through displacement of Sp1 and TFIID. J Virol 68:6411–6420
     [Google Scholar]
  42. Tan T. M., Gloss B., Bernard H. U., Ting R. C. 1994b; Mechanism of translation of the bicistronic mRNA encoding human papillomavirus type 16 E6–E7 genes. J Gen Virol 75:2663–2670
     [Google Scholar]
  43. Tan S. H., Baker C. C., Stunkel W., Bernard H. U. 2003; A transcriptional initiator overlaps with a conserved YY1 binding site in the long control region of human papillomavirus type 16. Virology 305:486–501
     [Google Scholar]
  44. Vousden K. 1993; Interactions of human papillomavirus transforming proteins with the products of tumor suppressor genes. FASEB J 7:872–879
     [Google Scholar]
  45. Walboomers J. M., Jacobs M. V., Manos M. M. 7 other authors 1999; Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19
     [Google Scholar]
  46. Weis L., Reinberg D. 1997; Accurate positioning of RNA polymerase II on a natural TATA-less promoter is independent of TATA-binding-protein-associated factors and initiator-binding proteins. Mol Cell Biol 17:2973–2984
     [Google Scholar]
  47. Werness B. A., Levine A. J., Howley P. M. 1990; Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79
     [Google Scholar]
  48. zur Hausen H. 1996; Papillomavirus infections – a major cause of human cancers. Biochim Biophys Acta 1288:F55–78
     [Google Scholar]
  49. zur Hausen H. 1999; Papillomaviruses in human cancers. Proc Assoc Am Physicians 111:581–587
     [Google Scholar]
  50. zur Hausen H. 2000; Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698
     [Google Scholar]
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A promoter within the E6 ORF of human papillomavirus type 16 contributes to the expression of the E7 oncoprotein from a monocistronic mRNA
J. Gen. Virol. 84, 3429 (2003); https://doi.org/10.1099/vir.0.19250-0
/content/journal/jgv/10.1099/vir.0.19250-0
/content/journal/jgv/10.1099/vir.0.19250-0
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