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Basic mechanisms of high‐risk human papillomavirus‐induced carcinogenesis: Roles of E6 and E7 proteins
Open accessAbstract
Human papillomaviruses (HPV) are believed to be the primary causal agents for development of pre‐neoplastic and malignant lesions of the uterine cervix, and high‐risk types such as type 16 and 18 are associated with more than 90% of all cervical carcinomas. The E6 and E7 genes of HPV are thought to play causative roles, since E6 promotes the degradation of p53 through its interaction with E6AP, an E3 ubiquitin ligase, whereas E7 binds to the retinoblastoma protein (pRb) and disrupts its complex formation with E2F transcription factors. Although prophylactic vaccines have become available, it is still necessary to clarify the mechanisms of HPV‐induced carcinogenesis because of the widespread nature of HPV infection. Approximately 493 000 new cases of cervical cancer are diagnosed each year with approximately 274 000 mortalities due to invasive cervical cancer. In the present article, the mechanisms of HPV16 E6‐ and E7‐induced multistep carcinogenesis and recently identified functions of these onco‐proteins are reviewed. (Cancer Sci 2007; 98: 1505–1511)
Overview
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TL;DR
This review summarizes how high-risk HPV E6 and E7 oncoproteins drive cervical carcinogenesis by inactivating p53 and pRb family proteins and by targeting additional cellular pathways. It emphasizes that overexpression of E6/E7, usually after viral integration, is a bottleneck step that cooperates with further genetic and epigenetic changes.
Key findings
- High-risk HPV types (16, 18, 31, 33, 45, 51, 52, 58, etc.) are associated with more than 90% of cervical cancers; HPV16 accounts for approximately half and HPV18 for another 10–20%. Approximately 493,000 new cervical cancer cases and 274,000 deaths occur annually.
- E6 promotes degradation of p53 through interaction with E6AP, an E3 ubiquitin ligase, while E7 binds pRb family proteins and disrupts pRb–E2F complexes; together they cause polyploidy and genomic instability.
- E6 has p53-independent functions, including hTERT/telomerase induction and degradation of PDZ-domain proteins such as DLG, Scribble, MUPP1, MAGI-1/-2/-3, GIPC, PATJ, PTPN3, and PSD95; E7 targets many proteins including p27, p21, p600, and PP2A.
- Integration and high-level E6/E7 expression are proposed as the bottleneck step; additional events reported in cervical cancers include PIK3CA, c-myc, ErbB2, and cIAP1 amplification, ras mutation, and decreased PTEN and TSLC1 expression.
Methods
- Narrative review; no primary experimental data, sample, or systematic analysis are reported.
- Synthesizes published literature and the authors’ recent work on HPV16 E6- and E7-induced multistep carcinogenesis, the HPV life cycle, and target proteins of E6 and E7 (Table 1; Figs 1–5).
Limitations
- The paper does not state formal limitations; it notes that further exploration is needed for TSC2/Tuberin as a possible E6 target.
- Evident from the text: this is a narrative review without stated systematic search or inclusion criteria, and some mechanistic claims rely on cited reviews, speculation, or a personal communication (A. Suhrbier, 2007) regarding E7-mediated pRb cleavage.
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Claims the paper makes
57 Sources not found · 14 Own interpretation
In the paper
“The most manifest function of the E6 protein is to promote the degradation of p53 through its interaction with a cellular protein, E6 associated protein (E6AP), an E3 ubiquitin ligase (9)”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“in the presence of E6, a repressor complex of TERT promoter, containing USF1 and USF2, is replaced by Myc, which corresponds to higher levels of TERT transcription and consequently, telomerase activity.(35)”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
What the sources say
- Not matchedcites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainstates a cause- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“The interaction of E7 with cyclin-dependent kinase (CDK)2/cyclin A, (60) as well as CDK2/cyclin E, (61) has also been reported.”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > IRF1
What the sources say
- Not matchedcites [60]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“For evasion of the immune system, E7 also interacts with p48, (64) as well as IRF1.(8)”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > IRF1
What the sources say
- Not matchedcites [64]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“E6 and Myc interaction has been shown to activate the telomerase reverse transcriptase promoter, (34)”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
What the sources say
- Not matchedcites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
- Probably not a substantial claim. 9
- It may state two separate claims as one. 18
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Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > Tyk2
“TSC2 (tubulin)”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
“The tumor suppressor gene TSC2 product, Tuberin”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > HPV infection and HPV-induced transformation
“The ultimate development of cervical cancer is rarely accompanied by high expression of E6 and E7 proteins.”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > HPV infection and HPV-induced transformation
“CIN III (severe dysplasia, carcinoma in situ) and invasive cancer lesions often display high-level expression of E6 and E7”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
“Therefore, its down regulation through p53 with E6/E6AP has been revealed as a novel tumor suppressor mechanism blocking development of HPV-induced cervical carcinogenesis.”
§ Basic mechanisms of high-risk human papillomavirusinduced carcinogenesis: Roles of E6 and E7 proteins > The functions of HPV onco-proteins E6 and E7
“its down-regulation by E6 might contribute to the development of cervical cancer.”
Citations
Cites
Epidemiologic classification of human papillomavirus types associated with cervical cancer
Muñoz, N., Bosch, F. X., de Sanjosé, S., Herrero, R., Castellsagué, X., Shah, K. V., Snijders, P. J. F., & Meijer, C. J. L. M. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa021641 · Cited by 6,249
Papillomaviruses and cancer: from basic studies to clinical application
Hausen, H. Z. (2002) · Nature reviews. Cancer · doi:10.1038/nrc798 · Cited by 4,094
The regulation of E2F by pRB-family proteins.
Dyson, N. (1998) · Genes & Development · doi:10.1101/gad.12.15.2245 · Cited by 2,317
Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., & Sklar, J. (1991) · Cell · doi:10.1016/0092-8674(91)90111-b · Cited by 1,691
Role of a p53 polymorphism in the development of human papilloma-virus-associated cancer
Storey, A., Thomas, M., Kalita, A., Harwood, C. A., Gardiol, D., Mantovani, F., Breuer, J., Leigh, I. M., Matlashewski, G., & Banks, L. (1998) · Nature · doi:10.1038/30400 · Cited by 971
Notch1 functions as a tumor suppressor in mouse skin
Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H. C., Dotto, G. P., & Radtke, F. (2003) · Nature Genetics · doi:10.1038/ng1099 · Cited by 969
Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation
Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J. C., Krishna, S., METZGER, D., Chambon, P., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.13.3427 · Cited by 867
The Ets family of transcription factors
Wasylyk, B., Hahn, S. L., & Giovane, A. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb19864.x · Cited by 839
Mechanisms of human papillomavirus-induced oncogenesis
Münger, K., Baldwin, A., Edwards, K. M., Hayakawa, H., Nguyen, C. L., Owens, M., Grace, M., & Huh, K. (2004) · Journal of Virology · doi:10.1128/jvi.78.21.11451-11460.2004 · Cited by 815
Telomerase activation by the E6 gene product of human papillomavirus type 16
Klingelhutz, A. J., Foster, S. A., & McDougall, J. K. (1996) · Nature · doi:10.1038/380079a0 · Cited by 660
Cited by
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092
The HECT Family of E3 Ubiquitin Ligases: Multiple Players in Cancer Development
Bernassola, F., Karin, M., Ciechanover, A., & Melino, G. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.06.001 · Cited by 541
Human papillomavirus vaccine against cervical cancer: Opportunity and challenge
Wang, R., Pan, W. D., Lei, J., Huang, W., Li, Y., Wu, D., Gao, C., Ma, D., & Liao, S. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.11.039 · Cited by 530
Enhanced Protein Degradation by Branched Ubiquitin Chains
Meyer, H., & Rapé, M. (2014) · Cell · doi:10.1016/j.cell.2014.03.037 · Cited by 500
Papillomavirus E6 oncoproteins
Pol, S. V., & Klingelhutz, A. J. (2013) · Virology · doi:10.1016/j.virol.2013.04.026 · Cited by 374
Metadata
- Authors
- Narisawa‐Saito, M., & Kiyono, T.
- Affiliations
- National Cancer Center Research Institute (JP)
- Corresponding author
- Kiyono, Tohru
- ORCID
- Kiyono, Tohru
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2007-07-23
- Volume
- 98
- Issue
- 10
- Pages
- 1505-1511
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC11158331
- OpenAlex
- W2011499737
- Cited by
- 528
- References
- 85
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 46 · 2023: 24 · 2022: 33 · 2021: 43 · 2020: 32 · 2019: 24 · 2018: 36 · 2017: 27 · 2016: 23 · 2015: 25 · 2014: 25 · 2013: 26 · 2012: 27
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- human papillomavirus, HPV16, HPV 18, cervical cancer, carcinogenesis, E6 oncoprotein, E7 oncoprotein, p53 degradation, UBE3A, retinoblastoma protein, E2F transcription factors, viral oncogenesis, HPV vaccine
- MeSH terms
- Cell Transformation, Neoplastic, Cell Transformation, Viral, Uterine Cervical Neoplasms, Female, Humans, Oncogene Proteins, Viral, Repressor Proteins, Papillomaviridae, Papillomavirus Infections, Papillomavirus E7 Proteins
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