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Gene Program Signatures for Papillomavirus E2-Mediated Senescence in Cervical Cancer Cells

Finding the Points of No Return

  • Chapter
The Oncogenomics Handbook

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Infection with the high-risk types of human papillomavirus is strongly linked to the development of cancers of the uterine cervix. Carcinogenesis depends on the continuous expression of the viral E6 and E7 oncogenes in the affected individual. Transcription of these oncogenes can be negatively regulated by the viral E2 protein. Carcinogenic progression of human papillomavirus (HPV)-positive lesions is accompanied by the integration of the viral DNA into the cellular genome and the disruption of the viral E2 open reading frame. When reintroduced into HPV-positive cancer cells, E2 proteins suppress cellular growth through senescence induction. E2 repression of E6/E7 is necessary and sufficient for this process, indicating that important senescence mediators must be inhibited by the viral oncoproteins for both the initiation and maintenance of HPV-associated carcinogenesis. We describe in this chapter the use of an E2-based inducible senescence system to determine the transcriptome of HPV-positive cells during an early, yet irreversibly committed senescence state. Insights into the regulation of specific genes and gene groups during E2 senescence compared to their regulation during E6/E7 immortalization might elucidate mechanisms of senescence inhibition by the HPV oncogenes. We will discuss how future studies of bona fide regulators of the balance between senescence and carcinogenesis might ultimately lead to novel drug targets, diagnostic markers, and more refined approaches for cancer treatment both within and outside of the HPV context.

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References

  1. Howley PM, Lowy DR. Papillomavirinae: the viruses and their replication. In: Howley PM, Knipe DM, eds. Fields virology. Vol. 2. Philadelphia: Lippincott Williams and Wilkins, 2001:2197–2229.

    Google Scholar 

  2. Group IW. Human papillomaviruses. IARC monograph on the evaluation of carcinogenic risks to humans. Lyon, France: International Agency for Research on Cancer, 1995.

    Google Scholar 

  3. Ferenczy A, Franco E. Persistent human papillomavirus infection and cervical neoplasia. Lancet 2002; 3:11–16.

    Article  CAS  Google Scholar 

  4. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 1999; 80:827–841.

    Article  PubMed  CAS  Google Scholar 

  5. Franco EL, Rohan TE, Villa LL. Epidemiologic evidence and human papillomavirus infection as a necessary cause of cervical cancer. J Natl Cancer Inst 1999; 91:506–511.

    Article  PubMed  CAS  Google Scholar 

  6. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12–19.

    Article  PubMed  CAS  Google Scholar 

  7. Khleif SN, DeGregori J, Yee CL, et al. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc Natl Acad Sci USA 1996; 93:4350–4354.

    Article  PubMed  CAS  Google Scholar 

  8. 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; 63: 4417–4421.

    PubMed  Google Scholar 

  9. 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; 8:3905–3910.

    PubMed  CAS  Google Scholar 

  10. Pecoraro G, Morgan D, Defendi V. Differential effects of human papillomavirus type 6, 16 and 18 DNAs on immortalization and transformation of human cervical epithelial cells. Proc Natl Acad Sci USA 1989, 563–567.

    Google Scholar 

  11. Woodworth CD, Doninger J, DiPaolo JA. Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol 1989;63:159–164.

    PubMed  CAS  Google Scholar 

  12. DiPaolo JA, Woodworth CD, Popescu NC, Notario V, Doniger J. Induction of human cervical squamous cell carcinoma by sequential transfection with human papillomavirus 16 DNA and viral Harvey ras. Oncogene 1989; 4:395–399.

    PubMed  CAS  Google Scholar 

  13. Durst M, Gallahan D, Jay G, Rhim JS. Glucocorticoid-enhanced neoplastic transformation of human keratinocytes by human papillomavirus type 16 and an activated ras oncogene. Virology 1989; 173:767–771.

    Article  PubMed  CAS  Google Scholar 

  14. Hurlin PJ, Kaur P, Smith PP, Perez-Reyes N, Blanton RA, McDougall JK. Progression of human papillomavirus type 18-immortalized human keratinocytes to a malignant phenotype. Proc Natl Acad Sci USA 1991; 88: 570–574.

    Article  PubMed  CAS  Google Scholar 

  15. Chen TM, Pecoraro G, Defendi V. Genetic analysis of in vitro progression of human papillomavirus-transfected human cervical cells. Cancer Res 1993; 53:1167–1171.

    PubMed  CAS  Google Scholar 

  16. Schwarz E, Freese UK, Gissman L, et al. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 1985; 314:111–114.

    Article  PubMed  CAS  Google Scholar 

  17. Alvarez-Salas LM, Cullinan AE, Siwkowski A, Hampel A, DiPaolo JA. Inhibition of HPV-16 E6/E7 immortalization of normal keratinocytes by hairpin ribozymes. Proc Natl Acad Sci USA 1998; 95:1189–1194.

    Article  PubMed  CAS  Google Scholar 

  18. Dowhanick JJ, McBride AA, Howley PM. Suppression of cellular proliferation by the papillomavirus E2 protein. J Virol 1995; 69:7791–7799.

    PubMed  CAS  Google Scholar 

  19. 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; 72:3925–3934.

    PubMed  CAS  Google Scholar 

  20. Hu G, Liu W, Hanania EG, Fu S, Wang T, Deisseroth AB. Suppression of tumorigenesis by transcription units expressing the antisense E6 and E7 messenger RNA (mRNA) for the transforming proteins of the human papilloma virus and the sense mRNA for the retinoblastoma gene in cervical carcinoma cells. Cancer Gene Ther 1995; 2:19–32.

    PubMed  Google Scholar 

  21. Hwang ES, Riese DJ, Settleman J, et al. Inhibition of cervical carcinoma cell line proliferation by the introduction of a bovine papillomavirus regulatory gene. J Virol 1993; 67:3720–3729.

    PubMed  CAS  Google Scholar 

  22. Venturini F, Braspenning J, Homann M, Gissmann L, Sczakiel G. Kinetic selection of HPV 16 E6/E7-directed antisense nucleic acids: anti-proliferative effects on HPV 16-transformed cells. Nucleic Acids Res 1999; 27: 1585–1592.

    Article  PubMed  CAS  Google Scholar 

  23. 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; 51:831–834.

    Article  Google Scholar 

  24. Watanabe S, Kanda T, Yoshiike K. Growth dependence of human papillomavirus 16 DNA-positive cervical cancer cell lines and human papillomavirus 16-transformed human and rat cells on the viral oncoproteins. Jpn J Cancer Res 1993; 84:1043–1049.

    PubMed  CAS  Google Scholar 

  25. Griep AE, Herber R, Jeon S, Lohse JK, Dubielzig RR, Lambert PF. Tumorigenicity by human papillomavirus type 16 E6 and E7 in transgenic mice correlates with alterations in epithelial cell growth and differentiation. J Virol 1993; 67:1373–1384.

    PubMed  CAS  Google Scholar 

  26. Comerford SA, Maika SD, Laimins LA, Messing A, Elsasser HP, Hammer RE. E6 and E7 expression from the HPV 18 LCR: development of genital hyperplasia and neoplasia in transgenic mice. Oncogene 1995; 10:587–597.

    PubMed  CAS  Google Scholar 

  27. Arbeit JM, Munger K, Howley PM, Hanahan D. Neuroepithelial carcinomas in mice transgenic with human papillomavirus type 16 E6/E7 ORFs. Am J Pathology 1993; 142:1187–1197.

    CAS  Google Scholar 

  28. Herber R, Liem A, Pitot H, Lambert PF. Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene. J Virol 1996; 70:1873–1881.

    PubMed  CAS  Google Scholar 

  29. Song S, Pitot HC, Lambert PF. The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals. J Virol 1999; 73:5887–5893.

    PubMed  CAS  Google Scholar 

  30. Riley RR, Duensing S, Brake T, Munger K, Lambert PF, Arbeit JM. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res 2003;63:4862–4871.

    PubMed  CAS  Google Scholar 

  31. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002; 89:213–228.

    Article  PubMed  CAS  Google Scholar 

  32. Kao WH, Beaudenon SL, Talis AL, Huibregtse JM, Howley PM. Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J Virol 2000; 74:6408–6417.

    Article  PubMed  CAS  Google Scholar 

  33. 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; 63:1129–1136.

    Article  PubMed  CAS  Google Scholar 

  34. Gao Q, Singh L, Kumar A, Srinivasan S, Wazer DE, Band V. Human papillomavirus type 16 E6-induced degradation of E6TP1 correlates with its ability to immortalize human mammary epithelial cells. J Virol 2001; 75:4459–4466.

    Article  PubMed  CAS  Google Scholar 

  35. Gao Q, Srinivasan S, Boyer SN, Wazer DE, Band V. The E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation. Mol Cell Biol 1999; 19:733–744.

    PubMed  CAS  Google Scholar 

  36. Gross-Mesilaty S, Reinstein E, Bercovich B, et al. Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Natl Acad Sci USA 1998; 95:8058–8063.

    Article  PubMed  CAS  Google Scholar 

  37. Thomas M, Banks L. Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 1999; 80(Pt 6):1513–1517.

    PubMed  CAS  Google Scholar 

  38. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000; 14:3065–3073.

    Article  PubMed  CAS  Google Scholar 

  39. Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 2000; 19:5270–5280.

    Article  PubMed  CAS  Google Scholar 

  40. Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M. Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 1997; 94:11,612–11,616.

    Article  PubMed  CAS  Google Scholar 

  41. Lee SS, Weiss RS, Javier RT. Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 1997; 94:6670–6675.

    Article  PubMed  CAS  Google Scholar 

  42. Patel D, Huang SM, Baglia LA, McCance DJ. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J 1999; 18:5061–5072.

    Article  PubMed  CAS  Google Scholar 

  43. Zimmermann H, Degenkolbe R, Bernard HU, O’Connor MJ. The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300. J Virol 1999; 73: 6209–6219.

    PubMed  CAS  Google Scholar 

  44. Kumar A, Zhao Y, Meng G, et al. Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol Cell Biol 2002; 22:5801–5812.

    Article  PubMed  CAS  Google Scholar 

  45. Klingelhutz AJ, Foster SA, McDougall JK. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 1996; 380:79–81.

    Article  PubMed  CAS  Google Scholar 

  46. Dyson N, Howley PM, Munger K, Harlow E. The human papillomavirus-16 E7 oncoprotein is able to bind the retinoblastoma gene product. Science 1989; 243:934–937.

    Article  PubMed  CAS  Google Scholar 

  47. Dyson N, Guida P, Munger K, Harlow E. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins. J Virol 1992; 66:6893–6902.

    PubMed  CAS  Google Scholar 

  48. Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA. Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev 1997; 11: 2090–2100.

    PubMed  CAS  Google Scholar 

  49. Jones DL, Alani RM, Munger K. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev 1997; 11: 2101–2111.

    Article  PubMed  CAS  Google Scholar 

  50. Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Durr P. Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 1996; 13:2323–2330.

    PubMed  CAS  Google Scholar 

  51. Massimi P, Pim D, Banks L. Human papillomavirus type 16 E7 binds to the conserved carboxy-terminal region of the TATA box binding protein and this contributes to E7 transforming activity. J Gen Virol 1997; 78(Pt 10): 2607–2613.

    PubMed  CAS  Google Scholar 

  52. Brehm A, Nielsen SJ, Miska EA, et al. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 1999; 18:2449–2458.

    Article  PubMed  CAS  Google Scholar 

  53. Antinore MJ, Birrer MJ, Patel D, Nader L, McCance DJ. The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors. EMBO J 1996; 15:1950–1960.

    PubMed  CAS  Google Scholar 

  54. Nead MA, Baglia LA, Antinore MJ, Ludlow JW, McCance DJ. Rb binds c-Jun and activates transcription. EMBO J 1998; 17:2342–2352.

    Article  PubMed  CAS  Google Scholar 

  55. Zwerschke W, Mannhardt B, Massimi P, et al. Allosteric activation of acid alpha-glucosidase by the human papillomavirus E7 protein. J Biol Chem 2000; 275:9534–9541.

    Article  PubMed  CAS  Google Scholar 

  56. Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Durr P. Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc Natl Acad Sci USA 1999; 96:1291–1296.

    Article  PubMed  CAS  Google Scholar 

  57. Mazurek S, Zwerschke W, Jansen-Durr P, Eigenbrodt E. Effects of the human papilloma virus HPV-16 E7 oncoprotein on glycolysis and glutaminolysis: role of pyruvate kinase type M2 and the glycolytic-enzyme complex. Biochem J 2001; 356:247–256.

    Article  PubMed  CAS  Google Scholar 

  58. Duensing S, Duensing A, Crum CP, Munger K. Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype. Cancer Res 2001; 61: 2356–2360.

    PubMed  CAS  Google Scholar 

  59. Duensing S, Lee LY, Duensing A, et al. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc Natl Acad Sci USA 2000; 97:10,002–10,007.

    Article  PubMed  CAS  Google Scholar 

  60. Duensing S, Munger K. Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. J Virol 2003; 77: 12,331–12,335.

    Article  PubMed  CAS  Google Scholar 

  61. 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; 61:962–971.

    PubMed  CAS  Google Scholar 

  62. Durst M, Kleinheinz A, Hotz M, Gissmann L. The physical state of human papillomavirus type 16 DNA in benign and malignant genital tumours. J Gen Virol 1985; 66:1515–1522.

    PubMed  Google Scholar 

  63. Jeon S, Lambert PF. Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol 1995; 69:2989–2997.

    PubMed  CAS  Google Scholar 

  64. Park T-W, Fujiwara H, Wright TC. Molecular biology of cervical cancer and its precursors. Cancer 1995; 76:1902–1913.

    Article  PubMed  CAS  Google Scholar 

  65. Southern SA, Herrington CS. Disruption of cell cycle control by human papillomaviruses with special reference to cervical carcinoma. Int J Gynecol Cancer 2000; 10:263–274.

    Article  PubMed  Google Scholar 

  66. zur Hausen H. Papillomavirus causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000; 92:690–698.

    Article  PubMed  Google Scholar 

  67. Desaintes C, Demeret C. Control of papillomavirus DNA replication and transcription. Semin Cancer Biol 1996; 7:339–347.

    Article  PubMed  CAS  Google Scholar 

  68. McBride AA, Romanczuk H, Howley PM. The papillomavirus E2 regulatory proteins. J Biol Chem 1991; 266:18,411–18,414.

    PubMed  CAS  Google Scholar 

  69. Hines CS, Meghoo C, Shetty S, Biburger M, Brenowitz M, Hegde RS. DNA structure and flexibility in the sequence-specific binding of papillomavirus E2 proteins. J Mol Biol 1998; 276:809–818.

    Article  PubMed  CAS  Google Scholar 

  70. Hedge RS, Rossman SR, Laimins LA, Sigler PB. Crystal structure at 1.7A of the bovine papillomavirus-1 E2 DNA-binding domain bound to its DNA target. Nature 1992; 359:505–512.

    Article  Google Scholar 

  71. Hegde RS, Wang A-F, Kim S-S, Schapira M. Subunit rearrangement accompanies sequence-specific DNA binding by the bovine papillomavirus-1 E2 protein. J Mol Biol 1998; 276:797–908.

    Article  PubMed  CAS  Google Scholar 

  72. Li R, Knight J, Bream G, Stenlund A, Botchan M. Specific recognition nucleotides and their context determine the affinity of E2 protein for 17 binding sites in the BPV-1 genome. Genes Dev 1989; 3:510–526.

    Article  PubMed  CAS  Google Scholar 

  73. Kim S-S, Tam JK, Wang A-F, Hegde RS. The structural basis of DNA target discrimination by papillomavirus E2 proteins. J Biol Chem 2000; 275:31,245–31,254.

    Article  PubMed  CAS  Google Scholar 

  74. Chin MT, Hirochika R, Hirochika H, Broker TR, Chow LT. Regulation of human papillomavirus type 11 enhancer and E6 promoter by activating and repressing proteins from the E2 open reading frame: functional and biochemical studies. J Virol 1988; 62:2994–3002.

    PubMed  CAS  Google Scholar 

  75. Cripe TP, Haugen TH, Turk JP, et al. 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; 6:3745–3753.

    PubMed  CAS  Google Scholar 

  76. Dostatni N, Lambert PF, Sousa R, Ham J, Howley PM, Yaniv M. The functional BPV-1 E2 transactiving protein can act as a repressor by preventing formulation of the initiation complex. Genes Dev 1991;5:1657–1671.

    Article  PubMed  CAS  Google Scholar 

  77. Hermonat PL, Spalholz BA, Howley PM. The bovine papillomavirus P2443 promoter is E2 trans-responsive: evidence for E2 autoregulation. EMBO J 1988; 7:2815–2822.

    PubMed  CAS  Google Scholar 

  78. Hirochika H, Broker TR, Chow LT. Enhancers and trans-acting E2 transcriptional factors of papillomaviruses. J Virol 1987; 61:2599–2606.

    PubMed  CAS  Google Scholar 

  79. Hirochika H, Hirochika R, Broker TR, Chow LT. Functional mapping of the human papillomavirus type 11 transcriptional enhancer and its interaction with the trans-acting E2 proteins. Genes Dev 1988;2:54–67.

    Article  PubMed  CAS  Google Scholar 

  80. Phelps WC, Howley PM. Transcriptional trans-activation by the human papillomavirus type 16 E2 gene product. J Virol 1987; 61:1630–1638.

    PubMed  CAS  Google Scholar 

  81. Thierry F, Howley PM. Functional analysis of E2 mediated repression of the HPV-18 P105 promoter. New Biol 1991; 3:90–100.

    PubMed  CAS  Google Scholar 

  82. Lee D, Lee B, Kim J, Kim DW, Choe J. cAMP response element-binding protein-binding protein binds to human papillomavirus E2 protein and activates E2-dependent transcription. J Biol Chem 2000; 275:7045–7051.

    Article  PubMed  CAS  Google Scholar 

  83. Lee D, Hwang SG, Kim J, Choe J. Functional Interaction between p/CAF and human papillomavirus E2 protein. J Biol Chem 2002; 277:6483–6489.

    Article  PubMed  CAS  Google Scholar 

  84. Breiding DE, Sverdrup F, Grossel MJ, Moscufo N, Boonchai W, Androphy E. Functional interaction of a novel cellular protein with the papillomavirus E2 transactivation domain. Mol Cell Biol 1997; 17:7208–7219.

    PubMed  CAS  Google Scholar 

  85. Benson JD, Lawande R, Howley PM. Conserved interaction of the papillomavirus E2 transcriptional activator proteins with human and yeast TFIIB proteins. J Virol 1997; 71:8041–8047.

    PubMed  CAS  Google Scholar 

  86. Rank NM, Lambert PF. Bovine papillomavirus type 1 E2 transcriptional regulators directly bind two cellular transcription factors, TFIID and TFIIB. J Virol 1995; 69:6323–6334.

    PubMed  CAS  Google Scholar 

  87. Demeret C, Desaintes C, Yaniv M, Thierry F. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol 1997; 71:9343–9349.

    PubMed  CAS  Google Scholar 

  88. 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; 64:2849–2859.

    PubMed  CAS  Google Scholar 

  89. Tan S-H, Gloss B, Bernard H-U. 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;20:251–256.

    Article  PubMed  CAS  Google Scholar 

  90. Romanczuk H, Howley PM. Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity. Proc Natl Acad Sci USA 1992; 89:3159–3163.

    Article  PubMed  CAS  Google Scholar 

  91. 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.

    Article  PubMed  CAS  Google Scholar 

  92. 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; 16:504–514.

    Article  PubMed  CAS  Google Scholar 

  93. Desaintes C, Goyat S, Garbay S, Yaniv M, Thierry F. Papillomavirus E2 induces p53-independent apoptosis in HeLa cells. Oncogene 1999; 18:4538–4545.

    Article  PubMed  CAS  Google Scholar 

  94. Demeret C, Garcia-Carranca A, Thierry F. Transcription-independent triggering of the extrinsic pathway of apoptosis by human papillomavirus 18 E2 protein. Oncogene 2003; 22:168–175.

    Article  PubMed  CAS  Google Scholar 

  95. Goodwin EC, Yang E, Lee C-J, Lee H-W, DiMaio D, Hwang E-S. Rapid induction of senescence in human cervical carcinoma cells. Proc Natl Acad Sci USA 2000; 97:10,978–10,983.

    Article  PubMed  CAS  Google Scholar 

  96. Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM. Papillomavirus E2 induces senescence in HPV-positive cells via pRB-and p21CIP-dependent pathways. EMBO J 2000;19:5762–5771.

    Article  PubMed  CAS  Google Scholar 

  97. 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: 1551–1563.

    Article  PubMed  CAS  Google Scholar 

  98. Campisi J. Cancer, aging and cellular senescence. In Vivo 2000; 14:183–188.

    PubMed  CAS  Google Scholar 

  99. Lloyd AC. Limits to lifespan. Nature Cell Biol 2002; 4:E25–E27.

    Article  PubMed  CAS  Google Scholar 

  100. Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92:9363–9367.

    Article  PubMed  CAS  Google Scholar 

  101. von Zglinicki T, Nilsson E, Docke WD, Brunk UT. Lipofuscin accumulation and ageing of fibroblasts. Gerontology 1995; 41(Suppl 2):95–108.

    Google Scholar 

  102. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science 2002; 295:2446–2449.

    Article  PubMed  CAS  Google Scholar 

  103. Serrano M, Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 2001; 13:748–753.

    Article  PubMed  CAS  Google Scholar 

  104. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001; 11:S27–S31.

    PubMed  CAS  Google Scholar 

  105. Lundberg AS, Hahn WC, Gupta P, Weinberg RA. Genes involved in senescence and immortalization. Curr Opin Cell Biol 2000; 12:705–709.

    Article  PubMed  CAS  Google Scholar 

  106. Schmitt CA, Fridman JS, Yang M, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109:335–346.

    Article  PubMed  CAS  Google Scholar 

  107. Smith JR, Pereira-Smith OM. Replicative senescence: implications for in vivo aging and tumor suppression. Science 1996; 273:63–67.

    Article  PubMed  CAS  Google Scholar 

  108. Campisi J, Kim SH, Lim CS, Rubio M. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol 2001; 36:1619–1637.

    Article  PubMed  CAS  Google Scholar 

  109. Cao L, Li W, Kim S, Brodie SG, Deng CX. Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev 2003; 17:201–213.

    Article  PubMed  CAS  Google Scholar 

  110. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96:701–712.

    Article  PubMed  CAS  Google Scholar 

  111. Tyner SD, Venkatachalam S, Choi J, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 2002; 415:45–53.

    Article  PubMed  CAS  Google Scholar 

  112. Goodwin EC, DiMaio D. Induced senescence in HeLa cervical carcinoma cells containing elevated telomerase activity and extended telomeres. Cell Growth Differ 2001; 12:525–534.

    PubMed  CAS  Google Scholar 

  113. Lee CJ, Suh EJ, Kang HT, et al. Induction of senescence-like state and suppression of telomerase activity through inhibition of HPV E6/E7 gene expression in cells immortalized by HPV16 DNA. Exp Cell Res 2002; 277: 173–182.

    Article  PubMed  CAS  Google Scholar 

  114. 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; 74:2679–2686.

    Article  PubMed  CAS  Google Scholar 

  115. 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: 12,513–12,518.

    Article  PubMed  CAS  Google Scholar 

  116. Krtolica A, Parrinello S, Lockett S, Desprez P-Y, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 2001; 98: 12,072–12,077.

    Article  PubMed  CAS  Google Scholar 

  117. Roninson IB. Tumor cell senescence in cancer treatment. Cancer Res 2003; 63:2705–2715.

    PubMed  CAS  Google Scholar 

  118. 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: 7093–7098.

    Article  PubMed  CAS  Google Scholar 

  119. DiMaio D, Settleman J. Bovine papillomavirus mutant temperature defective for transformation, replication and transactivation. EMBO J 1988; 7:1197–1204.

    PubMed  CAS  Google Scholar 

  120. Aplan PD, Johnson BE, Russell E, Chervinsky DS, Kirsch IR. Cloning and characterization of TCTA, a gene located at the site of a t (1;3) translocation. Cancer Res 1995; 55:1917–1921.

    PubMed  CAS  Google Scholar 

  121. Takahashi C, Sheng Z, Horan TP, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 1998; 95:13,221–13,226.

    Article  PubMed  CAS  Google Scholar 

  122. Wang M, Liu YE, Greene J, et al. Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 1997; 14:2767–2774.

    Article  PubMed  CAS  Google Scholar 

  123. Nees M, Geoghegan JM, Hyman T, Frank S, Miller L, Woodworth CD. Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes. J Virol 2001; 75:4283–4296.

    Article  PubMed  CAS  Google Scholar 

  124. Segev N. Ypt/rab gtpases: regulators of protein trafficking. Sci STKE 2001; 2001:RE11.

    Article  PubMed  CAS  Google Scholar 

  125. Tisdale EJ, Balch WE. Rab2 is essential for the maturation of pre-Golgi intermediates. J Biol Chem 1996; 271:29,372–29,379.

    Article  PubMed  CAS  Google Scholar 

  126. Wilson DB, Wilson MP. Identification and subcellular localization of human rab5b, a new member of the ras-related superfamily of GTPases. J Clin Invest 1992; 89:996–1005.

    Article  PubMed  CAS  Google Scholar 

  127. Zahraoui A, Joberty G, Arpin M, et al. A small rab GTPase is distributed in cytoplasmic vesicles in nonpolarized cells but colocalizes with the tight junction marker ZO-1 in polarized epithelial cells. J Cell Biol 1994; 124:101–115.

    Article  PubMed  CAS  Google Scholar 

  128. Bandyopadhyay D, Medrano EE. The emerging role of epigenetics in cellular and organismal aging. Exp Gerontol 2003; 38:1299–1307.

    Article  PubMed  CAS  Google Scholar 

  129. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science 2003; 299:1355–1359.

    Article  PubMed  CAS  Google Scholar 

  130. Howard BH. Replicative senescence: considerations relating to the stability of heterochromatin domains. Exp Gerontol 1996; 31:281–293.

    Article  PubMed  CAS  Google Scholar 

  131. Ogryzko VV, Hirai TH, Russanova VR, Barbie DA, Howard BH. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol 1996; 16:5210–5218.

    PubMed  CAS  Google Scholar 

  132. Terao Y, Nishida J, Horiuchi S, et al. Sodium butyrate induces growth arrest and senescence-like phenotypes in gynecologic cancer cells. Int J Cancer 2001; 94:257–267.

    Article  PubMed  CAS  Google Scholar 

  133. Finzer P, Kuntzen C, Soto U, zur Hausen H, Rosl F. Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression. Oncogene 2001; 20:4768–4776.

    Article  PubMed  CAS  Google Scholar 

  134. Bandyopadhyay D, Okan NA, Bales E, Nascimento L, Cole PA, Medrano EE. Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res 2002; 62:6231–6239.

    PubMed  CAS  Google Scholar 

  135. Klochendler-Yeivin A, Muchardt C, Yaniv M. SWI/SNF chromatin remodeling and cancer. Curr Opin Genet Dev 2002; 12:73–79.

    Article  PubMed  CAS  Google Scholar 

  136. Eissenberg JC, Elgin SC. The HP1 protein family: getting a grip on chromatin. Curr Opin Genet Dev 2000; 10:204–210.

    Article  PubMed  CAS  Google Scholar 

  137. Dimova D, Nackerdien Z, Furgeson S, Eguchi S, Osley MA. A role for transcriptional repressors in targeting the yeast Swi/Snf complex. Mol Cell 1999; 4:75–83.

    Article  PubMed  CAS  Google Scholar 

  138. Hall AH, Alexander KA. RNA Interference of human papillomavirus Type 18 E6 and E7 induces senescence in HeLa cells. J Virol 2003; 77:6066–6069.

    Article  PubMed  CAS  Google Scholar 

  139. Chang BD, Swift ME, Shen M, Fang J, Broude EV, Roninson IB. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci USA 2002; 99:389–394.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Informatics, Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH

    Sarah S. Williams & Bruce J. Aronow PhD

  2. Division of Hematology/Oncology, Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH

    Susanne I. Wells PhD

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  1. Sarah S. Williams
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  2. Bruce J. Aronow PhD
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  1. CuraGen Corporation, New Haven, CT

    William J. LaRochelle PhD  & Richard A. Shimkets PhD  & 

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Williams, S.S., Aronow, B.J., Wells, S.I. (2005). Gene Program Signatures for Papillomavirus E2-Mediated Senescence in Cervical Cancer Cells. In: LaRochelle, W.J., Shimkets, R.A. (eds) The Oncogenomics Handbook. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-893-5:69

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  • DOI: https://doi.org/10.1385/1-59259-893-5:69

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