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The E8 repression domain can replace the E2 transactivation domain for growth inhibition of HeLa cells by papillomavirus E2 proteins

  1. Frank Stubenrauch†,*,
  2. Elke Straub,
  3. Jasmin Fertey,
  4. Thomas Iftner

Article first published online: 21 JUN 2007

DOI: 10.1002/ijc.22907

Issue

International Journal of Cancer

International Journal of Cancer

Volume 121, Issue 10, pages 2284–2292, 15 November 2007

Additional Information

How to Cite

Stubenrauch, F., Straub, E., Fertey, J. and Iftner, T. (2007), The E8 repression domain can replace the E2 transactivation domain for growth inhibition of HeLa cells by papillomavirus E2 proteins. Int. J. Cancer, 121: 2284–2292. doi: 10.1002/ijc.22907

Author Information

  1. Sektion Experimentelle Virologie, Institut fuer Medizinische Virologie und Epidemiologie der Viruskrankheiten, Universitaetsklinikum Tuebingen, Elfriede-Aulhorn-Str.6, Tuebingen, Germany

  1. †

    Fax: +49-7071-295419.

*Sektion Experimentelle Virologie, Institut fuer Medizinische Virologie und Epidemiologie der Viruskrankheiten, Universitaetsklinikum Tuebingen, Elfriede-Aulhorn-Str. 6, D72076 Tuebingen, Germany

Publication History

  1. Issue published online: 25 SEP 2007
  2. Article first published online: 21 JUN 2007
  3. Manuscript Accepted: 10 MAY 2007
  4. Manuscript Received: 16 JAN 2007

Funded by

  • Deutsche Forschungsgemeinschaft. Grant Number: Stu 218/3-1

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References

  • 1
    Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F. Carcinogenicity of human papillomaviruses. Lancet Oncol 2005; 6: 204.
  • 2
    Wentzensen N, Vinokurova S, von Knebel Doeberitz M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 2004; 64: 3878–84.
  • 3
    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; 314: 111–14.
  • 4
    Jiang M, Milner J. Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene 2002; 21: 6041–8.
  • 5
    Hall AH, Alexander KA. RNA interference of human papillomavirus type 18 E6 and E7 induces senescence in HeLa cells. J Virol 2003; 77: 6066–9.
  • 6
    Butz K, Ristriani T, Hengstermann A, Denk C, Scheffner M, Hoppe-Seyler F. siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 2003; 22: 5938–45.
  • 7
    von Knebel Doeberitz M, Rittmuller C, zur Hausen H, Durst M. Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV E6-E7 anti-sense RNA. Int J Cancer 1992; 51: 831–4.
    Direct Link:
  • 8
    Munger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh K. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004; 78: 11451–60.
  • 9
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993; 75: 495–505.
  • 10
    Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989; 243: 934–7.
  • 11
    Chellappan S, Kraus VB, Kroger B, Munger K, Howley PM, Phelps WC, Nevins JR. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA 1992; 89: 4549–53.
  • 12
    Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 1996; 56: 4620–4.
  • 13
    Gonzalez SL, Stremlau M, He X, Basile JR, Munger K. Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7. J Virol 2001; 75: 7583–91.
  • 14
    Smotkin D, Prokoph H, Wettstein FO. Oncogenic and nononcogenic human genital papillomaviruses generate the E7 mRNA by different mechanisms. J Virol 1989; 63: 1441–7.
  • 15
    Bernard BA, Bailly C, Lenoir MC, Darmon M, Thierry F, Yaniv M. The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol 1989; 63: 4317–24.
  • 16
    Romanczuk H, Thierry F, Howley PM. Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters. J Virol 1990; 64: 2849–59.
  • 17
    Tan SH, Gloss B, Bernard HU. During negative regulation of the human papillomavirus-16 E6 promoter, the viral E2 protein can displace Sp1 from a proximal promoter element. Nucleic Acids Res 1992; 20: 251–6.
  • 18
    Stubenrauch F, Hummel M, Iftner T, Laimins LA. The E8E2C protein, a negative regulator of viral transcription and replication, is required for extrachromosomal maintenance of human papillomavirus type 31 in keratinocytes. J Virol 2000; 74: 1178–86.
  • 19
    Thierry F, Yaniv M. The BPV1-E2 trans-acting protein can be either an activator or a repressor of the HPV18 regulatory region. EMBO J 1987; 6: 3391–7.
  • 20
    Hwang ES, Riese DJ,II, Settleman J, Nilson LA, Honig J, Flynn S, DiMaio D. Inhibition of cervical carcinoma cell line proliferation by the introduction of a bovine papillomavirus regulatory gene. J Virol 1993; 67: 3720–9.
  • 21
    Dowhanick JJ, McBride AA, Howley PM. Suppression of cellular proliferation by the papillomavirus E2 protein. J Virol 1995; 69: 7791–9.
  • 22
    Desaintes C, Demeret C, Goyat S, Yaniv M, Thierry F. Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis. EMBO J 1997; 16: 504–14.
  • 23
    Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM. Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways. EMBO J 2000; 19: 5762–71.
  • 24
    Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA 2000; 97: 12513–8.
  • 25
    Hegde RS, Androphy EJ. Crystal structure of the E2 DNA-binding domain from human papillomavirus type 16: implications for its DNA binding-site selection mechanism. J Mol Biol 1998; 284: 1479–89.
  • 26
    Desaintes C, Demeret C. Control of papillomavirus DNA replication and transcription. Semin Cancer Biol 1996; 7: 339–47.
  • 27
    You J, Croyle JL, Nishimura A, Ozato K, Howley PM. Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 2004; 117: 349–60.
  • 28
    Stenlund A. Initition of DNA replication: lessons from viral initiator proteins. Nat Rev Mol Cell Biol 2003; 10: 777–85.
  • 29
    Goodwin EC, Naeger LK, Breiding DE, Androphy EJ, DiMaio D. Transactivation-competent bovine papillomavirus E2 protein is specifically required for efficient repression of human papillomavirus oncogene expression and for acute growth inhibition of cervical carcinoma cell lines. J Virol 1998; 72: 3925–34.
  • 30
    Lambert PF, Spalholz BA, Howley PM. A transcriptional repressor encoded by BPV-1 shares a common carboxy-terminal domain with the E2 transactivator. Cell 1987; 50: 69–78.
  • 31
    Nishimura A, Ono T, Ishimoto A, Dowhanick JJ, Frizzell MA, Howley PM, Sakai H. Mechanisms of human papillomavirus E2-mediated repression of viral oncogene expression and cervical cancer cell growth inhibition. J Virol 2000; 74: 3752–60.
  • 32
    Wu SY, Lee AY, Hou SY, Kemper JK, Erdjument-Bromage H, Tempst P, Chiang CM. Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev 2006; 20: 2383–96.
  • 33
    Choe J, Vaillancourt P, Stenlund A, Botchan M. Bovine papillomavirus type 1 encodes two forms of a transcriptional repressor: structural and functional analysis of new viral cDNAs. J Virol 1989; 63: 1743–55.
  • 34
    Doorbar J, Parton A, Hartley K, Banks L, Crook T, Stanley M, Crawford L. Detection of novel splicing patterns in a HPV16-containing keratinocyte cell line. Virology 1990; 178: 254–62.
  • 35
    Rotenberg MO, Chow LT, Broker TR. Characterization of rare human papillomavirus type 11 mRNAs coding for regulatory and structural proteins, using the polymerase chain reaction. Virology 1989; 172: 489–97.
  • 36
    Palermo-Dilts DA, Broker TR, Chow LT. Human papillomavirus type 1 produces redundant as well as polycistronic mRNAs in plantar warts. J Virol 1990; 64: 3144–9.
  • 37
    Jeckel S, Loetzsch E, Huber E, Stubenrauch F, Iftner T. Identification of the E9/E2C cDNA and functional characterization of the gene product reveal a new repressor of transcription and replication in cottontail rabbit papillomavirus. J Virol 2003; 77: 8736–44.
  • 38
    Snijders PJ, van den Brule AJ, Schrijnemakers HF, Raaphorst PM, Meijer CJ, Walboomers JM. Human papillomavirus type 33 in a tonsillar carcinoma generates its putative E7 mRNA via two E6* transcript species which are terminated at different early region poly(A) sites. J Virol 1992; 66: 3172–8.
  • 39
    Stubenrauch F, Zobel T, Iftner T. The E8 domain confers a novel long-distance transcriptional repression activity on the E8E2C protein of high-risk human papillomavirus type 31. J Virol 2001; 75: 4139–49.
  • 40
    Zobel T, Iftner T, Stubenrauch F. The papillomavirus E8-E2C protein represses DNA replication from extrachromosomal origins. Mol Cell Biol 2003; 23: 8352–62.
  • 41
    Stubenrauch F, Colbert AM, Laimins LA. Transactivation by the E2 protein of oncogenic human papillomavirus type 31 is not essential for early and late viral functions. J Virol 1998; 72: 8115–23.
  • 42
    Barsoum J, Prakash SS, Han P, Androphy EJ. Mechanism of action of the papillomavirus E2 repressor: repression in the absence of DNA binding. J Virol 1992; 66: 3941–5.
  • 43
    Karstensen B, Poppelreuther S, Bonin M, Walter M, Iftner T, Stubenrauch F. Gene expression profiles reveal an upregulation of E2F and downregulation of interferon targets by HPV18 but no changes between keratinocytes with integrated or episomal viral genomes. Virology 2006; 353: 200–9.
  • 44
    Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29: e45.
  • 45
    Francis DA, Schmid SI, Howley PM. Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells. J Virol 2000; 74: 2679–86.
  • 46
    DeFilippis RA, Goodwin EC, Wu L, DiMaio D. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J Virol 2003; 77: 1551–63.
  • 47
    Schneider-Gadicke A, Schwarz E. Different human cervical carcinoma cell lines show similar transcription patterns of human papillomavirus type 18 early genes. EMBO J 1986; 5: 2285–92.
  • 48
    Psyrri A, DeFilippis RA, Edwards AP, Yates KE, Manuelidis L, DiMaio D. Role of the retinoblastoma pathway in senescence triggered by repression of the human papillomavirus E7 protein in cervical carcinoma cells. Cancer Res 2004; 64: 3079–86.
  • 49
    Wells SI, Aronow BJ, Wise TM, Williams SS, Couget JA, Howley PM. Transcriptome signature of irreversible senescence in human papillomavirus-positive cervical cancer cells. Proc Natl Acad Sci USA 2003; 100: 7093–8.
  • 50
    Frattini MG, Hurst SD, Lim HB, Swaminathan S, Laimins LA. Abrogation of a mitotic checkpoint by E2 proteins from oncogenic human papillomaviruses correlates with increased turnover of the p53 tumor suppressor protein. EMBO J 1997; 16: 318–31.
  • 51
    Webster K, Parish J, Pandya M, Stern PL, Clarke AR, Gaston K. The human papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway. J Biol Chem 2000; 275: 87–94.
  • 52
    Blachon S, Bellanger S, Demeret C, Thierry F. Nucleo-cytoplasmic shuttling of high risk human papillomavirus E2 proteins induces apoptosis. J Biol Chem 2005; 280: 36088–98.
  • 53
    Demeret C, Garcia-Carranca A, Thierry F. Transcription-independent triggering of the extrinsic pathway of apoptosis by human papillomavirus 18 E2 protein. Oncogene 2003; 22: 168–75.
  • 54
    Bechtold V, Beard P, Raj K. Human papillomavirus type 16 E2 protein has no effect on transcription from episomal viral DNA. J Virol 2003; 77: 2021–8.
  • 55
    Monini P, Blitz IL, Cassai E. Cooperative DNA binding of the bovine papillomavirus E2 transcriptional activator is antagonized by truncated E2 polypeptides. J Virol 1993; 67: 5668–76.
  • 56
    Schweiger MR, You J, Howley PM. Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function. J Virol 2006; 80: 4276–85.
  • 57
    Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 2003; 100: 8758–63.
  • 58
    Baxter MK, McPhillips MG, Ozato K, McBride AA. The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4. J Virol 2005; 79: 4806–18.
  • 59
    Ilves I, Maemets K, Silla T, Janikson K, Ustav M. Brd4 is involved in multiple processes of the bovine papillomavirus type 1 life cycle. J Virol 2006; 80: 3660–5.
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