Research Article
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Year 2025, Volume: 15 Issue: 3, 489 - 494, 30.09.2025
https://doi.org/10.33808/clinexphealthsci.1473034

Abstract

References

  • Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2021;71(3):209-249. https://doi.org/10.3322/caac.21660
  • WHO. HPV vaccine global market study. Available online: https://wwwwhoint/publications/m/item/who-hpv-vaccine-global-market-study-april-2022 (Accessed on: 14 March 2024).
  • Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics 2022;72(1):7-33. https://doi.org/10.3322/caac.21708
  • Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ. Epidemiologic classification of human papillomavirus types associated with cervical cancer. The New England Journal of Medicine 2003;348(6):518-527. https://doi.org/10.1056/NEJMoa021641
  • Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F. The HPV E6/E7 oncogenes: Key factors for viral carcinogenesis and therapeutic targets. Trends in Microbiology 2018;26(2):158-168. https://doi.org/10.1016/j.tim.2017.07.007
  • Vats A, Trejo-Cerro O, Massimi P, Banks L. Regulation of HPV E7 stability by E6-associated protein (E6AP). Journal of Virology 2022;96(16):e0066322. https://doi.org/10.1128/jvi.00663-22
  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. The EMBO Journal 1989;8(12):3905-3910. https://doi.org/10.1002/j.1460-2075.1989.tb08570.x
  • Lim J, Lilie H, Kalbacher H, Roos N, Frecot DI, Feige M, Conrady M, Votteler T, Cousido-Siah A, Corradini Bartoli G, Iftner T, Trave G, Simon C. Evidence for direct interaction between the oncogenic proteins E6 and E7 of high-risk human papillomavirus (HPV). Journal of Biological Chemistry 2023;299(8):104954. https://doi.org/10.1016/j.jbc.2023.104954
  • Phelps WC, Yee CL, Münger K, Howley PM. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell 1988;53(4):539-547. https://doi.org/10.1016/0092-8674(88)90570-3
  • Clemens KE, Brent R, Gyuris J, Munger K. Dimerization of the human papillomavirus E7 oncoprotein in vivo. Virology 1995;214(1):289-293. https://doi.org/10.1006/viro.1995.9926
  • García-Alai MM, Alonso LG, de Prat-Gay G. The N-terminal module of HPV16 E7 is an intrinsically disordered domain that confers conformational and recognition plasticity to the oncoprotein. Biochemistry 2007;46(37):10405-10412. https://doi.org/10.1021/bi7007917
  • Noval MG, Gallo M, Perrone S, Salvay AG, Chemes LB, de Prat-Gay G. Conformational dissection of a viral Intrinsically disordered domain involved in cellular transformation. PLOS One 2013;8(9):e72760. https://doi.org/10.1371/journal.pone.0072760
  • Dahiya A, Gavin MR, Luo RX, Dean DC. Role of the LXCXE binding site in Rb function. Molecular and Cellular Biology. 2000;20(18):6799-6805. https://doi.org/10.1128/MCB.20.18.6799-6805.2000
  • Dyson N, Howley PM, Münger K, Harlow E. The human Papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;243(4893):934-937. https://doi.org/10.1126/science.2537532
  • Selvey LA, Dunn LA, Tindle RW, Park DS, Frazer IH. Human papillomavirus (HPV) type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. The Journal of General Virology 1994;75( Pt 7):1647-1653. https://doi.org/10.1099/0022-1317-75-7-1647
  • Smotkin D, Wettstein FO. The major human papillomavirus protein in cervical cancers is a cytoplasmic phosphoprotein. Journal of Virology. 1987;61(5):1686-1689. https://doi.org/10.1128/jvi.61.5.1686-1689.1987
  • Reinstein E, Scheffner M, Oren M, Ciechanover A, Schwartz A. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene. 2000;19(51):5944-5950. https://doi.org/10.1038/sj.onc.1203989
  • Chakrabarti O, Krishna S. Molecular interactions of 'high risk' human papillomaviruses E6 and E7 oncoproteins: implications for tumour progression. Journal of biosciences. 2003;28(3):337-348. https://doi.org/10.1007/bf02970152
  • Đukić A, Lulić L, Thomas M, Skelin J, Bennett Saidu NE, Grce M, Banks L, Tomaić V. HPV oncoproteins and the ubiquitin proteasome system: A signature of malignancy? Pathogens 2020; 9(2)133. https://doi.org/10.3390/pathogens9020133.
  • Liu X, Clements A, Zhao K, Marmorstein R. Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. The Journal of Biological Chemistry 2006;281(1):578-586. https://doi.org/10.1074/jbc.M508455200
  • Shao Y, Wang P, Zheng Y, Cui H, Lou Z, Li S, Huang F, Wu C. A replicative recombinant HPV16 E7 expression virus upregulates CD36 in C33A cells. Frontiers in Microbiology. 2023;14:1259510. https://doi.org/10.3389/fmicb.2023.1259510
  • McIntyre MC, Frattini MG, Grossman SR, Laimins LA. Human papillomavirus type 18 E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization, and transformation but not for Rb binding. Journal of Virology. 1993;67(6):3142-3150. https://doi.org/10.1128/jvi.67.6.3142-3150.1993
  • Alonso LG, García-Alai MM, Nadra AD, Lapeña AN, Almeida FL, Gualfetti P, Prat-Gay GD. High-risk (HPV16) human papillomavirus E7 oncoprotein is highly stable and extended, with conformational transitions that could explain its multiple cellular binding partners. Biochemistry 2002;41(33):10510-10518. https://doi.org/10.1021/bi025579n
  • Dallaire F, Schreiner S, Blair GE, Dobner T, Branton PE, Blanchette P. The human Adenovirus type 5 E4orf6/E1B55K E3 ubiquitin ligase complex enhances E1A functional activity. mSphere 2016;1(1):e00015-15. https://doi.org/10.1128/mSphere.00015-15
  • Ressler S, Scheiden R, Dreier K, Laich A, Müller-Holzner E, Pircher H, Morandell D, Stein I, Viertler HP, Santer FR, Widschwendter A, Even J, Jansen-Dürr P, Capesius C, Zwerschke W. High-risk human papillomavirus E7 oncoprotein detection in cervical squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(23):7067-7072. https://doi.org/10.1158/1078-0432.ccr-07-1222
  • Knapp AA, McManus PM, Bockstall K, Moroianu J. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein. Virology. 2009;383(1):60-68. https://doi.org/10.1016/j.virol.2008.09.037
  • Cesur Ö, Nicol C, Groves H, Mankouri J, Blair GE, Stonehouse NJ. The subcellular localisation of the human Papillomavirus (HPV) 16 E7 protein in cervical cancer cells and its perturbation by RNA aptamers. Viruses. 2015;7(7):3443-3461. https://doi.org/10.3390/v7072780
  • Oh KJ, Kalinina A, Wang J, Nakayama K, Nakayama KI, Bagchi S. The papillomavirus E7 oncoprotein is ubiquitinated by UbcH7 and Cullin 1- and Skp2-containing E3 ligase. Journal of Virology 2004;78(10):5338-5346. https://doi.org/10.1128/jvi.78.10.5338-5346.2004
  • Rey O, Lee S, Baluda MA, Swee J, Ackerson B, Chiu R, Park NH. The E7 oncoprotein of human papillomavirus type 16 interacts with F-actin in vitro and in vivo. Virology 2000;268(2):372-381. https://doi.org/10.1006/viro.1999.0175
  • Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Dürr P. Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proceedings of the National Academy of Sciences of the United States of America 1999;96(4):1291-1296. https://doi.org/10.1073/pnas.96.4.1291

is HPV16 E7 Oncoprotein Labile if it is Unliganded?

Year 2025, Volume: 15 Issue: 3, 489 - 494, 30.09.2025
https://doi.org/10.33808/clinexphealthsci.1473034

Abstract

Objective: Human papillomavirus (HPV) infection is a major global health concern due to its association with several types of cancer, particularly cervical cancer. Among the various viral proteins produced by HPV, E6 and E7 oncoproteins have been identified as key players in the oncogenic transformation of infected cells. HPV E7 oncoprotein primarily targets the retinoblastoma protein (pRb) and related family members, retinoblastoma-like protein 2 (p130) and retinoblastoma-like protein 1 (p107) and disrupts their association with E2F transcription factors, releasing the E2F for transcriptional activation of genes required for cell cycle progression. E7 is an unstable protein with a half-life of less than 2 hours. We aimed to investigate whether the stability of the E7 protein would change when it has a binding partner such as pRb, p130 and p107.
Methods: We transfected HEK293T cells with either Green Fluorescent Protein tagged E7 (GFP-E7) construct alone or together with one of the pRb (RB1), p130 (RBL2) or p107 (RBL1) constructs and observed the expression of GFP-E7 under a fluorescent microscope. We have also analysed the expression levels of E7, pRb, p130 and p107 by western blotting using specific antibodies.
Results: We showed that E7 expression was more prominent in human embryonic kidney 293T (HEK293T) cells where one of the cellular target proteins was co-expressed.
Conclusion: HPV E7 oncoprotein is an indispensable component for the pathogenesis of cervical cancer, and understanding the molecular mechanisms of how E7 maintains its stability in the cell may enable the development of targeted treatment approaches.

Ethical Statement

Bu çalışma hücreler ile gerçekleştirildiğinden etik kurul onayı gerekmemektedir.

References

  • Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2021;71(3):209-249. https://doi.org/10.3322/caac.21660
  • WHO. HPV vaccine global market study. Available online: https://wwwwhoint/publications/m/item/who-hpv-vaccine-global-market-study-april-2022 (Accessed on: 14 March 2024).
  • Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics 2022;72(1):7-33. https://doi.org/10.3322/caac.21708
  • Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ. Epidemiologic classification of human papillomavirus types associated with cervical cancer. The New England Journal of Medicine 2003;348(6):518-527. https://doi.org/10.1056/NEJMoa021641
  • Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F. The HPV E6/E7 oncogenes: Key factors for viral carcinogenesis and therapeutic targets. Trends in Microbiology 2018;26(2):158-168. https://doi.org/10.1016/j.tim.2017.07.007
  • Vats A, Trejo-Cerro O, Massimi P, Banks L. Regulation of HPV E7 stability by E6-associated protein (E6AP). Journal of Virology 2022;96(16):e0066322. https://doi.org/10.1128/jvi.00663-22
  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. The EMBO Journal 1989;8(12):3905-3910. https://doi.org/10.1002/j.1460-2075.1989.tb08570.x
  • Lim J, Lilie H, Kalbacher H, Roos N, Frecot DI, Feige M, Conrady M, Votteler T, Cousido-Siah A, Corradini Bartoli G, Iftner T, Trave G, Simon C. Evidence for direct interaction between the oncogenic proteins E6 and E7 of high-risk human papillomavirus (HPV). Journal of Biological Chemistry 2023;299(8):104954. https://doi.org/10.1016/j.jbc.2023.104954
  • Phelps WC, Yee CL, Münger K, Howley PM. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell 1988;53(4):539-547. https://doi.org/10.1016/0092-8674(88)90570-3
  • Clemens KE, Brent R, Gyuris J, Munger K. Dimerization of the human papillomavirus E7 oncoprotein in vivo. Virology 1995;214(1):289-293. https://doi.org/10.1006/viro.1995.9926
  • García-Alai MM, Alonso LG, de Prat-Gay G. The N-terminal module of HPV16 E7 is an intrinsically disordered domain that confers conformational and recognition plasticity to the oncoprotein. Biochemistry 2007;46(37):10405-10412. https://doi.org/10.1021/bi7007917
  • Noval MG, Gallo M, Perrone S, Salvay AG, Chemes LB, de Prat-Gay G. Conformational dissection of a viral Intrinsically disordered domain involved in cellular transformation. PLOS One 2013;8(9):e72760. https://doi.org/10.1371/journal.pone.0072760
  • Dahiya A, Gavin MR, Luo RX, Dean DC. Role of the LXCXE binding site in Rb function. Molecular and Cellular Biology. 2000;20(18):6799-6805. https://doi.org/10.1128/MCB.20.18.6799-6805.2000
  • Dyson N, Howley PM, Münger K, Harlow E. The human Papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;243(4893):934-937. https://doi.org/10.1126/science.2537532
  • Selvey LA, Dunn LA, Tindle RW, Park DS, Frazer IH. Human papillomavirus (HPV) type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. The Journal of General Virology 1994;75( Pt 7):1647-1653. https://doi.org/10.1099/0022-1317-75-7-1647
  • Smotkin D, Wettstein FO. The major human papillomavirus protein in cervical cancers is a cytoplasmic phosphoprotein. Journal of Virology. 1987;61(5):1686-1689. https://doi.org/10.1128/jvi.61.5.1686-1689.1987
  • Reinstein E, Scheffner M, Oren M, Ciechanover A, Schwartz A. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene. 2000;19(51):5944-5950. https://doi.org/10.1038/sj.onc.1203989
  • Chakrabarti O, Krishna S. Molecular interactions of 'high risk' human papillomaviruses E6 and E7 oncoproteins: implications for tumour progression. Journal of biosciences. 2003;28(3):337-348. https://doi.org/10.1007/bf02970152
  • Đukić A, Lulić L, Thomas M, Skelin J, Bennett Saidu NE, Grce M, Banks L, Tomaić V. HPV oncoproteins and the ubiquitin proteasome system: A signature of malignancy? Pathogens 2020; 9(2)133. https://doi.org/10.3390/pathogens9020133.
  • Liu X, Clements A, Zhao K, Marmorstein R. Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. The Journal of Biological Chemistry 2006;281(1):578-586. https://doi.org/10.1074/jbc.M508455200
  • Shao Y, Wang P, Zheng Y, Cui H, Lou Z, Li S, Huang F, Wu C. A replicative recombinant HPV16 E7 expression virus upregulates CD36 in C33A cells. Frontiers in Microbiology. 2023;14:1259510. https://doi.org/10.3389/fmicb.2023.1259510
  • McIntyre MC, Frattini MG, Grossman SR, Laimins LA. Human papillomavirus type 18 E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization, and transformation but not for Rb binding. Journal of Virology. 1993;67(6):3142-3150. https://doi.org/10.1128/jvi.67.6.3142-3150.1993
  • Alonso LG, García-Alai MM, Nadra AD, Lapeña AN, Almeida FL, Gualfetti P, Prat-Gay GD. High-risk (HPV16) human papillomavirus E7 oncoprotein is highly stable and extended, with conformational transitions that could explain its multiple cellular binding partners. Biochemistry 2002;41(33):10510-10518. https://doi.org/10.1021/bi025579n
  • Dallaire F, Schreiner S, Blair GE, Dobner T, Branton PE, Blanchette P. The human Adenovirus type 5 E4orf6/E1B55K E3 ubiquitin ligase complex enhances E1A functional activity. mSphere 2016;1(1):e00015-15. https://doi.org/10.1128/mSphere.00015-15
  • Ressler S, Scheiden R, Dreier K, Laich A, Müller-Holzner E, Pircher H, Morandell D, Stein I, Viertler HP, Santer FR, Widschwendter A, Even J, Jansen-Dürr P, Capesius C, Zwerschke W. High-risk human papillomavirus E7 oncoprotein detection in cervical squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(23):7067-7072. https://doi.org/10.1158/1078-0432.ccr-07-1222
  • Knapp AA, McManus PM, Bockstall K, Moroianu J. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein. Virology. 2009;383(1):60-68. https://doi.org/10.1016/j.virol.2008.09.037
  • Cesur Ö, Nicol C, Groves H, Mankouri J, Blair GE, Stonehouse NJ. The subcellular localisation of the human Papillomavirus (HPV) 16 E7 protein in cervical cancer cells and its perturbation by RNA aptamers. Viruses. 2015;7(7):3443-3461. https://doi.org/10.3390/v7072780
  • Oh KJ, Kalinina A, Wang J, Nakayama K, Nakayama KI, Bagchi S. The papillomavirus E7 oncoprotein is ubiquitinated by UbcH7 and Cullin 1- and Skp2-containing E3 ligase. Journal of Virology 2004;78(10):5338-5346. https://doi.org/10.1128/jvi.78.10.5338-5346.2004
  • Rey O, Lee S, Baluda MA, Swee J, Ackerson B, Chiu R, Park NH. The E7 oncoprotein of human papillomavirus type 16 interacts with F-actin in vitro and in vivo. Virology 2000;268(2):372-381. https://doi.org/10.1006/viro.1999.0175
  • Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Dürr P. Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proceedings of the National Academy of Sciences of the United States of America 1999;96(4):1291-1296. https://doi.org/10.1073/pnas.96.4.1291
There are 30 citations in total.

Details

Primary Language English
Subjects Molecular Targets, Medical Biochemistry - Proteins, Peptides and Proteomics, Gene and Molecular Therapy
Journal Section Articles
Authors

Özlem Cesur Günay 0000-0002-1670-696X

Nicola Stonehouse 0000-0003-1146-5519

Early Pub Date September 30, 2025
Publication Date September 30, 2025
Submission Date April 26, 2024
Acceptance Date July 31, 2025
Published in Issue Year 2025 Volume: 15 Issue: 3

Cite

APA Cesur Günay, Ö., & Stonehouse, N. (2025). is HPV16 E7 Oncoprotein Labile if it is Unliganded? Clinical and Experimental Health Sciences, 15(3), 489-494. https://doi.org/10.33808/clinexphealthsci.1473034
AMA Cesur Günay Ö, Stonehouse N. is HPV16 E7 Oncoprotein Labile if it is Unliganded? Clinical and Experimental Health Sciences. September 2025;15(3):489-494. doi:10.33808/clinexphealthsci.1473034
Chicago Cesur Günay, Özlem, and Nicola Stonehouse. “Is HPV16 E7 Oncoprotein Labile If It Is Unliganded?”. Clinical and Experimental Health Sciences 15, no. 3 (September 2025): 489-94. https://doi.org/10.33808/clinexphealthsci.1473034.
EndNote Cesur Günay Ö, Stonehouse N (September 1, 2025) is HPV16 E7 Oncoprotein Labile if it is Unliganded? Clinical and Experimental Health Sciences 15 3 489–494.
IEEE Ö. Cesur Günay and N. Stonehouse, “is HPV16 E7 Oncoprotein Labile if it is Unliganded?”, Clinical and Experimental Health Sciences, vol. 15, no. 3, pp. 489–494, 2025, doi: 10.33808/clinexphealthsci.1473034.
ISNAD Cesur Günay, Özlem - Stonehouse, Nicola. “Is HPV16 E7 Oncoprotein Labile If It Is Unliganded?”. Clinical and Experimental Health Sciences 15/3 (September2025), 489-494. https://doi.org/10.33808/clinexphealthsci.1473034.
JAMA Cesur Günay Ö, Stonehouse N. is HPV16 E7 Oncoprotein Labile if it is Unliganded? Clinical and Experimental Health Sciences. 2025;15:489–494.
MLA Cesur Günay, Özlem and Nicola Stonehouse. “Is HPV16 E7 Oncoprotein Labile If It Is Unliganded?”. Clinical and Experimental Health Sciences, vol. 15, no. 3, 2025, pp. 489-94, doi:10.33808/clinexphealthsci.1473034.
Vancouver Cesur Günay Ö, Stonehouse N. is HPV16 E7 Oncoprotein Labile if it is Unliganded? Clinical and Experimental Health Sciences. 2025;15(3):489-94.

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