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. 1993 Aug;67(8):4455–4463. doi: 10.1128/jvi.67.8.4455-4463.1993

Nuclear factor I and epithelial cell-specific transcription of human papillomavirus type 16.

D Apt 1, T Chong 1, Y Liu 1, H U Bernard 1
PMCID: PMC237828  PMID: 8392590

Abstract

The transcription of human papillomavirus type 16 (HPV-16) is mediated by the viral enhancer. Epithelial cell-specific activation is achieved by the cooperative interaction of apparently ubiquitous transcriptional factors. One of them, nuclear factor I (NFI), binds seven sites within the HPV-16 enhancer. Point mutations on enhancer fragments, which retain epithelial cell specificity, verify the functional contribution of NFI. In band shift experiments, the epithelial cell-derived NFI proteins CTF-1, CTF-2, and CTF-3 form a characteristic pattern of heterodimeric complexes which are observed in all epithelial cells tested. Divergence from this pattern in fibroblasts, liver cells, and lymphoid cells correlates with the lack of HPV-16 enhancer activation. The HPV-16 enhancer can be activated by CTF-1 in SL-2 cells, which lack NFI-like proteins. However, exogenous CTF-1 fails to overcome the inactivity of the viral enhancer in fibroblasts. Western immunoblot and supershift analysis shows that exogenously introduced CTF-1 proteins form different heterodimer complexes with the given subset of endogenous NFI proteins in epithelial or fibroblast cells. Polymerase chain reaction analysis and cDNA library screens identified the endogenous fibroblast type NFI as NFI-X, an NFI family member originally cloned from hamster liver cells. The strict correlation between the activation or lack of activation of the HPV-16 enhancer and cell-specific subsets of NFI proteins argues for the pivotal role of NFI binding sites in the epithelial cell-specific function of the viral enhancer.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amemiya K., Traub R., Durham L., Major E. O. Interaction of a nuclear factor-1-like protein with the regulatory region of the human polyomavirus JC virus. J Biol Chem. 1989 Apr 25;264(12):7025–7032. [PubMed] [Google Scholar]
  2. Cereghini S., Raymondjean M., Carranca A. G., Herbomel P., Yaniv M. Factors involved in control of tissue-specific expression of albumin gene. Cell. 1987 Aug 14;50(4):627–638. doi: 10.1016/0092-8674(87)90036-5. [DOI] [PubMed] [Google Scholar]
  3. Chakraborty T., Das G. C. Identification of HeLa cell nuclear factors that bind to and activate the early promoter of human polyomavirus BK in vitro. Mol Cell Biol. 1989 Sep;9(9):3821–3828. doi: 10.1128/mcb.9.9.3821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan W. K., Chong T., Bernard H. U., Klock G. Transcription of the transforming genes of the oncogenic human papillomavirus-16 is stimulated by tumor promotors through AP1 binding sites. Nucleic Acids Res. 1990 Feb 25;18(4):763–769. doi: 10.1093/nar/18.4.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chan W. K., Klock G., Bernard H. U. Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia. J Virol. 1989 Aug;63(8):3261–3269. doi: 10.1128/jvi.63.8.3261-3269.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chong T., Apt D., Gloss B., Isa M., Bernard H. U. 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. J Virol. 1991 Nov;65(11):5933–5943. doi: 10.1128/jvi.65.11.5933-5943.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chong T., Chan W. K., Bernard H. U. Transcriptional activation of human papillomavirus 16 by nuclear factor I, AP1, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers. Nucleic Acids Res. 1990 Feb 11;18(3):465–470. doi: 10.1093/nar/18.3.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Courey A. J., Tjian R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988 Dec 2;55(5):887–898. doi: 10.1016/0092-8674(88)90144-4. [DOI] [PubMed] [Google Scholar]
  9. Cripe T. P., Alderborn A., Anderson R. D., Parkkinen S., Bergman P., Haugen T. H., Pettersson U., Turek L. P. 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. 1990 May;2(5):450–463. [PubMed] [Google Scholar]
  10. Cripe T. P., Haugen T. H., Turk J. P., Tabatabai F., Schmid P. G., 3rd, Dürst M., Gissmann L., Roman A., Turek L. P. Transcriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer, and by viral E2 trans-activator and repressor gene products: implications for cervical carcinogenesis. EMBO J. 1987 Dec 1;6(12):3745–3753. doi: 10.1002/j.1460-2075.1987.tb02709.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Diamond M. I., Miner J. N., Yoshinaga S. K., Yamamoto K. R. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science. 1990 Sep 14;249(4974):1266–1272. doi: 10.1126/science.2119054. [DOI] [PubMed] [Google Scholar]
  12. Dollard S. C., Broker T. R., Chow L. T. Regulation of the human papillomavirus type 11 E6 promoter by viral and host transcription factors in primary human keratinocytes. J Virol. 1993 Mar;67(3):1721–1726. doi: 10.1128/jvi.67.3.1721-1726.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dynan W. S. Modularity in promoters and enhancers. Cell. 1989 Jul 14;58(1):1–4. doi: 10.1016/0092-8674(89)90393-0. [DOI] [PubMed] [Google Scholar]
  14. Falvey E., Schibler U. How are the regulators regulated? FASEB J. 1991 Mar 1;5(3):309–314. doi: 10.1096/fasebj.5.3.2001790. [DOI] [PubMed] [Google Scholar]
  15. Field J., Nikawa J., Broek D., MacDonald B., Rodgers L., Wilson I. A., Lerner R. A., Wigler M. Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method. Mol Cell Biol. 1988 May;8(5):2159–2165. doi: 10.1128/mcb.8.5.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gil G., Smith J. R., Goldstein J. L., Slaughter C. A., Orth K., Brown M. S., Osborne T. F. Multiple genes encode nuclear factor 1-like proteins that bind to the promoter for 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8963–8967. doi: 10.1073/pnas.85.23.8963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gloss B., Bernard H. U., Seedorf K., Klock G. The upstream regulatory region of the human papilloma virus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones. EMBO J. 1987 Dec 1;6(12):3735–3743. doi: 10.1002/j.1460-2075.1987.tb02708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gloss B., Chong T., Bernard H. U. Numerous nuclear proteins bind the long control region of human papillomavirus type 16: a subset of 6 of 23 DNase I-protected segments coincides with the location of the cell-type-specific enhancer. J Virol. 1989 Mar;63(3):1142–1152. doi: 10.1128/jvi.63.3.1142-1152.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gloss B., Yeo-Gloss M., Meisterenst M., Rogge L., Winnacker E. L., Bernard H. U. Clusters of nuclear factor I binding sites identify enhancers of several papillomaviruses but alone are not sufficient for enhancer function. Nucleic Acids Res. 1989 May 11;17(9):3519–3533. doi: 10.1093/nar/17.9.3519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Graves R. A., Tontonoz P., Ross S. R., Spiegelman B. M. Identification of a potent adipocyte-specific enhancer: involvement of an NF-1-like factor. Genes Dev. 1991 Mar;5(3):428–437. doi: 10.1101/gad.5.3.428. [DOI] [PubMed] [Google Scholar]
  21. Gronostajski R. M. Analysis of nuclear factor I binding to DNA using degenerate oligonucleotides. Nucleic Acids Res. 1986 Nov 25;14(22):9117–9132. doi: 10.1093/nar/14.22.9117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gutman A., Wasylyk B. Nuclear targets for transcription regulation by oncogenes. Trends Genet. 1991 Feb;7(2):49–54. doi: 10.1016/0168-9525(91)90231-E. [DOI] [PubMed] [Google Scholar]
  23. 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. 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. 1992 Jun;11(6):2271–2281. doi: 10.1002/j.1460-2075.1992.tb05286.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jackson S. P., MacDonald J. J., Lees-Miller S., Tjian R. GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell. 1990 Oct 5;63(1):155–165. doi: 10.1016/0092-8674(90)90296-q. [DOI] [PubMed] [Google Scholar]
  25. Jackson S. P., Tjian R. O-glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell. 1988 Oct 7;55(1):125–133. doi: 10.1016/0092-8674(88)90015-3. [DOI] [PubMed] [Google Scholar]
  26. Jones K. A., Kadonaga J. T., Rosenfeld P. J., Kelly T. J., Tjian R. A cellular DNA-binding protein that activates eukaryotic transcription and DNA replication. Cell. 1987 Jan 16;48(1):79–89. doi: 10.1016/0092-8674(87)90358-8. [DOI] [PubMed] [Google Scholar]
  27. Kumar K. U., Pater A., Pater M. M. Human JC virus perfect palindromic nuclear factor 1-binding sequences important for glial cell-specific expression in differentiating embryonal carcinoma cells. J Virol. 1993 Jan;67(1):572–576. doi: 10.1128/jvi.67.1.572-576.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mack D. H., Laimins L. A. A keratinocyte-specific transcription factor, KRF-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9102–9106. doi: 10.1073/pnas.88.20.9102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Martinez E., Dusserre Y., Wahli W., Mermod N. Synergistic transcriptional activation by CTF/NF-I and the estrogen receptor involves stabilized interactions with a limiting target factor. Mol Cell Biol. 1991 Jun;11(6):2937–2945. doi: 10.1128/mcb.11.6.2937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. McQuillan J. J., Rosen G. D., Birkenmeier T. M., Dean D. C. Identification of a protein that interacts with the nuclear factor-1 (NF-1) binding site in cells that do not express NF-1: comparison to NF-1, cellular distribution, and effect on transcription. Nucleic Acids Res. 1991 Dec 11;19(23):6627–6631. doi: 10.1093/nar/19.23.6627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mermod N., O'Neill E. A., Kelly T. J., Tjian R. The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Cell. 1989 Aug 25;58(4):741–753. doi: 10.1016/0092-8674(89)90108-6. [DOI] [PubMed] [Google Scholar]
  32. Mink S., Härtig E., Jennewein P., Doppler W., Cato A. C. A mammary cell-specific enhancer in mouse mammary tumor virus DNA is composed of multiple regulatory elements including binding sites for CTF/NFI and a novel transcription factor, mammary cell-activating factor. Mol Cell Biol. 1992 Nov;12(11):4906–4918. doi: 10.1128/mcb.12.11.4906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nagata K., Guggenheimer R. A., Hurwitz J. Specific binding of a cellular DNA replication protein to the origin of replication of adenovirus DNA. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6177–6181. doi: 10.1073/pnas.80.20.6177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nakshatri H., Pater M. M., Pater A. Ubiquitous and cell-type-specific protein interactions with human papillomavirus type 16 and type 18 enhancers. Virology. 1990 Sep;178(1):92–103. doi: 10.1016/0042-6822(90)90382-2. [DOI] [PubMed] [Google Scholar]
  35. Paonessa G., Gounari F., Frank R., Cortese R. Purification of a NF1-like DNA-binding protein from rat liver and cloning of the corresponding cDNA. EMBO J. 1988 Oct;7(10):3115–3123. doi: 10.1002/j.1460-2075.1988.tb03178.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Perkins K. K., Admon A., Patel N., Tjian R. The Drosophila Fos-related AP-1 protein is a developmentally regulated transcription factor. Genes Dev. 1990 May;4(5):822–834. doi: 10.1101/gad.4.5.822. [DOI] [PubMed] [Google Scholar]
  37. Plumb M., Fulton R., Breimer L., Stewart M., Willison K., Neil J. C. Nuclear factor 1 activates the feline leukemia virus long terminal repeat but is posttranscriptionally down-regulated in leukemia cell lines. J Virol. 1991 Apr;65(4):1991–1999. doi: 10.1128/jvi.65.4.1991-1999.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pugh B. F., Tjian R. Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell. 1990 Jun 29;61(7):1187–1197. doi: 10.1016/0092-8674(90)90683-6. [DOI] [PubMed] [Google Scholar]
  39. Rossi P., Karsenty G., Roberts A. B., Roche N. S., Sporn M. B., de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. doi: 10.1016/s0092-8674(88)80033-3. [DOI] [PubMed] [Google Scholar]
  40. Rupp R. A., Kruse U., Multhaup G., Göbel U., Beyreuther K., Sippel A. E. Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. Nucleic Acids Res. 1990 May 11;18(9):2607–2616. doi: 10.1093/nar/18.9.2607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Santoro C., Mermod N., Andrews P. C., Tjian R. A family of human CCAAT-box-binding proteins active in transcription and DNA replication: cloning and expression of multiple cDNAs. Nature. 1988 Jul 21;334(6179):218–224. doi: 10.1038/334218a0. [DOI] [PubMed] [Google Scholar]
  43. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schüle R., Muller M., Otsuka-Murakami H., Renkawitz R. Cooperativity of the glucocorticoid receptor and the CACCC-box binding factor. Nature. 1988 Mar 3;332(6159):87–90. doi: 10.1038/332087a0. [DOI] [PubMed] [Google Scholar]
  45. Sibbet G. J., Campo M. S. Multiple interactions between cellular factors and the non-coding region of human papillomavirus type 16. J Gen Virol. 1990 Nov;71(Pt 11):2699–2707. doi: 10.1099/0022-1317-71-11-2699. [DOI] [PubMed] [Google Scholar]
  46. Tanaka M., Herr W. Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell. 1990 Feb 9;60(3):375–386. doi: 10.1016/0092-8674(90)90589-7. [DOI] [PubMed] [Google Scholar]
  47. Tanese N., Pugh B. F., Tjian R. Coactivators for a proline-rich activator purified from the multisubunit human TFIID complex. Genes Dev. 1991 Dec;5(12A):2212–2224. doi: 10.1101/gad.5.12a.2212. [DOI] [PubMed] [Google Scholar]
  48. Thierry F., Spyrou G., Yaniv M., Howley P. Two AP1 sites binding JunB are essential for human papillomavirus type 18 transcription in keratinocytes. J Virol. 1992 Jun;66(6):3740–3748. doi: 10.1128/jvi.66.6.3740-3748.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zorbas H., Rein T., Krause A., Hoffmann K., Winnacker E. L. Nuclear factor I (NF I) binds to an NF I-type site but not to the CCAAT site in the human alpha-globin gene promoter. J Biol Chem. 1992 Apr 25;267(12):8478–8484. [PubMed] [Google Scholar]
  50. de Vries E., van Driel W., Tromp M., van Boom J., van der Vliet P. C. Adenovirus DNA replication in vitro: site-directed mutagenesis of the nuclear factor I binding site of the Ad2 origin. Nucleic Acids Res. 1985 Jul 11;13(13):4935–4952. doi: 10.1093/nar/13.13.4935. [DOI] [PMC free article] [PubMed] [Google Scholar]

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