# Establishment of basal epithelial identity by papillomavirus oncoproteins

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $243,750

## Abstract

PROJECT SUMMARY/ABSTRACT
High-risk human papillomaviruses (HPVs) infect mucosal epithelia and cause nearly 5% of cancers worldwide.
Other HPVs infect cutaneous epithelia and cause benign or pathogenic lesions. One hallmark of papillomavirus
biology is the virus’ ability to establish persistent infections in the proliferative basal layer of stratified squamous
epithelia. The mechanisms used by papillomaviruses to direct cells to be retained in the basal layer of stratified
epithelia, which are dynamic tissues that are subject to constant cell turnover, are poorly understood. The goal
of this proposal is to test whether specific activities of the HPV E6 and E7 oncoproteins from mucosal and
cutaneous HPV genotypes drive cell retention in the basal epithelial layer. The work will use a powerful model
developed in my lab to track the migration of epithelial cells in engineered three-dimensional tissue.
We hypothesize that different papillomaviruses activate YAP1 and/or inhibit Notch signaling to promote cell
persistence in the basal epithelial layer. We have identified several mechanisms by which HPV E6 and E7
proteins repress epithelial differentiation in response to a stimulus in two-dimensional cell culture models. Our
data support that the ability of HPV E6 and E7 proteins to repress the commitment to epithelial differentiation is
correlated with their ability to promote basal identity. We found that high-risk mucosal HPV E7 proteins bind and
degrade the tumor suppressor PTPN14. PTPN14 degradation activates YAP1, a powerful driver of epithelial cell
proliferation and basal identity. When high-risk HPV E7 proteins activate YAP1, cells resist differentiation signals
and are more likely to be retained in the basal epithelial layer. Cutaneous HPV E6 proteins bind the transcriptional
co-regulator MAML1. E6 binding to MAML1 blocks Notch signaling, repressing differentiation. We predict that
E6 binding to MAML1 directs basal identity.
The work will systematically determine which activities of E6 and E7 promote basal identity and whether
interfering with such activities will prevent HPV-infected cells from being retained in the basal epithelial layer.
The aims are 1) to test whether inhibition of HPV E7-mediated PTPN14 degradation limits basal cell retention
and 2) to determine whether HPV E6 proteins promote basal cell retention by repressing Notch signaling. We
have developed a robust and physiologically relevant assay for epithelial basal cell identity. We are ideally poised
to apply the assay to identify the basis of the basal retention activities of HPV oncoproteins. Understanding the
mechanisms by which HPV establish and maintain basal epithelial identity, which is required for persistent
infections, will elucidate principles of epithelial biology and tumor virology. It will, in the long term, enable new
therapeutic approaches to treat HPV-positive cancers and premalignant lesions.

## Key facts

- **NIH application ID:** 10808676
- **Project number:** 1R21AI176035-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth A White
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $243,750
- **Award type:** 1
- **Project period:** 2023-12-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808676

## Citation

> US National Institutes of Health, RePORTER application 10808676, Establishment of basal epithelial identity by papillomavirus oncoproteins (1R21AI176035-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10808676. Licensed CC0.

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