# PTRF, a novel regulator of oncogene-induced senescence

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $195,625

## Abstract

A well-established and intriguing function of K-Ras is its ability to promote oncogene-induced senescence
(OIS) through the elevation of reactive oxygen species (ROS). Since senescent cells can not proliferate,
cellular senescence is a powerful tumor suppressor mechanism. In vivo data suggest that OIS is a barrier that
prevents oncogenic K-Ras-transformed cells to proliferate and progress to higher grades of malignancy. The
identification of the molecular signaling through which cells expressing oncogenic K-Ras undergo OIS is
fundamental for gaining insights into how premalignant lesions restrain from progressing to cancer. PTRF is an
essential component in the biogenesis and function of caveolae, flask-shaped invaginations of the plasma
membrane involved in signal transduction. Our published data show that PTRF promotes oxidative stress-
induced premature senescence.
Central hypothesis: we advance the novel paradigm that PTRF-mediated pro-oxidative signaling promotes
oncogenic K-Ras-induced senescence in premalignant lung lesions and prevents the progression to malignant
adenocarcinomas.
This hypothesis will be tested by pursuing two specific aims:
Aim 1: Determine if PTRF promotes oncogenic K-Ras-induced cellular senescence. Hypothesis: activation
of NOX2 by PTRF in caveolae is promoted by oncogenic K-Ras and leads to ROS-dependent cellular
senescence.
Aim 2: Determine if a lack of PTRF promotes tumorigenesis in mouse models of K-Ras-induced lung
cancer. Hypothesis: PTRF-mediated OIS is a tumor suppressor mechanism: the genetic ablation of PTRF
inhibits the formation of premalignant and senescent-positive lung lesions in favor of malignant and senescent-
negative adenocarcinomas.
These investigations will provide novel insights into the molecular mechanisms that regulate oncogene-induced
senescence at the cellular and animal levels. Our studies also propose the concept that therapeutic
strategies aimed at boosting PTRF-mediated signaling may represent novel and better therapeutic options
than those centered on inhibition of K-Ras, which have failed in the past. In fact, they would allow the
enhancement of pro-senescent and anti-tumorigenic K-Ras-dependent pathways and therefore the inhibition of
the progression to lung adenocarcinoma.

## Key facts

- **NIH application ID:** 9851780
- **Project number:** 5R21AG061614-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daniela Volonte
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851780

## Citation

> US National Institutes of Health, RePORTER application 9851780, PTRF, a novel regulator of oncogene-induced senescence (5R21AG061614-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851780. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*