Papillomaviruses cause benign and malignant epitheliomas in vertebrates, and are grouped into genera of related viruses. Alpha genus HPV's cause anogenital and head and neck cancers that arise from the influence of the virally encoded E6 and E7 oncoproteins. Beta genus HPV types are associated with cutaneous squamous cell carcinomas in immunosuppressed patients, and other HPV types can cause disabling warts in immunosuppressed and HIV infected persons. The action of the virally encoded E6 oncoprotein is critical for the production of both benign epitheliomas and cancers in all HPV types, and the cancer phenotype can be inhibited if E6 expression is inhibited. Therefore, an understanding of the structure of E6 and how E6 interacts with its cellular targets is critical to potential interventions. In the first award cycle of this renewal application, we defined the three dimensional molecular structure of E6 proteins bound to their cellular targets, which is a finding that had been sought for decades. In addition, this application elucidated a newly described cellular target of beta genus E6 called MAML1. MAML1 is a transcriptional coactivator of Notch signaling, so discovery of this association is an important advance in understanding the biology of both human (MAML is the target of E6 proteins in the beta and mu genera) and animal E6 proteins. When E6 proteins bind their cellular targets (called LxxLL docking motifs in the target protein), they undergo an allosteric change in shape to interact with additional proteins such as the p53 tumor suppressor. In this renewal application, we will extend the analysis of E6 structure to additional E6 proteins of medical importance, determine at the molecular level how E6 interacts with additional cellular proteins such as the p53 tumor suppressor, and determine the surface domains of E6 that are required for critical aspects of the papillomavirus life cycle.

Public Health Relevance

Human papillomaviruses cause genital cancer (cervix and anal) and cancers of the head and neck. The virus produces E6 and E7 oncoproteins that cause the cancer. This application has elucidated the structure of two E6 proteins, and now continues to define the structure of additional E6 proteins, and will determine how E6 interacts with other cellular proteins to cause cancer. Understanding the structure of E6 and how E6 interacts with other proteins could facilitate the design of compounds to treat cancers caused by HPV.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134737-08
Application #
9280613
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2010-02-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Strickland, Sydney Webb; Vande Pol, Scott (2016) The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC. J Virol 90:5611-5621
Martinez-Zapien, Denise; Ruiz, Francesc Xavier; Poirson, Juline et al. (2016) Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529:541-5
Vande Pol, Scott (2015) Papillomavirus E6 Oncoproteins Take Common Structural Approaches to Solve Different Biological Problems. PLoS Pathog 11:e1005138
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Zanier, Katia; Stutz, Christina; Kintscher, Susanne et al. (2014) The E6AP binding pocket of the HPV16 E6 oncoprotein provides a docking site for a small inhibitory peptide unrelated to E6AP, indicating druggability of E6. PLoS One 9:e112514

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