Skip to main content
SpringerLink
Log in
Book cover

Human Papillomavirus (HPV)-Associated Oropharyngeal Cancer pp 69–101Cite as

HPV Virology: Cellular Targets of HPV Oncogenes and Transformation

  • Chapter
  • First Online:

  • 1004 Accesses

Abstract

A subtype of head and neck cancer (HNC) characterized by infection with human papillomavirus (HPV) is clinically and molecularly distinct from classical HNC. In general these tumors arise in younger patients and respond better to therapy, while also expressing wild-type tumor suppressor proteins. Owing to these observations, efforts are currently being made to understand HPV+ HNC biology to improve clinical treatment regimens and develop novel therapeutic agents. To best predict which treatment strategies and novel therapeutics will have the most impact in patient care, a working understanding of how the HPV arsenal of oncogenes manipulates and transforms cells is crucial. This chapter will highlight the most important and clinically interesting cellular targets of the HPV oncogenes; the mechanisms by which the viral oncogenes subvert cell cycle checkpoints, DNA repair, immune surveillance, and cell death to promote malignant transformation; and promising future therapeutic options to target the functions of HPV oncogenes.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abbate EA, Voitenleitner C, Botchan MR (2006) Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association. Mol Cell 24:877–889

    CAS  PubMed  Google Scholar 

  • Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, Martin BK et al (2013) The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature 500:207–211

    CAS  PubMed Central  PubMed  Google Scholar 

  • Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ et al (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333:1154–1157

    CAS  PubMed Central  PubMed  Google Scholar 

  • Akagi K, Li J, Broutian TR, Padilla-Nash H, Xiao W, Jiang B et al (2014) Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Res 24:185–199

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alter BP, Giri N, Savage SA, Quint WG, de Koning MN, Schiffman M (2013) Squamous cell carcinomas in patients with Fanconi anemia and dyskeratosis congenita: a search for human papillomavirus. Int J Cancer 133:1513–1515

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andreassen PR, D’Andrea AD, Taniguchi T (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18:1958–1963

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35

    CAS  PubMed Central  PubMed  Google Scholar 

  • Antonsson A, Payne E, Hengst K, McMillan NA (2006) The human papillomavirus type 16 E7 protein binds human interferon regulatory factor-9 via a novel PEST domain required for transformation. J Interferon Cytokine Res 26:455–461

    CAS  PubMed  Google Scholar 

  • Arbeit JM, Howley PM, Hanahan D (1996) Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci U S A 93:2930–2935

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ashrafi GH, Haghshenas M, Marchetti B, Campo MS (2006) E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Int J Cancer 119:2105–2112

    CAS  PubMed  Google Scholar 

  • Asumalahti K, Veal C, Laitinen T, Suomela S, Allen M, Elomaa O et al (2002) Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Hum Mol Genet 11:589–597

    CAS  PubMed  Google Scholar 

  • Avvakumov N, Torchia J, Mymryk JS (2003) Interaction of the HPV E7 proteins with the pCAF acetyltransferase. Oncogene 22:3833–3841

    CAS  PubMed  Google Scholar 

  • Baker CC, Phelps WC, Lindgren V, Braun MJ, Gonda MA, Howley PM (1987) Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. J Virol 61:962–971

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barbaresi S, Cortese MS, Quinn J, Ashrafi GH, Graham SV, Campo MS (2010) Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain. J Gen Virol 91:521–530

    CAS  PubMed  Google Scholar 

  • Bernard BA, Bailly C, Lenoir MC, Darmon M, Thierry F, Yaniv M (1989) The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol 63:4317–4324

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bernat A, Avvakumov N, Mymryk JS, Banks L (2003) Interaction between the HPV E7 oncoprotein and the transcriptional coactivator p300. Oncogene 22:7871–7881

    PubMed  Google Scholar 

  • Boon SS, Banks L (2013) High-risk human papillomavirus E6 oncoproteins interact with 14-3-3zeta in a PDZ binding motif-dependent manner. J Virol 87:1586–1595

    CAS  PubMed Central  PubMed  Google Scholar 

  • Boulenouar S, Weyn C, Van Noppen M, Moussa Ali M, Favre M, Delvenne PO et al (2010) Effects of HPV-16 E5, E6 and E7 proteins on survival, adhesion, migration and invasion of trophoblastic cells. Carcinogenesis 31:473–480

    CAS  PubMed  Google Scholar 

  • Boyer SN, Wazer DE, Band V (1996) E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 56:4620–4624

    CAS  PubMed  Google Scholar 

  • Brake T, Lambert PF (2005) Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci U S A 102:2490–2495

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ et al (1999) The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 18:2449–2458

    CAS  PubMed Central  PubMed  Google Scholar 

  • Byg LM, Vidlund J, Vasiljevic N, Clausen D, Forslund O, Norrild B (2012) NF-kappaB signalling is attenuated by the E7 protein from cutaneous human papillomaviruses. Virus Res 169:48–53

    CAS  PubMed  Google Scholar 

  • Campo MS, Graham SV, Cortese MS, Ashrafi GH, Araibi EH, Dornan ES et al (2010) HPV-16 E5 down-regulates expression of surface HLA class I and reduces recognition by CD8 T cells. Virology 407:137–142

    CAS  PubMed  Google Scholar 

  • Carro MS, Spiga FM, Quarto M, Di Ninni V, Volorio S, Alcalay M et al (2006) DEK Expression is controlled by E2F and deregulated in diverse tumor types. Cell Cycle 5:1202–1207

    CAS  PubMed  Google Scholar 

  • Chaurushiya MS, Weitzman MD (2009) Viral manipulation of DNA repair and cell cycle checkpoints. DNA Repair (Amst) 8:1166–1176

    CAS  Google Scholar 

  • Chen SL, Lin ST, Tsai TC, Hsiao WC, Tsao YP (2007) ErbB4 (JM-b/CYT-1)-induced expression and phosphorylation of c-Jun is abrogated by human papillomavirus type 16 E5 protein. Oncogene 26:42–53

    PubMed  Google Scholar 

  • Chen SL, Lin YK, Li LY, Tsao YP, Lo HY, Wang WB et al (1996) E5 proteins of human papillomavirus types 11 and 16 transactivate the c-fos promoter through the NF1 binding element. J Virol 70:8558–8563

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H et al (2011) Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment. Dev Cell 20:342–352

    CAS  PubMed  Google Scholar 

  • Cheng S, Schmidt-Grimminger DC, Murant T, Broker TR, Chow LT (1995) Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 9:2335–2349

    CAS  PubMed  Google Scholar 

  • Cho YS, Kang JW, Cho M, Cho CW, Lee S, Choe YK et al (2001) Down modulation of IL-18 expression by human papillomavirus type 16 E6 oncogene via binding to IL-18. FEBS Lett 501:139–145

    CAS  PubMed  Google Scholar 

  • Conrad M, Bubb VJ, Schlegel R (1993) The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein. J Virol 67:6170–6178

    CAS  PubMed Central  PubMed  Google Scholar 

  • Conrad M, Goldstein D, Andresson T, Schlegel R (1994) The E5 protein of HPV-6, but not HPV-16, associates efficiently with cellular growth factor receptors. Virology 200:796–800

    CAS  PubMed  Google Scholar 

  • Crusius K, Kaszkin M, Kinzel V, Alonso A (1999) The human papillomavirus type 16 E5 protein modulates phospholipase C-gamma-1 activity and phosphatidyl inositol turnover in mouse fibroblasts. Oncogene 18:6714–6718

    CAS  PubMed  Google Scholar 

  • Crusius K, Rodriguez I, Alonso A (2000) The human papillomavirus type 16 E5 protein modulates ERK1/2 and p38 MAP kinase activation by an EGFR-independent process in stressed human keratinocytes. Virus Genes 20:65–69

    CAS  PubMed  Google Scholar 

  • D’Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3:23–34

    PubMed  Google Scholar 

  • Desaintes C, Demeret C, Goyat S, Yaniv M, Thierry F (1997) Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis. EMBO J 16:504–514

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Deshpande A, Sicinski P, Hinds PW (2005) Cyclins and cdks in development and cancer: a perspective. Oncogene 24:2909–2915

    CAS  PubMed  Google Scholar 

  • Di Domenico F, Foppoli C, Blarzino C, Perluigi M, Paolini F, Morici S et al (2009) Expression of human papilloma virus type 16 E5 protein in amelanotic melanoma cells regulates endo-cellular pH and restores tyrosinase activity. J Exp Clin Cancer Res 28:4

    PubMed Central  PubMed  Google Scholar 

  • DiMaio D, Petti LM (2013) The E5 proteins. Virology 445:99–114

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dowhanick JJ, Mcbride AA, Howley PM (1995) Suppression of Cellular Proliferation by the Papillomavirus E2 Protein. J Virol 69:7791–7799

    CAS  PubMed Central  PubMed  Google Scholar 

  • Du M, Fan X, Hong E, Chen JJ (2002) Interaction of oncogenic papillomavirus E6 proteins with fibulin-1. Biochem Biophys Res Commun 296:962–969

    CAS  PubMed  Google Scholar 

  • Duensing A, Liu Y, Perdreau SA, Kleylein-Sohn J, Nigg EA, Duensing S (2007) Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates. Oncogene 26:6280–6288

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Duensing S, Duensing A, Flores ER, Do A, Lambert PF, Munger K (2001b) Centrosome abnormalities and genomic instability by episomal expression of human papillomavirus type 16 in raft cultures of human keratinocytes. J Virol 75:7712–7716

    CAS  PubMed Central  PubMed  Google Scholar 

  • Duensing S, Lee LY, Duensing A, Basile J, Piboonniyom S, Gonzalez S et al (2000) 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 U S A 97:10002–10007

    CAS  PubMed Central  PubMed  Google Scholar 

  • Duensing S, Munger K (2002) The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res 62:7075–7082

    CAS  PubMed  Google Scholar 

  • Duensing S, Munger K (2003) Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. J Virol 77:12331–12335

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–2262

    CAS  PubMed  Google Scholar 

  • Dyson N, Howley PM, Munger K, Harlow E (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937

    CAS  PubMed  Google Scholar 

  • Espinosa AM, Alfaro A, Roman-Basaure E, Guardado-Estrada M, Palma I, Serralde C et al (2013) Mitosis is a source of potential markers for screening and survival and therapeutic targets in cervical cancer. PLoS ONE 8:e55975

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fan X, Liu Y, Heilman SA, Chen JJ (2013) Human papillomavirus E7 induces rereplication in response to DNA damage. J Virol 87:1200–1210

    CAS  PubMed Central  PubMed  Google Scholar 

  • Filippova M, Parkhurst L, Duerksen-Hughes PJ (2004) The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J Biol Chem 279:25729–25744

    CAS  PubMed  Google Scholar 

  • Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ (2002) The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis. J Biol Chem 277:21730–21739

    CAS  PubMed  Google Scholar 

  • Fischer M, Quaas M, Wintsche A, Muller GA, Engeland K (2014) Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. Nucleic Acids Res 42:163–180

    CAS  PubMed Central  PubMed  Google Scholar 

  • Freire R, van Vugt MA, Mamely I, Medema RH (2006) Claspin: timing the cell cycle arrest when the genome is damaged. Cell Cycle 5:2831–2834

    CAS  PubMed  Google Scholar 

  • French D, Belleudi F, Mauro MV, Mazzetta F, Raffa S, Fabiano V et al (2013) Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway. Mol Cancer 12:38

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gao GF, Jakobsen BK (2000) Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor. Immunol Today 21:630–636

    CAS  PubMed  Google Scholar 

  • Garnett TO, Duerksen-Hughes PJ (2006) Modulation of apoptosis by human papillomavirus (HPV) oncoproteins. Arch Virol 151:2321–2335

    CAS  PubMed Central  PubMed  Google Scholar 

  • Garnett TO, Filippova M, Duerksen-Hughes PJ (2006) Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ 13:1915–1926

    CAS  PubMed Central  PubMed  Google Scholar 

  • Genther Williams SM, Disbrow GL, Schlegel R, Lee D, Threadgill DW, Lambert PF (2005) Requirement of epidermal growth factor receptor for hyperplasia induced by E5, a high-risk human papillomavirus oncogene. Cancer Res 65:6534–6542

    CAS  PubMed  Google Scholar 

  • Gewin L, Myers H, Kiyono T, Galloway DA (2004) Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev 18:2269–2282

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gillespie KA, Mehta KP, Laimins LA, Moody CA (2012) Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol 86:9520–9526

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:709–720

    CAS  PubMed  Google Scholar 

  • Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goodwin EC, DiMaio D (2000) Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci U S A 97:12513–12518

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gross-Mesilaty S, Reinstein E, Bercovich B, Tobias KE, Schwartz AL, Kahana C et al (1998) Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Natl Acad Sci U S A 95:8058–8063

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gruener M, Bravo IG, Momburg F, Alonso A, Tomakidi P (2007) The E5 protein of the human papillomavirus type 16 down-regulates HLA-I surface expression in calnexin-expressing but not in calnexin-deficient cells. Virol J 4:116

    PubMed Central  PubMed  Google Scholar 

  • Guarguaglini G, Duncan PI, Stierhof YD, Holmstrom T, Duensing S, Nigg EA (2005) The forkhead-associated domain protein Cep170 interacts with Polo-like kinase 1 and serves as a marker for mature centrioles. Mol Biol Cell 16:1095–1107

    CAS  PubMed Central  PubMed  Google Scholar 

  • Halbert CL, Demers GW, Galloway DA (1991) The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65:473–478

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hanahan D, Weinberg Robert A (2011) Hallmarks of Cancer: The Next Generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J 8:3905–3910

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hebner CM, Wilson R, Rader J, Bidder M, Laimins LA (2006) Human papillomaviruses target the double-stranded RNA protein kinase pathway. J Gen Virol 87:3183–3193

    CAS  PubMed  Google Scholar 

  • Heilman SA, Nordberg JJ, Liu Y, Sluder G, Chen JJ (2009) Abrogation of the postmitotic checkpoint contributes to polyploidization in human papillomavirus E7-expressing cells. J Virol 83:2756–2764

    CAS  PubMed Central  PubMed  Google Scholar 

  • Helfer CM, Wang R, You J (2013) Analysis of the papillomavirus E2 and bromodomain protein Brd4 interaction using bimolecular fluorescence complementation. PLoS ONE 8:e77994

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hellner K, Mar J, Fang F, Quackenbush J, Munger K (2009) HPV16 E7 oncogene expression in normal human epithelial cells causes molecular changes indicative of an epithelial to mesenchymal transition. Virology 391:57–63

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hong S, Laimins LA (2013) The JAK-STAT Transcriptional Regulator, STAT-5, Activates the ATM DNA Damage Pathway to Induce HPV 31 Genome Amplification upon Epithelial Differentiation. PLoS Pathog 9:e1003295

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoskins EE, Gunawardena RW, Habash KB, Wise-Draper TM, Jansen M, Knudsen ES et al (2008) Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene 27:4798–4808

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoskins EE, Morreale RJ, Werner SP, Higginbotham JM, Laimins LA, Lambert PF et al (2012) The fanconi anemia pathway limits human papillomavirus replication. J Virol 86:8131–8138

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoskins EE, Morris TA, Higginbotham JM, Spardy N, Cha E, Kelly P et al (2009) Fanconi anemia deficiency stimulates HPV-associated hyperplastic growth in organotypic epithelial raft culture. Oncogene 28:674–685

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hovest MG, Krieg T, Herrmann G (2011) Differential roles for Chk1 and FANCD2 in ATR-mediated signalling for psoralen photoactivation-induced senescence. Exp Dermatol 20:883–889

    CAS  PubMed  Google Scholar 

  • Huang SM, McCance DJ (2002) Down regulation of the interleukin-8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 and P/CAF. J Virol 76:8710–8721

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huh KW, DeMasi J, Ogawa H, Nakatani Y, Howley PM, Munger K (2005) Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. Proc Natl Acad Sci U S A 102:11492–11497

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hwang ES, Nottoli T, Dimaio D (1995) The HPV16 E5 protein: expression, detection, and stable complex formation with transmembrane proteins in COS cells. Virology 211:227–233

    CAS  PubMed  Google Scholar 

  • Hwang SG, Lee D, Kim J, Seo T, Choe J (2002) Human papillomavirus type 16 E7 binds to E2F1 and activates E2F1-driven transcription in a retinoblastoma protein-independent manner. J Biol Chem 277:2923–2930

    CAS  PubMed  Google Scholar 

  • Iftner T, Elbel M, Schopp B, Hiller T, Loizou JI, Caldecott KW et al (2002) Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 21:4741–4748

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jeon S, Allen-Hoffmann BL, Lambert PF (1995) Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol 69:2989–2997

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jung YS, Kato I, Kim HR (2013) A novel function of HPV16-E6/E7 in epithelial-mesenchymal transition. Biochem Biophys Res Commun 435:339–344

    CAS  PubMed  Google Scholar 

  • Kanno T, Kanno Y, Siegel RM, Jang MK, Lenardo MJ, Ozato K (2004) Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell 13:33–43

    CAS  PubMed  Google Scholar 

  • Katich SC, Zerfass-Thome K, Hoffmann I (2001) Regulation of the Cdc25A gene by the human papillomavirus Type 16 E7 oncogene. Oncogene 20:543–550

    CAS  PubMed  Google Scholar 

  • Katzenellenbogen RA, Vliet-Gregg P, Xu M, Galloway DA (2009) NFX1-123 increases hTERT expression and telomerase activity posttranscriptionally in human papillomavirus type 16 E6 keratinocytes. J Virol 83:6446–6456

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kaur P, McDougall JK (1988) Characterization of primary human keratinocytes transformed by human papillomavirus type 18. J Virol 62:1917–1924

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kavanaugh GM, Wise-Draper TM, Morreale RJ, Morrison MA, Gole B, Schwemberger S et al (2011) The human DEK oncogene regulates DNA damage response signaling and repair. Nucleic Acids Res 39:7465–7476

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kaverina I, Krylyshkina O, Small JV (2002) Regulation of substrate adhesion dynamics during cell motility. Int J Biochem Cell Biol 34:746–761

    CAS  PubMed  Google Scholar 

  • Kim SH, Juhnn YS, Kang S, Park SW, Sung MW, Bang YJ et al (2006) Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3 K/Akt. Cell Mol Life Sci 63:930–938

    CAS  PubMed  Google Scholar 

  • Kim SH, Oh JM, No JH, Bang YJ, Juhnn YS, Song YS (2009) Involvement of NF-kappaB and AP-1 in COX-2 upregulation by human papillomavirus 16 E5 oncoprotein. Carcinogenesis 30:753–757

    CAS  PubMed  Google Scholar 

  • Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA, Yang RZ et al (2013) Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 73:4791–4800

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kivi N, Greco D, Auvinen P, Auvinen E (2008) Genes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expression. Oncogene 27:2532–2541

    CAS  PubMed  Google Scholar 

  • Kleine-Lowinski K, Rheinwald JG, Fichorova RN, Anderson DJ, Basile J, Munger K et al (2003) Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells. Int J Cancer 107:407–415

    CAS  PubMed  Google Scholar 

  • Klingelhutz AJ, Foster SA, McDougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380:79–82

    CAS  PubMed  Google Scholar 

  • Korzeniewski N, Spardy N, Duensing A, Duensing S (2011a) Genomic instability and cancer: lessons learned from human papillomaviruses. Cancer Lett 305:113–122

    CAS  PubMed Central  PubMed  Google Scholar 

  • Korzeniewski N, Treat B, Duensing S (2011b) The HPV-16 E7 oncoprotein induces centriole multiplication through deregulation of Polo-like kinase 4 expression. Mol Cancer 10:61

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kottemann MC, Smogorzewska A (2013) Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493:356–363

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14:467–475

    CAS  PubMed  Google Scholar 

  • Kutler DI, Wreesmann VB, Goberdhan A, Ben-Porat L, Satagopan J, Ngai I et al (2003) Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 95:1718–1721

    CAS  PubMed  Google Scholar 

  • Lai D, Tan CL, Gunaratne J, Quek LS, Nei W, Thierry F et al (2013) Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism. PLoS ONE 8:e75625

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee AY, Chiang CM (2009) Chromatin adaptor Brd4 modulates E2 transcription activity and protein stability. J Biol Chem 284:2778–2786

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee SS, Glaunsinger B, Mantovani F, Banks L, Javier RT (2000) Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high-risk papillomavirus type 18 E6 oncoproteins. J Virol 74:9680–9693

    CAS  PubMed Central  PubMed  Google Scholar 

  • Leechanachai P, Banks L, Moreau F, Matlashewski G (1992) The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene 7:19–25

    CAS  PubMed  Google Scholar 

  • Leptak C, Ramon y Cajal S, Kulke R, Kulke R, Horwitz BH, Riese DJ, Dotto GP et al (1991) Tumorigenic transformation of murine keratinocytes by the E5 genes of bovine papillomavirus type 1 and human papillomavirus type 16. J Virol 65:7078–7083

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liao S, Deng D, Hu X, Wang W, Li L, Li W et al (2013a) HPV16/18 E5, a promising candidate for cervical cancer vaccines, affects SCPs, cell proliferation and cell cycle, and forms a potential network with E6 and E7. Int J Mol Med 31:120–128

    CAS  PubMed  Google Scholar 

  • Liao S, Deng D, Zhang W, Hu X, Wang W, Wang H et al (2013b) Human papillomavirus 16/18 E5 promotes cervical cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo. Oncol Rep 29:95–102

    CAS  PubMed  Google Scholar 

  • Liu X, Dakic A, Zhang Y, Dai Y, Chen R, Schlegel R (2009) HPV E6 protein interacts physically and functionally with the cellular telomerase complex. Proc Natl Acad Sci U S A 106:18780–18785

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Y, Heilman SA, Illanes D, Sluder G, Chen JJ (2007) p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Cancer Res 67:2603–2610

    CAS  PubMed  Google Scholar 

  • Loncarek J, Hergert P, Magidson V, Khodjakov A (2008) Control of daughter centriole formation by the pericentriolar material. Nat Cell Biol 10:322–328

    CAS  PubMed Central  PubMed  Google Scholar 

  • Machida YJ, Dutta A (2007) The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev 21:184–194

    CAS  PubMed Central  PubMed  Google Scholar 

  • Massimi P, Shai A, Lambert P, Banks L (2008) HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background. Oncogene 27:1800–1804

    CAS  PubMed  Google Scholar 

  • Matsukura T, Koi S, Sugase M (1989) Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers. Virology 172:63–72

    CAS  PubMed  Google Scholar 

  • McKenna DJ, Patel D, McCance DJ (2014) miR-24 and miR-205 expression is dependent on HPV onco-protein expression in keratinocytes. Virology 448:210–216

    CAS  PubMed Central  PubMed  Google Scholar 

  • McLaughlin-Drubin ME, Huh KW, Munger K (2008) Human papillomavirus type 16 E7 oncoprotein associates with E2F6. J Virol 82:8695–8705

    CAS  PubMed Central  PubMed  Google Scholar 

  • McMurray HR, McCance DJ (2003) Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. J Virol 77:9852–9861

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mihaylov IS, Kondo T, Jones L, Ryzhikov S, Tanaka J, Zheng J et al (2002) Control of DNA replication and chromosome ploidy by geminin and cyclin A. Mol Cell Biol 22:1868–1880

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mileo AM, Abbruzzese C, Vico C, Bellacchio E, Matarrese P, Ascione B et al (2013) The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin. Carcinogenesis 34:2424–2433

    CAS  PubMed  Google Scholar 

  • Miura S, Kawana K, Schust DJ, Fujii T, Yokoyama T, Iwasawa Y et al (2010) CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV. J Virol 84:11614–11623

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moody CA, Laimins LA (2010) Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10:550–560

    CAS  PubMed  Google Scholar 

  • Moody CA, Laimins LA (2009) Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog 5:e1000605

    PubMed Central  PubMed  Google Scholar 

  • Muller M, Demeret C (2014) CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding. PLoS ONE 9:e92581

    PubMed Central  PubMed  Google Scholar 

  • Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nguyen CL, Eichwald C, Nibert ML, Munger K (2007) Human papillomavirus type 16 E7 oncoprotein associates with the centrosomal component gamma-tubulin. J Virol 81:13533–13543

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nguyen CL, Munger K (2008) Direct association of the HPV16 E7 oncoprotein with cyclin A/CDK2 and cyclin E/CDK2 complexes. Virology 380:21–25

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nguyen DX, Westbrook TF, McCance DJ (2002) Human papillomavirus type 16 E7 maintains elevated levels of the cdc25A tyrosine phosphatase during deregulation of cell cycle arrest. J Virol 76:619–632

    CAS  PubMed Central  PubMed  Google Scholar 

  • Niebler M, Qian X, Hofler D, Kogosov V, Kaewprag J, Kaufmann AM et al (2013) Post-translational control of IL-1beta via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53. PLoS Pathog 9:e1003536

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nishimura A, Ono T, Ishimoto A, Dowhanick JJ, Frizzell MA, Howley PM et al (2000) Mechanisms of human papillomavirus E2-mediated repression of viral oncogene expression and cervical cancer cell growth inhibition. J Virol 74:3752–3760

    CAS  PubMed Central  PubMed  Google Scholar 

  • Oh JM, Kim SH, Cho EA, Song YS, Kim WH, Juhnn YS (2010) Human papillomavirus type 16 E5 protein inhibits hydrogen-peroxide-induced apoptosis by stimulating ubiquitin-proteasome-mediated degradation of Bax in human cervical cancer cells. Carcinogenesis 31:402–410

    CAS  PubMed  Google Scholar 

  • Oh JM, Kim SH, Lee YI, Seo M, Kim SY, Song YS et al (2009) Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells. Carcinogenesis 30:141–149

    CAS  PubMed  Google Scholar 

  • Park JW, Shin MK, and Lambert PF (2013) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7’s induction of DNA damage response, an activity mediated by E7’s inactivation of pocket proteins. Oncogene

    Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Patel D, McCance DJ (2010) Compromised spindle assembly checkpoint due to altered expression of Ubch10 and Cdc20 in human papillomavirus type 16 E6- and E7-expressing keratinocytes. J Virol 84:10956–10964

    CAS  PubMed Central  PubMed  Google Scholar 

  • Paulsson K, Wang P (2003) Chaperones and folding of MHC class I molecules in the endoplasmic reticulum. Biochim Biophys Acta 1641:1–12

    CAS  PubMed  Google Scholar 

  • Pedroza-Saavedra A, Lam EW, Esquivel-Guadarrama F, Gutierrez-Xicotencatl L (2010) The human papillomavirus type 16 E5 oncoprotein synergizes with EGF-receptor signaling to enhance cell cycle progression and the down-regulation of p27(Kip1). Virology 400:44–52

    CAS  PubMed  Google Scholar 

  • Pim D, Collins M, Banks L (1992) Human papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptor. Oncogene 7:27–32

    CAS  PubMed  Google Scholar 

  • Pim D, Thomas M, Javier R, Gardiol D, Banks L (2000) HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase. Oncogene 19:719–725

    CAS  PubMed  Google Scholar 

  • Regan JA, Laimins LA (2008) Bap31 is a novel target of the human papillomavirus E5 protein. J Virol 82:10042–10051

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reuter S, Bartelmann M, Vogt M, Geisen C, Napierski I, Kahn T, Delius H, Lichter Pm Weitz S, Korn B, Schwarz E (1998) APM-1, a novel human gene, identified by aberrant co-transcription with papillomavirus oncogenes in a cervical carcinoma cell line, encodes a BTB/POZ-zinc finger protein with growth inhibitory activity. EMBO J 17(1):215−222

    Google Scholar 

  • Rey O, Lee S, Park NH (2000) Human papillomavirus type 16 E7 oncoprotein represses transcription of human fibronectin. J Virol 74:4912–4918

    CAS  PubMed Central  PubMed  Google Scholar 

  • Riaz N, Sherman EJ, Fury M, Lee N (2013) Should cetuximab replace Cisplatin for definitive chemoradiotherapy in locally advanced head and neck cancer? J Clin Oncol 31:287–288

    CAS  PubMed  Google Scholar 

  • Ricciotti E, FitzGerald GA (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986–1000

    CAS  PubMed Central  PubMed  Google Scholar 

  • Richards KH, Doble R, Wasson CW, Haider M, Blair GE, Wittmann M et al (2014) Human papillomavirus e7 oncoprotein increases production of the anti-inflammatory interleukin-18 binding protein in keratinocytes. J Virol 88:4173–4179

    PubMed Central  PubMed  Google Scholar 

  • Rieckmann T, Tribius S, Grob TJ, Meyer F, Busch CJ, Petersen C et al. (2013) HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Romick-Rosendale LE, Lui VW, Grandis JR, Wells SI (2013) The Fanconi anemia pathway: repairing the link between DNA damage and squamous cell carcinoma. Mutat Res 743–744:78–88

    PubMed  Google Scholar 

  • Ronco LV, Karpova AY, Vidal M, Howley PM (1998) Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rossjohn J, Pellicci DG, Patel O, Gapin L, Godfrey DI (2012) Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol 12:845–857

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sadasivam S, DeCaprio JA (2013) The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer 13:585–595

    CAS  PubMed Central  PubMed  Google Scholar 

  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505

    CAS  PubMed  Google Scholar 

  • Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Human papillomavirus and cervical cancer. Lancet 370:890–907

    CAS  PubMed  Google Scholar 

  • Schmitz M, Driesch C, Beer-Grondke K, Jansen L, Runnebaum IB, Dürst M (2012) Loss of gene function as a consequence of human papillomavirus DNA integration. Int J Cancer 131:E593−E602

    Google Scholar 

  • Schvartzman JM, Sotillo R, Benezra R (2010) Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 10:102–115

    CAS  PubMed  Google Scholar 

  • Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A et al (1985) Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314:111–114

    CAS  PubMed  Google Scholar 

  • Schweiger MR, Ottinger M, You J, Howley PM (2007) Brd4-independent transcriptional repression function of the papillomavirus e2 proteins. J Virol 81:9612–9622

    CAS  PubMed Central  PubMed  Google Scholar 

  • Scully C (2002) Oral squamous cell carcinoma; from an hypothesis about a virus, to concern about possible sexual transmission. Oral Oncol 38:227–234

    PubMed  Google Scholar 

  • Shin KH, Ahn JH, Kang MK, Lim PK, Yip FK, Baluda MA et al (2006) HPV-16 E6 oncoprotein impairs the fidelity of DNA end-joining via p53-dependent and -independent pathways. Int J Oncol 28:209–215

    CAS  PubMed  Google Scholar 

  • Shirasawa H, Tomita Y, Sekiya S, Takamizawa H, Simizu B (1987) Integration and transcription of human papillomavirus type 16 and 18 sequences in cell lines derived from cervical carcinomas. J Gen Virol 68(Pt 2):583–591

    CAS  PubMed  Google Scholar 

  • Sluder G, Thompson EA, Miller FJ, Hayes J, Rieder CL (1997) The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry. J Cell Sci 110(Pt 4):421–429

    CAS  PubMed  Google Scholar 

  • Smith J, Tho LM, Xu N, Gillespie DA (2010a) The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 108:73–112

    CAS  PubMed  Google Scholar 

  • Smith JA, White EA, Sowa ME, Powell ML, Ottinger M, Harper JW et al (2010b) Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc Natl Acad Sci U S A 107:3752–3757

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spanos WC, Hoover A, Harris GF, Wu S, Strand GL, Anderson ME et al (2008) The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth. J Virol 82:2493–2500

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spardy N, Covella K, Cha E, Hoskins EE, Wells SI, Duensing A et al (2009) Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of claspin. Cancer Res 69:7022–7029

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spardy N, Duensing A, Charles D, Haines N, Nakahara T, Lambert PF et al (2007) The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells. J Virol 81:13265–13270

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spardy N, Duensing A, Hoskins EE, Wells SI, Duensing S (2008) HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies. Cancer Res 68:9954–9963

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stevaux O, Dyson NJ (2002) A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14:684–691

    CAS  PubMed  Google Scholar 

  • Stoppler MC, Straight SW, Tsao G, Schlegel R, McCance DJ (1996) The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA. Virology 223:251–254

    CAS  PubMed  Google Scholar 

  • Straight SW, Herman B, McCance DJ (1995) The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes. J Virol 69:3185–3192

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333:1157–1160

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sunthamala N, Thierry F, Teissier S, Pientong C, Kongyingyoes B, Tangsiriwatthana T et al (2014) E2 proteins of high risk human papillomaviruses down-modulate STING and IFN-kappa transcription in keratinocytes. PLoS ONE 9:e91473

    PubMed Central  PubMed  Google Scholar 

  • Suprynowicz FA, Disbrow GL, Krawczyk E, Simic V, Lantzky K, Schlegel R (2008) HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells. Oncogene 27:1071–1078

    CAS  PubMed  Google Scholar 

  • Suprynowicz FA, Krawczyk E, Hebert JD, Sudarshan SR, Simic V, Kamonjoh CM et al (2010) The human papillomavirus type 16 E5 oncoprotein inhibits epidermal growth factor trafficking independently of endosome acidification. J Virol 84:10619–10629

    CAS  PubMed Central  PubMed  Google Scholar 

  • Szalmas A, Gyongyosi E, Ferenczi A, Laszlo B, Karosi T, Csomor P et al (2013) Activation of Src, Fyn and Yes non-receptor tyrosine kinases in keratinocytes expressing human papillomavirus (HPV) type 16 E7 oncoprotein. Virol J 10:79

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thierry F, Heard JM, Dartmann K, Yaniv M (1987) Characterization of a transcriptional promoter of human papillomavirus 18 and modulation of its expression by simian virus 40 and adenovirus early antigens. J Virol 61:134–142

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thierry F, Yaniv M (1987) The BPV1-E2 trans-acting protein can be either an activator or a repressor of the HPV18 regulatory region. EMBO J 6:3391–3397

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas JT, Laimins LA (1998) Human papillomavirus oncoproteins E6 and E7 independently abrogate the mitotic spindle checkpoint. J Virol 72:1131–1137

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas M, Banks L (1998) Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17:2943–2954

    CAS  PubMed  Google Scholar 

  • Thomas MC, Chiang CM (2005) E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation. Mol Cell 17:251–264

    CAS  PubMed  Google Scholar 

  • Thompson DA, Belinsky G, Chang TH, Jones DL, Schlegel R, Munger K (1997) The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints. Oncogene 15:3025–3035

    CAS  PubMed  Google Scholar 

  • Thomsen P, van Deurs B, Norrild B, Kayser L (2000) The HPV16 E5 oncogene inhibits endocytic trafficking. Oncogene 19:6023–6032

    CAS  PubMed  Google Scholar 

  • Tiala I, Wakkinen J, Suomela S, Puolakkainen P, Tammi R, Forsberg S et al (2008) The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice. Hum Mol Genet 17:1043–1051

    CAS  PubMed  Google Scholar 

  • Todorovic B, Nichols AC, Chitilian JM, Myers MP, Shepherd TG, Parsons SJ et al (2014) The human papillomavirus E7 proteins associate with p190RhoGAP and alter its function. J Virol 88:3653–3663

    PubMed Central  PubMed  Google Scholar 

  • Tomakidi P, Cheng H, Kohl A, Komposch G, Alonso A (2000) Connexin 43 expression is downregulated in raft cultures of human keratinocytes expressing the human papillomavirus type 16 E5 protein. Cell Tissue Res 301:323–327

    CAS  PubMed  Google Scholar 

  • Tsao YP, Li LY, Tsai TC, Chen SL (1996) Human papillomavirus type 11 and 16 E5 represses p21(WafI/SdiI/CipI) gene expression in fibroblasts and keratinocytes. J Virol 70:7535–7539

    CAS  PubMed Central  PubMed  Google Scholar 

  • van Zeeburg HJ, Snijders PJ, Pals G, Hermsen MA, Rooimans MA, Bagby G et al (2005) Generation and molecular characterization of head and neck squamous cell lines of fanconi anemia patients. Cancer Res 65:1271–1276

    PubMed  Google Scholar 

  • van Zeeburg HJ, Snijders PJ, Wu T, Gluckman E, Soulier J, Surralles J et al (2008) Clinical and molecular characteristics of squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 100:1649–1653

    PubMed Central  PubMed  Google Scholar 

  • Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y et al (2003) A p53-dependent checkpoint pathway prevents rereplication. Mol Cell 11:997–1008

    CAS  PubMed  Google Scholar 

  • Vidal L and Gillison ML (2008) Human papillomavirus in HNSCC: recognition of a distinct disease type. Hematol Oncol Clin North Am 22, 1125–42, vii

    Google Scholar 

  • Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C, Melsheimer P et al (2008) Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res 68:307–313

    CAS  PubMed  Google Scholar 

  • Vousden KH, Prives C (2009) Blinded by the Light: The Growing Complexity of p53. Cell 137:413–431

    CAS  PubMed  Google Scholar 

  • Wallace NA and Galloway DA (2014) Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses. Semin Cancer Biol

    Google Scholar 

  • Wallace NA, Robinson K, Howie HL, Galloway DA (2012) HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. PLoS Pathog 8:e1002807

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang X, Helfer CM, Pancholi N, Bradner JE, You J (2013) Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J Virol 87:3871–3884

    CAS  PubMed Central  PubMed  Google Scholar 

  • Watson RA, Thomas M, Banks L, Roberts S (2003) Activity of the human papillomavirus E6 PDZ-binding motif correlates with an enhanced morphological transformation of immortalized human keratinocytes. J Cell Sci 116:4925–4934

    CAS  PubMed  Google Scholar 

  • Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM (2000) Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways. EMBO J 19:5762–5771

    CAS  PubMed Central  PubMed  Google Scholar 

  • Westra WH (2009) The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol 3:78–81

    PubMed Central  PubMed  Google Scholar 

  • Wetherill LF, Holmes KK, Verow M, Muller M, Howell G, Harris M et al (2012) High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors. J Virol 86:5341–5351

    CAS  PubMed Central  PubMed  Google Scholar 

  • Winkler B, Crum CP, Fujii T, Ferenczy A, Boon M, Braun L et al (1984) Koilocytotic lesions of the cervix. The relationship of mitotic abnormalities to the presence of papillomavirus antigens and nuclear DNA content. Cancer 53:1081–1087

    CAS  PubMed  Google Scholar 

  • Wise-Draper TM, Draper DJ, Gutkind JS, Molinolo AA, Wikenheiser-Brokamp KA, Wells SI (2012) Future directions and treatment strategies for head and neck squamous cell carcinomas. Transl Res 160:167–177

    PubMed Central  PubMed  Google Scholar 

  • Wittekindt C, Wagner S, Mayer CS, and Klussmann JP (2012) [Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer]. Laryngorhinootologie 91 Suppl 1, S1–26

    Google Scholar 

  • Wu SY, Lee AY, Hou SY, Kemper JK, Erdjument-Bromage H, Tempst P et al (2006) Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev 20:2383–2396

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xie X, Piao L, Bullock BN, Smith A, Su T, Zhang M et al (2014) Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. Oncogene 33:1037–1046

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xue Y, Lim D, Zhi L, He P, Abastado JP, Thierry F (2012) Loss of HPV16 E2 Protein Expression Without Disruption of the E2 ORF Correlates with Carcinogenic Progression. Open Virol J 6:163–172

    PubMed Central  PubMed  Google Scholar 

  • Yaginuma Y, Eguchi A, Yoshimoto M, Ogawa K (2012) The PxDLLCxE sequence in conserved region 2 of human papilloma virus 18 protein E7 is required for E7 binding to centromere protein C. Oncology 83:210–217

    CAS  PubMed  Google Scholar 

  • Yim EK, Lee KH, Myeong J, Tong SY, Um SJ, Park JS (2007) Novel interaction between HPV E6 and BARD1 (BRCA1-associated ring domain 1) and its biologic roles. DNA Cell Biol 26:753–761

    CAS  PubMed  Google Scholar 

  • You J, Croyle JL, Nishimura A, Ozato K, Howley PM (2004) Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117:349–360

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zhang B, Srirangam A, Potter DA, Roman A (2005a) HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes. Oncogene 24:2585–2588

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Y, Fan S, Meng Q, Ma Y, Katiyar P, Schlegel R et al (2005b) BRCA1 interaction with human papillomavirus oncoproteins. J Biol Chem 280:33165–33177

    CAS  PubMed  Google Scholar 

  • Zhong ZH, Jiang WQ, Cesare AJ, Neumann AA, Wadhwa R, Reddel RR (2007) Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres. J Biol Chem 282:29314–29322

    CAS  PubMed  Google Scholar 

  • zur Hausen H (1999) Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol 9:405–411

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by two NIH awards: RO1 CA116316 and CA102357. Special thanks are given to Timothy Chlon for his critical input and discussion of the manuscript.

Author information

Authors and Affiliations

  1. Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7013, 45229, Cincinnati, OH, USA

    Eric A. Smith, Marie C. Matrka & Susanne I. Wells

Authors
  1. Eric A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie C. Matrka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanne I. Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric A. Smith .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Missouri, Columbia, Missouri, USA

    Daniel L. Miller

  2. Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana, USA

    M. Sharon Stack

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Smith, E.A., Matrka, M.C., Wells, S.I. (2015). HPV Virology: Cellular Targets of HPV Oncogenes and Transformation. In: Miller, D., Stack, M. (eds) Human Papillomavirus (HPV)-Associated Oropharyngeal Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-21100-8_4

Download citation

Publish with us

Policies and ethics

Search

Navigation