Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter January 8, 2020

Human papillomavirus oncoproteins and post-translational modifications: generating multifunctional hubs for overriding cellular homeostasis

  • Om Basukala ORCID logo , Vanessa Sarabia-Vega and Lawrence Banks ORCID logo EMAIL logo
From the journal Biological Chemistry

Abstract

Human papillomaviruses (HPVs) are major human carcinogens, causing around 5% of all human cancers, with cervical cancer being the most important. These tumors are all driven by the two HPV oncoproteins E6 and E7. Whilst their mechanisms of action are becoming increasingly clear through their abilities to target essential cellular tumor suppressor and growth control pathways, the roles that post-translational modifications (PTMs) of E6 and E7 play in the regulation of these activities remain unclear. Here, we discuss the direct consequences of some of the most common PTMs of E6 and E7, and how this impacts upon the multi-functionality of these viral proteins, and thereby contribute to the viral life cycle and to the induction of malignancy. Furthermore, it is becoming increasingly clear that these modifications, may, in some cases, offer novel routes for therapeutic intervention in HPV-induced disease.

Acknowledgments

We are very grateful to David Pim and Miranda Thomas for valuable comments on the manuscript. We also gratefully acknowledge research support provided by the Associazione Italiana per la Ricerca sul Cancro, funder id: http://dx.doi.org/10.13039/501100005010, grant number: 18578. Om Basukala and Vanessa Sarabia-Vega are recipients of ICGEB Arturo Falaschi Predoctoral Fellowships and are registered with the Open University UK.

References

Ackerman, P. and Osheroff, N. (1989). Regulation of casein kinase II activity by epidermal growth factor in human A-431 carcinoma cells. J. Biol. Chem. 264, 11958–11965.10.1016/S0021-9258(18)80160-0Search in Google Scholar

Armstrong, D.J. and Roman, A. (1995). Human papillomavirus type 6 E7 protein is a substrate in vitro of protein kinase C. Biochem. J. 312, 667–670.10.1042/bj3120667Search in Google Scholar

Banks, L., Pim, D., and Thomas, M. (2003). Viruses and the 26S proteasome: hacking into destruction. Trends Biochem. Sci. 28, 452–459.10.1016/S0968-0004(03)00141-5Search in Google Scholar

Barbosa, M.S., Edmonds, C., Fisher, C., Schiller, J.T., Lowy, D.R., and Vousden, K.H. (1990). The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. EMBO J. 9, 153–160.10.1002/j.1460-2075.1990.tb08091.xSearch in Google Scholar PubMed PubMed Central

Barnard, D., Diaz, H.B., Burke, T., Donoho, G., Beckmann, R., Jones, B., Barda, D., King, C., and Marshall, M. (2016). LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Invest. New Drugs 34, 49–60.10.1007/s10637-015-0310-ySearch in Google Scholar PubMed

Basukala, O., Mittal, S., Massimi, P., Bestagno, M., and Banks, L. (2019). The HPV-18 E7 CKII phospho acceptor site is required for maintaining the transformed phenotype of cervical tumour-derived cells. PLoS Pathog. 15, e1007769.10.1371/journal.ppat.1007769Search in Google Scholar PubMed PubMed Central

Bazzo Goulart, K.O., Guerra Godoy, A.E., Litvin, I.E., and Firmbach Pasqualotto, F. (2017). Expression analysis of transglutaminase 2 in premalignant lesions of the cervix. Appl. Cancer Res. 37, 27.10.1186/s41241-017-0018-8Search in Google Scholar

Ben-Saadon, R., Fajerman, I., Ziv, T., Hellman, U., Schwartz, A.L., and Ciechanover, A. (2004). The tumor suppressor protein p16(INK4a) and the human papillomavirus oncoprotein-58 E7 are naturally occurring lysine-less proteins that are degraded by the ubiquitin system. Direct evidence for ubiquitination at the N-terminal residue. J. Biol. Chem. 279, 41414–41421.10.1074/jbc.M407201200Search in Google Scholar PubMed

Berezutskaya, E. and Bagchi, S. (1997). The human papillomavirus E7 oncoprotein functionally interacts with the S4 subunit of the 26 S proteasome. J. Biol. Chem. 272, 30135–30140.10.1074/jbc.272.48.30135Search in Google Scholar PubMed

Bodily, J.M., Mehta, K.P., Cruz, L., Meyers, C., and Laimins, L.A. (2011). The E7 open reading frame acts in cis and in trans to mediate differentiation-dependent activities in the human papillomavirus type 16 life cycle. J. Virol. 85, 8852–8862.10.1128/JVI.00664-11Search in Google Scholar PubMed PubMed Central

Boon, S.S. and Banks, L. (2013). High-risk human papillomavirus E6 oncoproteins interact with 14-3-3zeta in a PDZ binding motif-dependent manner. J. Virol. 87, 1586–1595.10.1128/JVI.02074-12Search in Google Scholar PubMed PubMed Central

Boon, S.S., Tomaic, V., Thomas, M., Roberts, S., and Banks, L. (2015). Cancer-causing human papillomavirus E6 proteins display major differences in the phospho-regulation of their PDZ interactions. J. Virol. 89, 1579–1586.10.1128/JVI.01961-14Search in Google Scholar PubMed PubMed Central

Butz, K., Ristriani, T., Hengstermann, A., Denk, C., Scheffner, M., and Hoppe-Seyler, F. (2003). siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 22, 5938–5945.10.1038/sj.onc.1206894Search in Google Scholar PubMed

Calcada, E.O., Felli, I.C., Hosek, T., and Pierattelli, R. (2013). The heterogeneous structural behavior of E7 from HPV16 revealed by NMR spectroscopy. ChemBioChem 14, 1876–1882.10.1002/cbic.201300172Search in Google Scholar PubMed

Chemes, L.B., Sanchez, I.E., Smal, C., and de Prat-Gay, G. (2010). Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein. Structural modularity, intrinsic disorder and phosphorylation of human papillomavirus E7. FEBS J. 277, 973–988.10.1111/j.1742-4658.2009.07540.xSearch in Google Scholar PubMed

Chen, J. (2015). Signaling pathways in HPV-associated cancers and therapeutic implications. Rev. Med. Virol. 25 (Suppl 1), 24–53.10.1002/rmv.1823Search in Google Scholar PubMed

Chien, W.M., Parker, J.N., Schmidt-Grimminger, D.C., Broker, T.R., and Chow, L.T. (2000). Casein kinase II phosphorylation of the human papillomavirus-18 E7 protein is critical for promoting S-phase entry. Cell Growth Differ. 11, 425–435.Search in Google Scholar

Chin, C., Bae, J.H., Kim, M.J., Hwang, J.Y., Kim, S.J., Yoon, M.S., Lee, M.K., Kim, D.W., Chung, B.S., Kang, C.D., et al. (2005). Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells. Exp. Mol. Med. 37, 608–618.10.1038/emm.2005.74Search in Google Scholar PubMed

Cho-Chung, Y.S. and Nesterova, M.V. (2005). Tumor reversion: protein kinase A isozyme switching. Ann. N. Y. Acad. Sci. 1058, 76–86.10.1196/annals.1359.014Search in Google Scholar PubMed

Chua, M.M.J., Lee, M., and Dominguez, I. (2017a). Cancer-type dependent expression of CK2 transcripts. PLoS One 12, e0188854.10.1371/journal.pone.0188854Search in Google Scholar PubMed PubMed Central

Chua, M.M.J., Ortega, C.E., Sheikh, A., Lee, M., Abdul-Rassoul, H., Hartshorn, K.L., and Dominguez, I. (2017b). CK2 in cancer: cellular and biochemical mechanisms and potential therapeutic target. Pharmaceuticals 10, 18.10.3390/ph10010018Search in Google Scholar PubMed PubMed Central

Cullere, X., Rose, P., Thathamangalam, U., Chatterjee, A., Mullane, K.P., Pallas, D.C., Benjamin, T.L., Roberts, T.M., and Schaffhausen, B.S. (1998). Serine 257 phosphorylation regulates association of polyomavirus middle T antigen with 14-3-3 proteins. J. Virol. 72, 558–563.10.1128/JVI.72.1.558-563.1998Search in Google Scholar PubMed PubMed Central

Del Nonno, F., Pisani, G., Visca, P., Signore, F., Grillo, L.R., Baiocchini, A., Garbuglia, A.R., Sepe, S., Piacentini, M., and Falasca, L. (2011). Role and predictive strength of transglutaminase type 2 expression in premalignant lesions of the cervix. Modern Pathol. 24, 855.10.1038/modpathol.2011.40Search in Google Scholar PubMed

Delury, C.P., Marsh, E.K., James, C.D., Boon, S.S., Banks, L., Knight, G.L., and Roberts, S. (2013). The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18. J. Virol. 87, 9463–9472.10.1128/JVI.01234-13Search in Google Scholar PubMed PubMed Central

Dick, F.A. and Dyson, N.J. (2002). Three regions of the pRB pocket domain affect its inactivation by human papillomavirus E7 proteins. J. Virol. 76, 6224–6234.10.1128/JVI.76.12.6224-6234.2002Search in Google Scholar PubMed PubMed Central

Doorbar, J., Quint, W., Banks, L., Bravo, I.G., Stoler, M., Broker, T.R., and Stanley, M.A. (2012). The biology and life-cycle of human papillomaviruses. Vaccine 30 (Suppl 5), F55–70.10.1016/j.vaccine.2012.06.083Search in Google Scholar PubMed

Dyson, N., Howley, P.M., Munger, K., and Harlow, E. (1989). The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934–937.10.1126/science.2537532Search in Google Scholar PubMed

Engelke, C.G., Parsels, L.A., Qian, Y., Zhang, Q., Karnak, D., Robertson, J.R., Tanska, D.M., Wei, D., Davis, M.A., Parsels, J.D., et al. (2013). Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin. Cancer Res. 19, 4412–4421.10.1158/1078-0432.CCR-12-3748Search in Google Scholar PubMed PubMed Central

Findik, D., Song, Q., Hidaka, H., and Lavin, M. (1995). Protein kinase A inhibitors enhance radiation-induced apoptosis. J. Cell Biochem. 57, 12–21.10.1002/jcb.240570103Search in Google Scholar PubMed

Firzlaff, J.M., Galloway, D.A., Eisenman, R.N., and Luscher, B. (1989). The E7 protein of human papillomavirus type 16 is phosphorylated by casein kinase II. New Biol. 1, 44–53.Search in Google Scholar

Firzlaff, J.M., Luscher, B., and Eisenman, R.N. (1991). Negative charge at the casein kinase II phosphorylation site is important for transformation but not for Rb protein binding by the E7 protein of human papillomavirus type 16. Proc. Natl. Acad. Sci. USA 88, 5187–5191.10.1073/pnas.88.12.5187Search in Google Scholar PubMed PubMed Central

Forman, D., de Martel, C., Lacey, C.J., Soerjomataram, I., Lortet-Tieulent, J., Bruni, L., Vignat, J., Ferlay, J., Bray, F., Plummer, M., et al. (2012). Global burden of human papillomavirus and related diseases. Vaccine 30 (Suppl 5), F12–23.10.1016/j.vaccine.2012.07.055Search in Google Scholar PubMed

Gao, Q., Kumar, A., Srinivasan, S., Singh, L., Mukai, H., Ono, Y., Wazer, D.E., and Band, V. (2000). PKN binds and phosphorylates human papillomavirus E6 oncoprotein. J. Biol. Chem. 275, 14824–14830.10.1074/jbc.275.20.14824Search in Google Scholar

Garcia-Alai, M.M., Alonso, L.G., and de Prat-Gay, G. (2007). The N-terminal module of HPV16 E7 is an intrinsically disordered domain that confers conformational and recognition plasticity to the oncoprotein. Biochemistry 46, 10405–10412.10.1021/bi7007917Search in Google Scholar

Genovese, N.J., Banerjee, N.S., Broker, T.R., and Chow, L.T. (2008). Casein kinase II motif-dependent phosphorylation of human papillomavirus E7 protein promotes p130 degradation and S-phase induction in differentiated human keratinocytes. J. Virol. 82, 4862–4873.10.1128/JVI.01202-07Search in Google Scholar

Genovese, N.J., Broker, T.R., and Chow, L.T. (2011). Nonconserved lysine residues attenuate the biological function of the low-risk human papillomavirus E7 protein. J. Virol. 85, 5546–5554.10.1128/JVI.02166-10Search in Google Scholar

Heck, D.V., Yee, C.L., Howley, P.M., and Munger, K. (1992). Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc. Natl. Acad. Sci. USA 89, 4442–4446.10.1073/pnas.89.10.4442Search in Google Scholar

Hong, H.Y., Jeon, W.K., Bae, E.J., Kim, S.T., Lee, H.J., Kim, S.J., and Kim, B.C. (2010). 14-3-3 sigma and 14-3-3 zeta plays an opposite role in cell growth inhibition mediated by transforming growth factor-β1. Mol. Cells. 29, 305–309.10.1007/s10059-010-0037-8Search in Google Scholar

Huibregtse, J.M., Scheffner, M., and Howley, P.M. (1991). A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10, 4129–4135.10.1002/j.1460-2075.1991.tb04990.xSearch in Google Scholar

Huibregtse, J.M., Scheffner, M., and Howley, P.M. (1993). Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol. Cell Biol. 13, 4918–4927.10.1128/MCB.13.8.4918Search in Google Scholar

James, C.D. and Roberts, S. (2016). Viral interactions with PDZ domain-containing proteins-an oncogenic trait? Pathogens. 5, pii: E8. doi: 10.3390.10.3390/pathogens5010008Search in Google Scholar

Jensen, T.J., Loo, M.A., Pind, S., Williams, D.B., Goldberg, A.L., and Riordan, J.R. (1995). Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83, 129–135.10.1016/0092-8674(95)90241-4Search in Google Scholar

Jeon, J.H., Choi, K.H., Cho, S.Y., Kim, C.W., Shin, D.M., Kwon, J.C., Song, K.Y., Park, S.C., and Kim, I.G. (2003). Transglutaminase 2 inhibits Rb binding of human papillomavirus E7 by incorporating polyamine. EMBO J. 22, 5273–5282.10.1093/emboj/cdg495Search in Google Scholar PubMed PubMed Central

Jeon, J.H., Cho, S.Y., Kim, C.W., Shin, D.M., Jang, G.Y., Lee, H.J., Kang, H.S., Park, S.C., and Kim, I.G. (2006). Alteration of Rb binding to HPV 18 E7 modified by transglutaminase 2 with different type of polyamines. Front Biosci. 11, 1540–1548.10.2741/1902Search in Google Scholar PubMed

Jones, D.L., Thompson, D.A., and Munger, K. (1997). Destabilization of the RB tumor suppressor protein and stabilization of p53 contribute to HPV type 16 E7-induced apoptosis. Virology 239, 97–107.10.1006/viro.1997.8851Search in Google Scholar PubMed

Kamio, M., Yoshida, T., Ogata, H., Douchi, T., Nagata, Y., Inoue, M., Hasegawa, M., Yonemitsu, Y., and Yoshimura, A. (2004). SOCS1 [corrected] inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein. Oncogene 23, 3107–3115.10.1038/sj.onc.1207453Search in Google Scholar PubMed

Kao, W.H., Beaudenon, S.L., Talis, A.L., Huibregtse, J.M., and Howley, P.M. (2000). Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J. Virol. 74, 6408–6417.10.1128/JVI.74.14.6408-6417.2000Search in Google Scholar

Kehmeier, E., Ruhl, H., Voland, B., Stoppler, M.C., Androphy, E., and Stoppler, H. (2002). Cellular steady-state levels of “high risk” but not “low risk” human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53- and E6AP-binding capabilities. Virology 299, 72–87.10.1006/viro.2002.1502Search in Google Scholar PubMed

Kuhne, C., Gardiol, D., Guarnaccia, C., Amenitsch, H., and Banks, L. (2000). Differential regulation of human papillomavirus E6 by protein kinase A: conditional degradation of human discs large protein by oncogenic E6. Oncogene 19, 5884–5891.10.1038/sj.onc.1203988Search in Google Scholar PubMed

Kukic, P., Lo Piccolo, G.M., Nogueira, M.O., Svergun, D.I., Vendruscolo, M., Felli, I.C., and Pierattelli, R. (2019). The free energy landscape of the oncogene protein E7 of human papillomavirus type 16 reveals a complex interplay between ordered and disordered regions. Sci. Rep. 9, 5822.10.1038/s41598-019-41925-4Search in Google Scholar PubMed PubMed Central

Lee, J.O., Russo, A.A., and Pavletich, N.P. (1998). Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 391, 859–865.10.1038/36038Search in Google Scholar PubMed

Liang, Y.J., Chang, H.S., Wang, C.Y., and Yu, W.C. (2008). DYRK1A stabilizes HPV16E7 oncoprotein through phosphorylation of the threonine 5 and threonine 7 residues. Int. J. Biochem. Cell Biol. 40, 2431–2441.10.1016/j.biocel.2008.04.003Search in Google Scholar PubMed

Lin, W. and Chen, S. (2018). Checkpoint kinase 1 is overexpressed during HPV16-induced cervical carcinogenesis. Gynecol. Obstet. Invest. 83, 299–305.10.1159/000487943Search in Google Scholar PubMed

Lin, C.H., Chang, H.S., and Yu, W.C. (2008). USP11 stabilizes HPV-16E7 and further modulates the E7 biological activity. J. Biol. Chem. 283, 15681–15688.10.1074/jbc.M708278200Search in Google Scholar PubMed PubMed Central

Litchfield, D.W. (2003). Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem. J. 369, 1–15.10.1042/bj20021469Search in Google Scholar

Liu, X., Clements, A., Zhao, K., and Marmorstein, R. (2006). Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. J. Biol. Chem. 281, 578–586.10.1074/jbc.M508455200Search in Google Scholar PubMed

Liu, J., Cao, X.C., Xiao, Q., and Quan, M.F. (2015). Apigenin inhibits HeLa sphere-forming cells through inactivation of casein kinase 2alpha. Mol. Med. Rep. 11, 665–669.10.3892/mmr.2014.2720Search in Google Scholar PubMed

Lorand, L. and Graham, R.M. (2003). Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat. Rev. Mol. Cell Biol. 4, 140–156.10.1038/nrm1014Search in Google Scholar PubMed

Manzo-Merino, J., Thomas, M., Fuentes-Gonzalez, A.M., Lizano, M., and Banks, L. (2013). HPV E6 oncoprotein as a potential therapeutic target in HPV related cancers. Expert Opin. Ther. Targets 17, 1357–1368.10.1517/14728222.2013.832204Search in Google Scholar PubMed

Marin, O., Meggio, F., Marchiori, F., Borin, G., and Pinna, L.A. (1986). Site specificity of casein kinase-2 (TS) from rat liver cytosol. A study with model peptide substrates. Eur. J. Biochem. 160, 239–244.10.1111/j.1432-1033.1986.tb09962.xSearch in Google Scholar PubMed

Marin, O., Meggio, F., and Pinna, L.A. (1994). Design and synthesis of two new peptide substrates for the specific and sensitive monitoring of casein kinases-1 and -2. Biochem. Biophys. Res. Commun. 198, 898–905.10.1006/bbrc.1994.1128Search in Google Scholar PubMed

Massimi, P. and Banks, L. (1997). Repression of p53 transcriptional activity by the HPV E7 proteins. Virology 227, 255–259.10.1006/viro.1996.8315Search in Google Scholar PubMed

Massimi, P. and Banks, L. (2000). Differential phosphorylation of the HPV-16 E7 oncoprotein during the cell cycle. Virology. 276, 388–394.10.1006/viro.2000.0514Search in Google Scholar PubMed

Massimi, P., Pim, D., Storey, A., and Banks, L. (1996). HPV-16 E7 and adenovirus E1a complex formation with TATA box binding protein is enhanced by casein kinase II phosphorylation. Oncogene 12, 2325–2330.Search in Google Scholar

Mehanna, H., Beech, T., Nicholson, T., El-Hariry, I., McConkey, C., Paleri, V., and Roberts, S. (2013). Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer – systematic review and meta-analysis of trends by time and region. Head Neck 35, 747–755.10.1002/hed.22015Search in Google Scholar

Montagnoli, A., Fiore, F., Eytan, E., Carrano, A.C., Draetta, G.F., Hershko, A., and Pagano, M. (1999). Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev. 13, 1181–1189.10.1101/gad.13.9.1181Search in Google Scholar

Montano, R., Chung, I., Garner, K.M., Parry, D., and Eastman, A. (2012). Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol. Cancer Ther. 11, 427–438.10.1158/1535-7163.MCT-11-0406Search in Google Scholar

Muller, C., Alunni-Fabbroni, M., Kowenz-Leutz, E., Mo, X., Tommasino, M., and Leutz, A. (1999). Separation of C/EBPalpha-mediated proliferation arrest and differentiation pathways. Proc. Natl. Acad. Sci. USA 96, 7276–7281.10.1073/pnas.96.13.7276Search in Google Scholar

Murao, S., Collart, F.R., and Huberman, E. (1989). A protein containing the cystic fibrosis antigen is an inhibitor of protein kinases. J. Biol. Chem. 264, 8356–8360.10.1016/S0021-9258(18)83189-1Search in Google Scholar

Muslin, A.J., Tanner, J.W., Allen, P.M., and Shaw, A.S. (1996). Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897.10.1016/S0092-8674(00)81067-3Search in Google Scholar

Myung, J., Kim, K.B., and Crews, C.M. (2001). The ubiquitin-proteasome pathway and proteasome inhibitors. Med. Res. Rev. 21, 245–273.10.1002/med.1009Search in Google Scholar PubMed PubMed Central

Neal, C.L. and Yu, D. (2010). 14-3-3zeta as a prognostic marker and therapeutic target for cancer. Expert. Opin. Ther. Targets 14, 1343–1354.10.1517/14728222.2010.531011Search in Google Scholar PubMed PubMed Central

Nogueira, M.O., Hosek, T., Calcada, E.O., Castiglia, F., Massimi, P., Banks, L., Felli, I.C., and Pierattelli, R. (2017). Monitoring HPV-16 E7 phosphorylation events. Virology 503, 70–75.10.1016/j.virol.2016.12.030Search in Google Scholar PubMed

Nomine, Y., Masson, M., Charbonnier, S., Zanier, K., Ristriani, T., Deryckere, F., Sibler, A.P., Desplancq, D., Atkinson, R.A., Weiss, E., et al. (2006). Structural and functional analysis of E6 oncoprotein: insights in the molecular pathways of human papillomavirus-mediated pathogenesis. Mol. Cell 21, 665–678.10.1016/j.molcel.2006.01.024Search in Google Scholar PubMed

Oh, K.J., Kalinina, A., Wang, J., Nakayama, K., Nakayama, K.I., and Bagchi, S. (2004). The papillomavirus E7 oncoprotein is ubiquitinated by UbcH7 and Cullin 1- and Skp2-containing E3 ligase. J. Virol. 78, 5338–5346.10.1128/JVI.78.10.5338-5346.2004Search in Google Scholar PubMed PubMed Central

Ohlenschlager, O., Seiboth, T., Zengerling, H., Briese, L., Marchanka, A., Ramachandran, R., Baum, M., Korbas, M., Meyer-Klaucke, W., Durst, M., et al. (2006). Solution structure of the partially folded high-risk human papilloma virus 45 oncoprotein E7. Oncogene 25, 5953–5959.10.1038/sj.onc.1209584Search in Google Scholar PubMed

Ohta, T. and Xiong, Y. (2001). Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases. Cancer Res. 61, 1347–1353.Search in Google Scholar

Ortega, C.E., Seidner, Y., and Dominguez, I. (2014). Mining CK2 in cancer. PLoS One 9, e115609.10.1371/journal.pone.0115609Search in Google Scholar PubMed PubMed Central

Pagano, M.A., Meggio, F., Ruzzene, M., Andrzejewska, M., Kazimierczuk, Z., and Pinna, L.A. (2004). 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2. Biochem. Biophys. Res. Commun. 321, 1040–1044.10.1016/j.bbrc.2004.07.067Search in Google Scholar PubMed

Palmer, R.H., Ridden, J., and Parker, P.J. (1995). Cloning and expression patterns of two members of a novel protein-kinase-C-related kinase family. Eur. J. Biochem. 227, 344–351.10.1111/j.1432-1033.1995.tb20395.xSearch in Google Scholar PubMed

Perea, S.E., Reyes, O., Puchades, Y., Mendoza, O., Vispo, N.S., Torrens, I., Santos, A., Silva, R., Acevedo, B., Lopez, E., et al. (2004). Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cancer Res. 64, 7127–7129.10.1158/0008-5472.CAN-04-2086Search in Google Scholar PubMed

Perea, Y., Farina, H.G., Hernandez, I., Mendoza, O., Serrano, J.M., Reyes, O., Gomez, D.E., Gomez, R.E., Acevedo, B.E., Alonso, D.F., et al. (2008a). Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int. J. Cancer 122, 57–62.10.1002/ijc.23013Search in Google Scholar PubMed

Perea, S.E., Reyes, O., Baladron, I., Perera, Y., Farina, H., Gil, J., Rodriguez, A., Bacardi, D., Marcelo, J.L., Cosme, K., et al. (2008b). CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo. Mol. Cell Biochem. 316, 163–167.10.1007/s11010-008-9814-5Search in Google Scholar PubMed

Perea, S.E., Baladron, I., Valenzuela, C., and Perera, Y. (2018). CIGB-300: a peptide-based drug that impairs the Protein Kinase CK2-mediated phosphorylation. Semin. Oncol. 45, 58–67.10.1053/j.seminoncol.2018.04.006Search in Google Scholar PubMed

Phillips, A.C. and Vousden, K.H. (1997). Analysis of the interaction between human papillomavirus type 16 E7 and the TATA-binding protein, TBP. J. Gen. Virol. 78, 905–909.10.1099/0022-1317-78-4-905Search in Google Scholar PubMed

Pierre, F., Chua, P.C., O’Brien, S.E., Siddiqui-Jain, A., Bourbon, P., Haddach, M., Michaux, J., Nagasawa, J., Schwaebe, M.K., Stefan, E., et al. (2011). Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J. Med. Chem. 54, 635–654.10.1021/jm101251qSearch in Google Scholar

Piirsoo, A., Piirsoo, M., Kala, M., Sankovski, E., Lototskaja, E., Levin, V., Salvi, M., and Ustav, M. (2019). Activity of CK2α protein kinase is required for efficient replication of some HPV types. PLoS Pathog. 15, e1007788.10.1371/journal.ppat.1007788Search in Google Scholar

Prives, C. (1990). The replication functions of SV40 T antigen are regulated by phosphorylation. Cell 61, 735–738.10.1016/0092-8674(90)90179-ISearch in Google Scholar

Propper, D.J., Saunders, M.P., Salisbury, A.J., Long, L., O’Byrne, K.J., Braybrooke, J.P., Dowsett, M., Taylor, M., Talbot, D.C., Ganesan, T.S., et al. (1999). Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects. Clin. Cancer Res. 5, 1682–1689.Search in Google Scholar

Rabalski, A.J., Gyenis, L., and Litchfield, D.W. (2016). Molecular pathways: emergence of protein kinase CK2 (CSNK2) as a potential target to inhibit survival and DNA damage response and repair pathways in cancer cells. Clin. Cancer Res. 22, 2840–2847.10.1158/1078-0432.CCR-15-1314Search in Google Scholar PubMed

Reinstein, E., Scheffner, M., Oren, M., Ciechanover, A., and Schwartz, A. (2000). Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene 19, 5944–5950.10.1038/sj.onc.1203989Search in Google Scholar PubMed

Rey, O., Lee, S., Baluda, M.A., Swee, J., Ackerson, B., Chiu, R., and Park, N.H. (2000). The E7 oncoprotein of human papillomavirus type 16 interacts with F-actin in vitro and in vivo. Virology 268, 372–381.10.1006/viro.1999.0175Search in Google Scholar PubMed

Roden, R.B.S. and Stern, P.L. (2018). Opportunities and challenges for human papillomavirus vaccination in cancer. Nat. Rev. Cancer 18, 240–254.10.1038/nrc.2018.13Search in Google Scholar PubMed PubMed Central

Roman, A. and Munger, K. (2013). The papillomavirus E7 proteins. Virology 445, 138–168.10.1016/j.virol.2013.04.013Search in Google Scholar PubMed PubMed Central

Sapio, L., Di Maiolo, F., Illiano, M., Esposito, A., Chiosi, E., Spina, A., and Naviglio, S. (2014). Targeting protein kinase A in cancer therapy: an update. EXCLI J. 13, 843–855.Search in Google Scholar

Sarabia-Vega, V. and Banks, L. (2019). Acquisition of a phospho-acceptor site enhances HPV E6 PDZ-binding motif functional promiscuity. J. Gen. Virol., doi: 10.1099/jgv.0.001236. [Epub ahead of print].10.1099/jgv.0.001236Search in Google Scholar PubMed

Sarno, S., Vaglio, P., Meggio, F., Issinger, O.G., and Pinna, L.A. (1996). Protein kinase CK2 mutants defective in substrate recognition. Purification and kinetic analysis. J. Biol. Chem. 271, 10595–10601.10.1074/jbc.271.18.10595Search in Google Scholar PubMed

Scheffner, M., Werness, B.A., Huibregtse, J.M., Levine, A.J., and Howley, P.M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136.10.1016/0092-8674(90)90409-8Search in Google Scholar

Schiffman, M., Doorbar, J., Wentzensen, N., de Sanjose, S., Fakhry, C., Monk, B.J., Stanley, M.A., and Franceschi, S. (2016). Carcinogenic human papillomavirus infection. Nat. Rev. Dis. Primers. 2, 16086.10.1038/nrdp.2016.86Search in Google Scholar

Schwede, F., Maronde, E., Genieser, H., and Jastorff, B. (2000). Cyclic nucleotide analogs as biochemical tools and prospective drugs. Pharmacol. Ther. 87, 199–226.10.1016/S0163-7258(00)00051-6Search in Google Scholar

Selvey, L.A., Dunn, L.A., Tindle, R.W., Park, D.S., and Frazer, I.H. (1994). Human papillomavirus (HPV) type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. J. Gen. Virol. 75, 1647–1653.10.1099/0022-1317-75-7-1647Search in Google Scholar PubMed

Serrano, B., Brotons, M., Bosch, F.X., and Bruni, L. (2018). Epidemiology and burden of HPV-related disease. Best Pract. Res. Clin. Obstet. Gynaecol. 47, 14–26.10.1016/j.bpobgyn.2017.08.006Search in Google Scholar PubMed

Siddiqui-Jain, A., Drygin, D., Streiner, N., Chua, P., Pierre, F., O’Brien, S.E., Bliesath, J., Omori, M., Huser, N., Ho, C., et al. (2010). CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 70, 10288–10298.10.1158/0008-5472.CAN-10-1893Search in Google Scholar PubMed

Singh, M., Krajewski, M., Mikolajka, A., and Holak, T.A. (2005). Molecular determinants for the complex formation between the retinoblastoma protein and LXCXE sequences. J. Biol. Chem. 280, 37868–37876.10.1074/jbc.M504877200Search in Google Scholar PubMed

Smotkin, D. and Wettstein, F.O. (1987). The major human papillomavirus protein in cervical cancers is a cytoplasmic phosphoprotein. J. Virol. 61, 1686–1689.10.1128/jvi.61.5.1686-1689.1987Search in Google Scholar PubMed PubMed Central

Solares, A.M., Santana, A., Baladron, I., Valenzuela, C., Gonzalez, C.A., Diaz, A., Castillo, D., Ramos, T., Gomez, R., Alonso, D.F., et al. (2009). Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer 9, 146.10.1186/1471-2407-9-146Search in Google Scholar PubMed PubMed Central

Southern, S.A., Lewis, M.H., and Herrington, C.S. (2004). Induction of tetrasomy by human papillomavirus type 16 E7 protein is independent of pRb binding and disruption of differentiation. Br. J. Cancer 90, 1949–1954.10.1038/sj.bjc.6601827Search in Google Scholar PubMed PubMed Central

Thatte, J., Massimi, P., Thomas, M., Boon, S.S., and Banks, L. (2018). The HPV E6 PDZ binding motif links DNA damage response signaling to E6 inhibition of p53 transcriptional activity. J. Virol. 92, e00465–18.10.1128/JVI.00465-18Search in Google Scholar

Thomas, M. and Banks, L. (1998). Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17, 2943–2954.10.1038/sj.onc.1202223Search in Google Scholar PubMed

Thomas, M. and Banks, L. (1999). Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J. Gen. Virol. 80, 1513–1517.10.1099/0022-1317-80-6-1513Search in Google Scholar PubMed

Thomas, M., Massimi, P., Navarro, C., Borg, J.P., and Banks, L. (2005). The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins. Oncogene 24, 6222–6230.10.1038/sj.onc.1208757Search in Google Scholar PubMed

Thomas, M., Myers, M.P., Massimi, P., Guarnaccia, C., and Banks, L. (2016). Analysis of multiple HPV E6 PDZ interactions defines type-specific PDZ fingerprints that predict oncogenic potential. PLoS Pathog. 12, e1005766.10.1371/journal.ppat.1005766Search in Google Scholar PubMed PubMed Central

Tomaic, V. (2016). Functional roles of E6 and E7 oncoproteins in HPV-induced malignancies at diverse anatomical sites. Cancers (Basel) 8, pii: E95.10.3390/cancers8100095Search in Google Scholar PubMed PubMed Central

Tomaic, V., Pim, D., and Banks, L. (2009). The stability of the human papillomavirus E6 oncoprotein is E6AP dependent. Virology 393, 7–10.10.1016/j.virol.2009.07.029Search in Google Scholar PubMed

Tortora, G. and Ciardiello, F. (2002a). Protein kinase A as target for novel integrated strategies of cancer therapy. Ann. N.Y. Acad. Sci. 968, 139–147.10.1111/j.1749-6632.2002.tb04332.xSearch in Google Scholar PubMed

Tortora, G. and Ciardiello, F. (2002b). Protein kinase A type I: a target for cancer therapy. Clin. Cancer Res. 8, 303–304.Search in Google Scholar

Tortora, G. and Ciardiello, F. (2003). Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy. Ann. N.Y. Acad. Sci. 1002, 236–243.10.1196/annals.1281.026Search in Google Scholar PubMed

Tugizov, S., Berline, J., Herrera, R., Penaranda, M.E., Nakagawa, M., and Palefsky, J. (2005). Inhibition of human papillomavirus type 16 E7 phosphorylation by the S100 MRP-8/14 protein complex. J. Virol. 79, 1099–1112.10.1128/JVI.79.2.1099-1112.2005Search in Google Scholar PubMed PubMed Central

Vande Pol, S.B. and Klingelhutz, A.J. (2013). Papillomavirus E6 oncoproteins. Virology 445, 115–137.10.1016/j.virol.2013.04.026Search in Google Scholar PubMed PubMed Central

Vos, R.M., Altreuter, J., White, E.A., and Howley, P.M. (2009). The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J. Virol. 83, 8885–8892.10.1128/JVI.00605-09Search in Google Scholar PubMed PubMed Central

Wang, J., Sampath, A., Raychaudhuri, P., and Bagchi, S. (2001). Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells. Oncogene 20, 4740–4749.10.1038/sj.onc.1204655Search in Google Scholar PubMed

Watson, R.A., Thomas, M., Banks, L., and 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, 4925–4934.10.1242/jcs.00809Search in Google Scholar PubMed

Yamato, K., Yamada, T., Kizaki, M., Ui-Tei, K., Natori, Y., Fujino, M., Nishihara, T., Ikeda, Y., Nasu, Y., Saigo, K., et al. (2008). New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer. Cancer Gene Ther. 15, 140–153.10.1038/sj.cgt.7701118Search in Google Scholar PubMed

Yang, S.H., Kuo, T.C., Wu, H., Guo, J.C., Hsu, C., Hsu, C.H., Tien, Y.W., Yeh, K.H., Cheng, A.L., and Kuo, S.H. (2016). Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer. World J. Gastroenterol. 22, 7275–7288.10.3748/wjg.v22.i32.7275Search in Google Scholar PubMed PubMed Central

Yoshinouchi, M., Yamada, T., Kizaki, M., Fen, J., Koseki, T., Ikeda, Y., Nishihara, T., and Yamato, K. (2003). In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. Mol. Ther. 8, 762–768.10.1016/j.ymthe.2003.08.004Search in Google Scholar PubMed

Zhang, J.G., Farley, A., Nicholson, S.E., Willson, T.A., Zugaro, L.M., Simpson, R.J., Moritz, R.L., Cary, D., Richardson, R., Hausmann, G., et al. (1999). The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc. Natl. Acad. Sci. USA 96, 2071–2076.10.1073/pnas.96.5.2071Search in Google Scholar PubMed PubMed Central

Zhang, Y., Dasgupta, J., Ma, R.Z., Banks, L., Thomas, M., and Chen, X.S. (2007). Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J. Virol. 81, 3618–3626.10.1128/JVI.02044-06Search in Google Scholar PubMed PubMed Central

Zine El Abidine, A., Tomaic, V., Bel Haj Rhouma, R., Massimi, P., Guizani, I., Boubaker, S., Ennaifer, E., and Banks, L. (2017). A naturally occurring variant of HPV-16 E7 exerts increased transforming activity through acquisition of an additional phospho-acceptor site. Virology 500, 218–225.10.1016/j.virol.2016.10.023Search in Google Scholar PubMed

Received: 2019-11-04
Accepted: 2019-12-19
Published Online: 2020-01-08
Published in Print: 2020-04-28

©2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 26.4.2024 from https://www.degruyter.com/document/doi/10.1515/hsz-2019-0408/html
Scroll to top button