# High-risk HPV E6:  dysregulation of immortalization, growth, and differentiation through protein partnerships in HPV-associated cancers

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $376,438

## Abstract

PROJECT SUMMARY/ABSTRACT
 High-risk human papillomaviruses (HR HPVs) cause 5% of all cancers. There are preventive vaccines
against HPV, but less than 2% of the world's target population has received them. This leaves millions of women
and men at risk for HPV-associated cervical, anogenital, and head and neck cancers. We need to understand
how HR HPV establishes and maintains an active infection, while also driving cancer development, in order to
guide focused therapeutic interventions to prevent, arrest, and reverse disease.
 The greatest clinical risk factor for cervical cancer is a persistent HR HPV infection. This persistence
occurs through coordinated dysregulation of cellular pathways, which both support the infection and foster cancer
development. Underlying this dysregulation is the requirement that the HPV oncogenes E6 and E7 partner with
cellular proteins. Our work has focused on the E6 oncogene from HPV type 16 (16E6), the most common HR
HPV type in cancers. Previously, we found that 16E6 required the cellular protein NFX1-123, and its protein
partners cytoplasmic poly(A) binding proteins (PABPCs), to fully activate telomerase and the immortalization
pathway. Our current studies revealed that NFX1-123 is highly expressed in cervical cancers, and together 16E6,
NFX1-123, and PABPCs amplify telomerase, cellular growth, and longevity over time. We also discovered that
NFX1-123 is increased during differentiation and, together with 16E6, augments cellular differentiation cascades
and their host and viral gene targets while simultaneously protecting against concomitant cellular arrest and
senescence. These findings create a sightline for a new level of investigation that will uncover the connectivity
and control of growth and differentiation and the temporal changes driving and accelerating immortalization by
PABPCs, NFX1-123, and 16E6. These results will also delineate targets for future treatments that specifically
disrupt universal pathways required for HPV and its cancers.
 Our specific aims are: (1) Determine how 16E6, NFX1-123, and PABPCs work together in co-regulating
growth and differentiation to better establish a persistent infection. We will mimic the initial steps of establishing
a HR HPV infection to identify the way in which these proteins function to permit both differentiation and growth
in concert during the initial, foundational steps of a HR HPV infection. (2) Elucidate the mechanism of longitudinal,
sequential increases of hTERT and telomerase by 16E6, NFX1-123, and PABPCs. Telomerase activation leads
to cellular immortalization. We will leverage long-term cellular studies to determine the sequential changes to
hTERT, the catalytic subunit of telomerase, due to 16E6 with NFX1-123 and PABPCs and to create a roadmap
of molecular oncogenic progression that mirrors clinical chronology. Our proposed studies will elucidate the
temporal and interwoven dysregulation of oncogenic pathways by 16E6 and its host protein partners; th...

## Key facts

- **NIH application ID:** 10050875
- **Project number:** 2R01CA172742-07A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Rachel Adria Katzenellenbogen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,438
- **Award type:** 2
- **Project period:** 2014-06-04 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050875

## Citation

> US National Institutes of Health, RePORTER application 10050875, High-risk HPV E6:  dysregulation of immortalization, growth, and differentiation through protein partnerships in HPV-associated cancers (2R01CA172742-07A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10050875. Licensed CC0.

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