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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)
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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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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
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plainstates a cause- Asserted: passes — The authors put it forward as true.
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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
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- Not matchedcites [35]
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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.
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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]
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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.
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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.”
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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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