ArticleProceedings of the National Academy of Sciences of the United States of America2013
HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 41 citations in OpenAlex.
- How human papillomavirus (HPV) targets DNA repair pathways for viral replication: from guardian to accomplice.Microbiology and molecular biology reviews : MMBR · 2025Review
- YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia.eLife · 2022Article
- Article
- Establishment of a Three-Dimensional In Vitro Model of Equine Papillomavirus Type 2 Infection.Viruses · 2021Article
- E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer.Cell death and differentiation · 2021Article
- Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies.Viruses · 2020Review
- Genome-Wide Transcriptome Analysis of Human Papillomavirus 16-Infected Primary Keratinocytes Reveals Subtle Perturbations Mostly due to E7 Protein Expression.Journal of virology · 2020Article
- Targeting DNA Damage Response as a Strategy to Treat HPV Infections.International journal of molecular sciences · 2019Article
- Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The DNA damage response activates HPV16 late gene expression at the level of RNA processing.Nucleic acids research · 2018Article
- STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle.PLoS pathogens · 2018Article
- Evaluation of ODE-Bn-PMEG, an acyclic nucleoside phosphonate prodrug, as an antiviral against productive HPV infection in 3D organotypic epithelial cultures.Antiviral research · 2018Article
- Article
- Mechanisms by which HPV Induces a Replication Competent Environment in Differentiating Keratinocytes.Viruses · 2017Review
- Article
- Host cell restriction factors that limit transcription and replication of human papillomavirus.Virus research · 2017Review
- The human papillomavirus E7 oncoprotein as a regulator of transcription.Virus research · 2017Review
- HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy.Human vaccines & immunotherapeutics · 2017Article
- Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements.Journal of virology · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Human papillomaviruses (HPVs) amplify in differentiated strata of a squamous epithelium. The HPV E7 protein destabilizes the p130/retinoblastoma susceptibility protein family of tumor suppressors and reactivates S-phase reentry, thereby facilitating viral DNA amplification. The high-risk HPV E6 protein destabilizes the p53 tumor suppressor and many other host proteins. However, the critical E6 targets relevant to viral DNA amplification have not been identified, because functionally significant E6 mutants are not stably maintained in transfected cells. Using Cre-loxP recombination, which efficiently generates HPV genomic plasmids in transfected primary human keratinocytes, we have recapitulated a highly productive infection of HPV-18 in organotypic epithelial cultures. By using this system, we now report the characterization of four HPV-18 E6 mutations. An E6 null mutant accumulated high levels of p53 and amplified very poorly. p53 siRNA or ectopic WT E6 partially restored amplification, whereas three missense E6 mutations that did not effectively destabilize p53 complemented the null mutant poorly. Unexpectedly, in cis, two of the missense mutants amplified, albeit to a lower extent than the WT and only in cells with undetectable p53. These observations and others implicate p53 and additional host proteins in regulating viral DNA amplification and also suggest an inhibitory effect of E6 overexpression. We show that high levels of viral DNA amplification are critical for late protein expression and report several previously undescribed viral RNAs, including bicistronic transcripts predicted to encode E5 and L2 or an alternative form of E1^E4 and L1.
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