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Cutaneous β-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling
Open accessAbstract
The Notch signaling pathway is a key determinant in keratinocyte differentiation and growth cycle arrest, and has been reported to have a tumor suppressor function in skin. The papillomavirus life cycle is intricately linked to the differentiation status of keratinocytes. Papillomaviruses are associated with benign proliferative epithelial lesions in their respective hosts. Although human papillomaviruses (HPVs) associated with genital tract lesions have been extensively studied, studies of the cutaneous HPVs are more limited. In particular, it is well established that the E6 proteins of high-risk HPVs of the α-genus such as HPV16 and HPV18 mediate the degradation of p53 by its association with the ubiquitin ligase E6AP. In contrast, less is known about the cellular activities of the cutaneous HPVs of the β-genus. By using an unbiased proteomic approach, we identify MAML1 and other members of the Notch transcription complex as high-confidence cellular interacting proteins of E6 proteins of the β-genus HPVs and of the bovine papillomavirus type 1 associated with cutaneous fibropapillomas. We show that bovine papillomavirus type 1 and β-HPV E6 repress Notch transcriptional activation, and that this repression is dependent on an interaction with MAML1. Finally, we show that the expression levels of endogenous Notch target genes are repressed by β-HPV E6 proteins. These findings elucidate a mechanism of viral antagonism of Notch signaling, and suggest that Notch signaling is an important epithelial cell pathway target for the β-HPVs.
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“and may be responsible for the different cell type-specific tropisms of the two genera”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [69]
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“Both virus–host interactions are mediated by a similar motif in the cellular protein”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [69]
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“the E6 protein of genus alpha HPV binds specifically to the cellular E6AP protein”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [69]
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“while that of the genus beta HPV binds specifically to cellular MAML1.”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [69]
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Metadata
- Authors
- Tan, M. J. A., White, E. A., Sowa, M. E., Harper, J. W., Aster, J. C., & Howley, P. M.
- Affiliations
- Harvard University (US)
- Departments of Microbiology and Immunobiology and
- Brigham and Women's Hospital (US)
- Corresponding author
- Howley, Peter M.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-04-30
- Volume
- 109
- Issue
- 23
- Pages
- E1473-80
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3384212
- OpenAlex
- W2020553511
- Cited by
- 132
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 6 · 2021: 8 · 2020: 13 · 2019: 10 · 2018: 7 · 2017: 17 · 2016: 9 · 2015: 10 · 2014: 13 · 2013: 11 · 2012: 6
- FWCI
- 9.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- National Institutes of Health
- National Cancer Institute (P01 CA 50661, RC1CA145188, P01CA050661)
- National Institute of General Medical Sciences (R01GM054137)
- National Institute of Allergy and Infectious Diseases (F32AI080075)
- Topics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- E6 oncoprotein, Notch signaling, MAML1, bovine papillomavirus type 1, keratinocyte differentiation, Notch target genes
- MeSH terms
- Animals, Cell Line, DNA-Binding Proteins, Humans, Luciferases, Oncogene Proteins, Viral, Plasmids, Transcription Factors, Transfection, Blotting, Western, Signal Transduction, Proteomics, Mice, Receptors, Notch, Betapapillomavirus, Real-Time Polymerase Chain Reaction
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