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A novel C/EBP beta-YY1 complex controls the cell-type-specific activity of the human papillomavirus type 18 upstream regulatory region.
Abstract
The human papillomavirus type 18 (HPV-18) upstream regulatory region (URR) controls viral gene transcription in a cell-type-specific manner. The HPV-18 URR is active in HeLa cells but inactive in HepG2 cells. The activating activity of YY1 in HeLa cells is dependent on its functional interactions with the switch region which is critical for the HPV-18 URR activity in HeLa cells. Here, we show that a protein complex composed of C/EBP beta and YY1 binds the switch region which is detected only in HeLa cells, not in HepG2 cells. Transfection of C/EBP beta into HepG2 cells restored the formation of the C/EBP beta-YY1-switch region complex, accompanied by increased transcription directed by the HPV-18 URR. Mutations in the switch region that abolished the complex formation also abrogated C/EBP beta-induced transcriptional activation. This provides a strong correlation between the binding of the C/EBP beta-YY1 complex to the switch region and cell-type-specific URR activity. Taken together, we have identified a novel C/EBP beta-YY1 complex that binds the switch region and contributes to cell-type-specific HPV-18 URR activity.
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- Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990 Jun;9(6):1897–1906. [PMC free article] [PubMed] [Google Scholar]
- Baker CC, Phelps WC, Lindgren V, Braun MJ, Gonda MA, Howley PM. Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. J Virol. 1987 Apr;61(4):962–971. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 Sep;5(9):1538–1552. [PubMed] [Google Scholar]
- Chang CJ, Chen TT, Lei HY, Chen DS, Lee SC. Molecular cloning of a transcription factor, AGP/EBP, that belongs to members of the C/EBP family. Mol Cell Biol. 1990 Dec;10(12):6642–6653. [PMC free article] [PubMed] [Google Scholar]
- Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. [PMC free article] [PubMed] [Google Scholar]
- Chen PL, Riley DJ, Chen-Kiang S, Lee WH. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465–469. [PMC free article] [PubMed] [Google Scholar]
- Descombes P, Chojkier M, Lichtsteiner S, Falvey E, Schibler U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 1990 Sep;4(9):1541–1551. [PubMed] [Google Scholar]
- Descombes P, Schibler U. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell. 1991 Nov 1;67(3):569–579. [PubMed] [Google Scholar]
- de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed] [Google Scholar]
- Diehl JA, Hannink M. Identification of a C/EBP-Rel complex in avian lymphoid cells. Mol Cell Biol. 1994 Oct;14(10):6635–6646. [PMC free article] [PubMed] [Google Scholar]
- Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [PMC free article] [PubMed] [Google Scholar]
- Dürst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3812–3815. [PMC free article] [PubMed] [Google Scholar]
- Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989 Feb 17;243(4893):934–937. [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 1989 Dec 1;8(12):3905–3910. [PMC free article] [PubMed] [Google Scholar]
- Heck DV, Yee CL, Howley PM, Münger K. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4442–4446. [PMC free article] [PubMed] [Google Scholar]
- Henderson AJ, Zou X, Calame KL. C/EBP proteins activate transcription from the human immunodeficiency virus type 1 long terminal repeat in macrophages/monocytes. J Virol. 1995 Sep;69(9):5337–5344. [PMC free article] [PubMed] [Google Scholar]
- Hoppe-Seyler F, Butz K. Activation of human papillomavirus type 18 E6-E7 oncogene expression by transcription factor Sp1. Nucleic Acids Res. 1992 Dec 25;20(24):6701–6706. [PMC free article] [PubMed] [Google Scholar]
- Hoppe-Seyler F, Butz K, zur Hausen H. Repression of the human papillomavirus type 18 enhancer by the cellular transcription factor Oct-1. J Virol. 1991 Oct;65(10):5613–5618. [PMC free article] [PubMed] [Google Scholar]
- Hsu W, Chen-Kiang S. Convergent regulation of NF-IL6 and Oct-1 synthesis by interleukin-6 and retinoic acid signaling in embryonal carcinoma cells. Mol Cell Biol. 1993 Apr;13(4):2515–2523. [PMC free article] [PubMed] [Google Scholar]
- Hsu W, Kerppola TK, Chen PL, Curran T, Chen-Kiang S. Fos and Jun repress transcription activation by NF-IL6 through association at the basic zipper region. Mol Cell Biol. 1994 Jan;14(1):268–276. [PMC free article] [PubMed] [Google Scholar]
- Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987 Apr;1(2):133–146. [PubMed] [Google Scholar]
- Jundt F, Herr I, Angel P, Zur Hausen H, Bauknecht T. Transcriptional control of human papillomavirus type 18 oncogene expression in different cell lines: role of transcription factor YY1. Virus Genes. 1995;11(1):53–58. [PubMed] [Google Scholar]
- Katz S, Kowenz-Leutz E, Müller C, Meese K, Ness SA, Leutz A. The NF-M transcription factor is related to C/EBP beta and plays a role in signal transduction, differentiation and leukemogenesis of avian myelomonocytic cells. EMBO J. 1993 Apr;12(4):1321–1332. [PMC free article] [PubMed] [Google Scholar]
- Kaur P, McDougall JK. Characterization of primary human keratinocytes transformed by human papillomavirus type 18. J Virol. 1988 Jun;62(6):1917–1924. [PMC free article] [PubMed] [Google Scholar]
- Kinoshita S, Akira S, Kishimoto T. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1473–1476. [PMC free article] [PubMed] [Google Scholar]
- Kowenz-Leutz E, Twamley G, Ansieau S, Leutz A. Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression. Genes Dev. 1994 Nov 15;8(22):2781–2791. [PubMed] [Google Scholar]
- Kyo S, Inoue M, Nishio Y, Nakanishi K, Akira S, Inoue H, Yutsudo M, Tanizawa O, Hakura A. NF-IL6 represses early gene expression of human papillomavirus type 16 through binding to the noncoding region. J Virol. 1993 Feb;67(2):1058–1066. [PMC free article] [PubMed] [Google Scholar]
- Landschulz WH, Johnson PF, Adashi EY, Graves BJ, McKnight SL. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988 Jul;2(7):786–800. [PubMed] [Google Scholar]
- Landschulz WH, Johnson PF, McKnight SL. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988 Jun 24;240(4860):1759–1764. [PubMed] [Google Scholar]
- Landschulz WH, Johnson PF, McKnight SL. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science. 1989 Mar 31;243(4899):1681–1688. [PubMed] [Google Scholar]
- LeClair KP, Blanar MA, Sharp PA. The p50 subunit of NF-kappa B associates with the NF-IL6 transcription factor. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8145–8149. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- Lee YH, Yano M, Liu SY, Matsunaga E, Johnson PF, Gonzalez FJ. A novel cis-acting element controlling the rat CYP2D5 gene and requiring cooperativity between C/EBP beta and an Sp1 factor. Mol Cell Biol. 1994 Feb;14(2):1383–1394. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Mack DH, Laimins LA. 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. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- McCance DJ, Kopan R, Fuchs E, Laimins LA. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7169–7173. [PMC free article] [PubMed] [Google Scholar]
- Metz R, Ziff E. cAMP stimulates the C/EBP-related transcription factor rNFIL-6 to trans-locate to the nucleus and induce c-fos transcription. Genes Dev. 1991 Oct;5(10):1754–1766. [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Münger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 1989 Dec 20;8(13):4099–4105. [PMC free article] [PubMed] [Google Scholar]
- Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2207–2211. [PMC free article] [PubMed] [Google Scholar]
- Nerlov C, Ziff EB. Three levels of functional interaction determine the activity of CCAAT/enhancer binding protein-alpha on the serum albumin promoter. Genes Dev. 1994 Feb 1;8(3):350–362. [PubMed] [Google Scholar]
- Nishio Y, Isshiki H, Kishimoto T, Akira S. A nuclear factor for interleukin-6 expression (NF-IL6) and the glucocorticoid receptor synergistically activate transcription of the rat alpha 1-acid glycoprotein gene via direct protein-protein interaction. Mol Cell Biol. 1993 Mar;13(3):1854–1862. [PMC free article] [PubMed] [Google Scholar]
- Offord EA, Beard P. A member of the activator protein 1 family found in keratinocytes but not in fibroblasts required for transcription from a human papillomavirus type 18 promoter. J Virol. 1990 Oct;64(10):4792–4798. [PMC free article] [PubMed] [Google Scholar]
- Ossipow V, Descombes P, Schibler U. CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8219–8223. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Poli V, Mancini FP, Cortese R. IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell. 1990 Nov 2;63(3):643–653. [PubMed] [Google Scholar]
- Raynal MC, Liu ZY, Hirano T, Mayer L, Kishimoto T, Chen-Kiang S. Interleukin 6 induces secretion of IgG1 by coordinated transcriptional activation and differential mRNA accumulation. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8024–8028. [PMC free article] [PubMed] [Google Scholar]
- Ron D, Habener JF. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 1992 Mar;6(3):439–453. [PubMed] [Google Scholar]
- Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. [PubMed] [Google Scholar]
- Schneider-Gädicke A, Schwarz E. Different human cervical carcinoma cell lines show similar transcription patterns of human papillomavirus type 18 early genes. EMBO J. 1986 Sep;5(9):2285–2292. [PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- Smotkin D, Wettstein FO. 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. 1986 Jul;83(13):4680–4684. [PMC free article] [PubMed] [Google Scholar]
- Spergel JM, Chen-Kiang S. Interleukin 6 enhances a cellular activity that functionally substitutes for E1A protein in transactivation. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6472–6476. [PMC free article] [PubMed] [Google Scholar]
- Spergel JM, Hsu W, Akira S, Thimmappaya B, Kishimoto T, Chen-Kiang S. NF-IL6, a member of the C/EBP family, regulates E1A-responsive promoters in the absence of E1A. J Virol. 1992 Feb;66(2):1021–1030. [PMC free article] [PubMed] [Google Scholar]
- Stein B, Baldwin AS., Jr Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B. Mol Cell Biol. 1993 Nov;13(11):7191–7198. [PMC free article] [PubMed] [Google Scholar]
- Stein B, Cogswell PC, Baldwin AS., Jr Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction. Mol Cell Biol. 1993 Jul;13(7):3964–3974. [PMC free article] [PubMed] [Google Scholar]
- Stein B, Yang MX. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol. 1995 Sep;15(9):4971–4979. [PMC free article] [PubMed] [Google Scholar]
- 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. [PMC free article] [PubMed] [Google Scholar]
- Trautwein C, Caelles C, van der Geer P, Hunter T, Karin M, Chojkier M. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature. 1993 Aug 5;364(6437):544–547. [PubMed] [Google Scholar]
- Tsukada J, Saito K, Waterman WR, Webb AC, Auron PE. Transcription factors NF-IL6 and CREB recognize a common essential site in the human prointerleukin 1 beta gene. Mol Cell Biol. 1994 Nov;14(11):7285–7297. [PMC free article] [PubMed] [Google Scholar]
- Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991 Jan 18;251(4991):288–292. [PubMed] [Google Scholar]
- Vallejo M, Ron D, Miller CP, Habener JF. C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4679–4683. [PMC free article] [PubMed] [Google Scholar]
- Vinson CR, Sigler PB, McKnight SL. Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science. 1989 Nov 17;246(4932):911–916. [PubMed] [Google Scholar]
- Wegner M, Cao Z, Rosenfeld MG. Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta. Science. 1992 Apr 17;256(5055):370–373. [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Williams SC, Baer M, Dillner AJ, Johnson PF. CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity. EMBO J. 1995 Jul 3;14(13):3170–3183. [PMC free article] [PubMed] [Google Scholar]
- Williams SC, Cantwell CA, Johnson PF. A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro. Genes Dev. 1991 Sep;5(9):1553–1567. [PubMed] [Google Scholar]
- Woodworth CD, Waggoner S, Barnes W, Stoler MH, DiPaolo JA. Human cervical and foreskin epithelial cells immortalized by human papillomavirus DNAs exhibit dysplastic differentiation in vivo. Cancer Res. 1990 Jun 15;50(12):3709–3715. [PubMed] [Google Scholar]
- Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995 Jan 15;9(2):168–181. [PubMed] [Google Scholar]
- zur Hausen H. Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res. 1989 Sep 1;49(17):4677–4681. [PubMed] [Google Scholar]
- zur Hausen H. Viruses in human cancers. Science. 1991 Nov 22;254(5035):1167–1173. [PubMed] [Google Scholar]
- zur Hausen H. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology. 1991 Sep;184(1):9–13. [PubMed] [Google Scholar]