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J Virol. 1996 Oct; 70(10): 6529–6539.
PMCID: PMC190693

YY1 represses human papillomavirus type 16 transcription by quenching AP-1 activity.


YY1 is a multifunctional transcription factor that has been shown to regulate the expression of a number of cellular and viral genes, including the human papillomavirus (HPV) oncogenes E6 and E7. In this study, we have analyzed the YY1-mediated repression of the HPV type 16 (HPV-16) E6-E7 promoter. A systematic analysis to identify YY1 sites present in the HPV-16 long control region showed that of 30 potential YY1 binding motifs, 24 bound purified recombinant YY1 protein, but only 10 of these were able to bind YY1 when nuclear extracts of HeLa cells were used. Of these, only a cluster of five sites, located in the vicinity of an AP-1 motif, were found to be responsible for repressing the HPV-16 P97 promoter. All five sites were required for repression, the mutation of any one site giving rise to a four- to sixfold increase in transcriptional activity. The target for YY1-mediated repression was identified as being a highly conserved AP-1 site, and we propose that AP-1 may represent a common target for YY1 repression. We also provide data demonstrating that YY1 can bind the transcriptional coactivator CREB-binding protein and propose a potentially novel mechanism by which YY1 represses AP-1 activity as a result of this YY1-CREB-binding protein interaction.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Apt D, Chong T, Liu Y, Bernard HU. Nuclear factor I and epithelial cell-specific transcription of human papillomavirus type 16. J Virol. 1993 Aug;67(8):4455–4463. [PMC free article] [PubMed]
  • Apt D, Liu Y, Bernard HU. Cloning and functional analysis of spliced isoforms of human nuclear factor I-X: interference with transcriptional activation by NFI/CTF in a cell-type specific manner. Nucleic Acids Res. 1994 Sep 25;22(19):3825–3833. [PMC free article] [PubMed]
  • Arany Z, Sellers WR, Livingston DM, Eckner R. E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators. Cell. 1994 Jun 17;77(6):799–800. [PubMed]
  • Bannister AJ, Kouzarides T. CBP-induced stimulation of c-Fos activity is abrogated by E1A. EMBO J. 1995 Oct 2;14(19):4758–4762. [PMC free article] [PubMed]
  • Bannister AJ, Oehler T, Wilhelm D, Angel P, Kouzarides T. Stimulation of c-Jun activity by CBP: c-Jun residues Ser63/73 are required for CBP induced stimulation in vivo and CBP binding in vitro. Oncogene. 1995 Dec 21;11(12):2509–2514. [PubMed]
  • Bauknecht T, Angel P, Royer HD, zur Hausen H. Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO J. 1992 Dec;11(12):4607–4617. [PMC free article] [PubMed]
  • Bauknecht T, Jundt F, Herr I, Oehler T, Delius H, Shi Y, Angel P, Zur Hausen H. A switch region determines the cell type-specific positive or negative action of YY1 on the activity of the human papillomavirus type 18 promoter. J Virol. 1995 Jan;69(1):1–12. [PMC free article] [PubMed]
  • Bernard HU, Apt D. Transcriptional control and cell type specificity of HPV gene expression. Arch Dermatol. 1994 Feb;130(2):210–215. [PubMed]
  • Böhm S, Wilczynski SP, Pfister H, Iftner T. The predominant mRNA class in HPV16-infected genital neoplasias does not encode the E6 or the E7 protein. Int J Cancer. 1993 Nov 11;55(5):791–798. [PubMed]
  • Chan WK, Chong T, Bernard HU, 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. [PMC free article] [PubMed]
  • Chan WK, Klock G, Bernard HU. 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. [PMC free article] [PubMed]
  • Chen S, Mills L, Perry P, Riddle S, Wobig R, Lown R, Millette RL. Transactivation of the major capsid protein gene of herpes simplex virus type 1 requires a cellular transcription factor. J Virol. 1992 Jul;66(7):4304–4314. [PMC free article] [PubMed]
  • Chesters PM, Vousden KH, Edmonds C, McCance DJ. Analysis of human papillomavirus type 16 open reading frame E7 immortalizing function in rat embryo fibroblast cells. J Gen Virol. 1990 Feb;71(Pt 2):449–453. [PubMed]
  • Chevallier-Greco A, Manet E, Chavrier P, Mosnier C, Daillie J, Sergeant A. Both Epstein-Barr virus (EBV)-encoded trans-acting factors, EB1 and EB2, are required to activate transcription from an EBV early promoter. EMBO J. 1986 Dec 1;5(12):3243–3249. [PMC free article] [PubMed]
  • Chiang CM, Roeder RG. Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators. Science. 1995 Jan 27;267(5197):531–536. [PubMed]
  • Choo KB, Pan CC, Liu MS, Ng HT, Chen CP, Lee YN, Chao CF, Meng CL, Yeh MY, Han SH. Presence of episomal and integrated human papillomavirus DNA sequences in cervical carcinoma. J Med Virol. 1987 Feb;21(2):101–107. [PubMed]
  • Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993 Oct 28;365(6449):855–859. [PubMed]
  • Cripe TP, Alderborn A, Anderson RD, Parkkinen S, Bergman P, Haugen TH, Pettersson U, Turek LP. 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]
  • Cripe TP, Haugen TH, Turk JP, Tabatabai F, Schmid PG, 3rd, Dürst M, Gissmann L, Roman A, Turek LP. 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. [PMC free article] [PubMed]
  • Cullen AP, Reid R, Campion M, Lörincz AT. Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasm. J Virol. 1991 Feb;65(2):606–612. [PMC free article] [PubMed]
  • Dong XP, Stubenrauch F, Beyer-Finkler E, Pfister H. Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. Int J Cancer. 1994 Sep 15;58(6):803–808. [PubMed]
  • Dostatni N, Lambert PF, Sousa R, Ham J, Howley PM, Yaniv M. The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. Genes Dev. 1991 Sep;5(9):1657–1671. [PubMed]
  • Flanagan JR, Becker KG, Ennist DL, Gleason SL, Driggers PH, Levi BZ, Appella E, Ozato K. Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus. Mol Cell Biol. 1992 Jan;12(1):38–44. [PMC free article] [PubMed]
  • Fuchs PG, Girardi F, Pfister H. Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases? Int J Cancer. 1989 Jan 15;43(1):41–44. [PubMed]
  • Galloway DA, McDougall JK. Human papillomaviruses and carcinomas. Adv Virus Res. 1989;37:125–171. [PubMed]
  • Gius D, Laimins LA. Activation of human papillomavirus type 18 gene expression by herpes simplex virus type 1 viral transactivators and a phorbol ester. J Virol. 1989 Feb;63(2):555–563. [PMC free article] [PubMed]
  • Gloss B, Bernard HU. 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. 1990 Nov;64(11):5577–5584. [PMC free article] [PubMed]
  • Gloss B, Bernard HU, 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. [PMC free article] [PubMed]
  • Gloss B, Chong T, Bernard HU. 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. [PMC free article] [PubMed]
  • Gloss B, Yeo-Gloss M, Meisterenst M, Rogge L, Winnacker EL, Bernard HU. 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. [PMC free article] [PubMed]
  • Gorman CM, Moffat LF, Howard BH. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. [PMC free article] [PubMed]
  • Gualberto A, LePage D, Pons G, Mader SL, Park K, Atchison ML, Walsh K. Functional antagonism between YY1 and the serum response factor. Mol Cell Biol. 1992 Sep;12(9):4209–4214. [PMC free article] [PubMed]
  • Hahn S. The Yin and the Yang of mammalian transcription. Curr Biol. 1992 Mar;2(3):152–154. [PubMed]
  • Hariharan N, Kelley DE, Perry RP. Delta, a transcription factor that binds to downstream elements in several polymerase II promoters, is a functionally versatile zinc finger protein. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9799–9803. [PMC free article] [PubMed]
  • Higgins GD, Uzelin DM, Phillips GE, Burrell CJ. Presence and distribution of human papillomavirus sense and antisense RNA transcripts in genital cancers. J Gen Virol. 1991 Apr;72(Pt 4):885–895. [PubMed]
  • Higgins GD, Uzelin DM, Phillips GE, McEvoy P, Marin R, Burrell CJ. 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. 1992 Aug;73(Pt 8):2047–2057. [PubMed]
  • Hyde-DeRuyscher RP, Jennings E, Shenk T. DNA binding sites for the transcriptional activator/repressor YY1. Nucleic Acids Res. 1995 Nov 11;23(21):4457–4465. [PMC free article] [PubMed]
  • Ishiji T, Lace MJ, Parkkinen S, Anderson RD, Haugen TH, Cripe TP, Xiao JH, Davidson I, Chambon P, Turek LP. 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. [PMC free article] [PubMed]
  • Lee JS, Galvin KM, See RH, Eckner R, Livingston D, Moran E, Shi Y. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 1995 May 15;9(10):1188–1198. [PubMed]
  • Lee JS, See RH, Galvin KM, Wang J, Shi Y. Functional interactions between YY1 and adenovirus E1A. Nucleic Acids Res. 1995 Mar 25;23(6):925–931. [PMC free article] [PubMed]
  • Lee TC, Shi Y, Schwartz RJ. Displacement of BrdUrd-induced YY1 by serum response factor activates skeletal alpha-actin transcription in embryonic myoblasts. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9814–9818. [PMC free article] [PubMed]
  • Lewis BA, Tullis G, Seto E, Horikoshi N, Weinmann R, Shenk T. Adenovirus E1A proteins interact with the cellular YY1 transcription factor. J Virol. 1995 Mar;69(3):1628–1636. [PMC free article] [PubMed]
  • Liu R, Baillie J, Sissons JG, Sinclair JH. The transcription factor YY1 binds to negative regulatory elements in the human cytomegalovirus major immediate early enhancer/promoter and mediates repression in non-permissive cells. Nucleic Acids Res. 1994 Jul 11;22(13):2453–2459. [PMC free article] [PubMed]
  • Lu SY, Rodriguez M, Liao WS. YY1 represses rat serum amyloid A1 gene transcription and is antagonized by NF-kappa B during acute-phase response. Mol Cell Biol. 1994 Sep;14(9):6253–6263. [PMC free article] [PubMed]
  • Lundblad JR, Kwok RP, Laurance ME, Harter ML, Goodman RH. Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. Nature. 1995 Mar 2;374(6517):85–88. [PubMed]
  • Margolis DM, Somasundaran M, Green MR. Human transcription factor YY1 represses human immunodeficiency virus type 1 transcription and virion production. J Virol. 1994 Feb;68(2):905–910. [PMC free article] [PubMed]
  • May M, Dong XP, Beyer-Finkler E, Stubenrauch F, Fuchs PG, Pfister H. The E6/E7 promoter of extrachromosomal HPV16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. EMBO J. 1994 Mar 15;13(6):1460–1466. [PMC free article] [PubMed]
  • McBride AA, Romanczuk H, Howley PM. The papillomavirus E2 regulatory proteins. J Biol Chem. 1991 Oct 5;266(28):18411–18414. [PubMed]
  • Meier VS, Groner B. The nuclear factor YY1 participates in repression of the beta-casein gene promoter in mammary epithelial cells and is counteracted by mammary gland factor during lactogenic hormone induction. Mol Cell Biol. 1994 Jan;14(1):128–137. [PMC free article] [PubMed]
  • Montalvo EA, Shi Y, Shenk TE, Levine AJ. Negative regulation of the BZLF1 promoter of Epstein-Barr virus. J Virol. 1991 Jul;65(7):3647–3655. [PMC free article] [PubMed]
  • Montalvo EA, Cottam M, Hill S, Wang YJ. YY1 binds to and regulates cis-acting negative elements in the Epstein-Barr virus BZLF1 promoter. J Virol. 1995 Jul;69(7):4158–4165. [PMC free article] [PubMed]
  • Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989 Oct;63(10):4417–4421. [PMC free article] [PubMed]
  • Natesan S, Gilman M. YY1 facilitates the association of serum response factor with the c-fos serum response element. Mol Cell Biol. 1995 Nov;15(11):5975–5982. [PMC free article] [PubMed]
  • Natesan S, Gilman MZ. DNA bending and orientation-dependent function of YY1 in the c-fos promoter. Genes Dev. 1993 Dec;7(12B):2497–2509. [PubMed]
  • O'Connor M, Bernard HU. Oct-1 activates the epithelial-specific enhancer of human papillomavirus type 16 via a synergistic interaction with NFI at a conserved composite regulatory element. Virology. 1995 Feb 20;207(1):77–88. [PubMed]
  • Park K, Atchison ML. Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3' enhancer and the immunoglobulin heavy-chain mu E1 site. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9804–9808. [PMC free article] [PubMed]
  • Riggs KJ, Merrell KT, Wilson G, Calame K. Common factor 1 is a transcriptional activator which binds in the c-myc promoter, the skeletal alpha-actin promoter, and the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1991 Mar;11(3):1765–1769. [PMC free article] [PubMed]
  • Rivera VM, Sheng M, Greenberg ME. The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. Genes Dev. 1990 Feb;4(2):255–268. [PubMed]
  • Rösl F, Achtstätter T, Bauknecht T, Hutter KJ, Futterman G, zur Hausen H. Extinction of the HPV18 upstream regulatory region in cervical carcinoma cells after fusion with non-tumorigenic human keratinocytes under non-selective conditions. EMBO J. 1991 Jun;10(6):1337–1345. [PMC free article] [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature. 1985 Mar 7;314(6006):111–114. [PubMed]
  • Seto E, Lewis B, Shenk T. Interaction between transcription factors Sp1 and YY1. Nature. 1993 Sep 30;365(6445):462–464. [PubMed]
  • Seto E, Shi Y, Shenk T. YY1 is an initiator sequence-binding protein that directs and activates transcription in vitro. Nature. 1991 Nov 21;354(6350):241–245. [PubMed]
  • Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. [PubMed]
  • Shrivastava A, Calame K. An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res. 1994 Dec 11;22(24):5151–5155. [PMC free article] [PubMed]
  • Shrivastava A, Saleque S, Kalpana GV, Artandi S, Goff SP, Calame K. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science. 1993 Dec 17;262(5141):1889–1892. [PubMed]
  • Sibbet GJ, Campo MS. 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. [PubMed]
  • Tan SH, Leong LE, Walker PA, Bernard HU. 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. 1994 Oct;68(10):6411–6420. [PMC free article] [PubMed]
  • Usheva A, Shenk T. TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA. Cell. 1994 Mar 25;76(6):1115–1121. [PubMed]
  • Vincent CK, Gualberto A, Patel CV, Walsh K. Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle. Mol Cell Biol. 1993 Feb;13(2):1264–1272. [PMC free article] [PubMed]
  • von Knebel Doeberitz M, Rittmüller C, zur Hausen H, Dürst M. Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV E6-E7 anti-sense RNA. Int J Cancer. 1992 Jul 9;51(5):831–834. [PubMed]
  • Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990 Apr 6;248(4951):76–79. [PubMed]
  • Yant SR, Zhu W, Millinoff D, Slightom JL, Goodman M, Gumucio DL. High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster. Nucleic Acids Res. 1995 Nov 11;23(21):4353–4362. [PMC free article] [PubMed]
  • Ye J, Zhang X, Dong Z. Characterization of the human granulocyte-macrophage colony-stimulating factor gene promoter: an AP1 complex and an Sp1-related complex transactivate the promoter activity that is suppressed by a YY1 complex. Mol Cell Biol. 1996 Jan;16(1):157–167. [PMC free article] [PubMed]
  • Zhou Q, Gedrich RW, Engel DA. Transcriptional repression of the c-fos gene by YY1 is mediated by a direct interaction with ATF/CREB. J Virol. 1995 Jul;69(7):4323–4330. [PMC free article] [PubMed]
  • zur Hausen H. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology. 1991 Sep;184(1):9–13. [PubMed]

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