# A novel protein quality control system and its role in tumorigenesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $453,169

## Abstract

PROJECT DESCRIPTION
The overall goal of this application is to characterize a novel protein quality control (PQC) system in mammalian
cells and to elucidate its role in tumorigenesis. Oncogenic transformation is a progressive process during which
normal cells acquire a set of traits to overcome various constraints that govern their proliferation. Here we will
test the notion that a heightened ability to remove misfolded proteins may be a new characteristic of tumor cells.
Protein folding is a challenging process in normal unstressed cells, and even more so in incipient and established
neoplastic cells, which frequently encounter high oxidative stresses that damage proteins. However, PQC
systems that remove misfolded proteins in mammalian cells and the role of these systems in tumorigenesis are
not well understood. Our lab recently found that many mammalian tripartite motif (TRIM) proteins can specifically
recognize misfolded proteins and mark them for proteasomal degradation, and that certain TRIM can also directly
activate the proteasome. Moreover, we observed that the capacity to remove misfolded proteins is markedly
increased in cancer cells due to the up-regulation of TRIMs. This higher degradation power mitigates oxidative
stress associated with oncogenic growth and permits oncogenic growth. These findings indicate TRIMs as
versatile regulators of protein quality, connect the clearance of misfolded proteins to antioxidant defense, and
suggest a previously unrecognized characteristic of tumor cells. Our central hypothesis is that TRIM proteins
constitute a major PQC system in mammalian cells that are critical for antioxidant defense and oncogenic
transformation. We propose three specific aims. First, TRIM proteins exist in a large number including over 70
in humans. To gain a comprehensive view of the TRIM system, we will systematically investigate the role of all
human TRIMs in proteasomal degradation of misfolded proteins and define the molecular basis for their different
potency. Second, we will investigate how the accumulation of misfolded proteins causes high oxidative stress,
and how TRIMs ameliorate this stress through the clearance of misfolded proteins. Third, we will determine the
role of the TRIM system in cancer progression using cell and animal models. Moreover, our results suggest that
the removal of misfolded protein is highly sensitive to proteasome inhibition, which may provide an explanation
for proteasome-inhibitor-based therapies for cancer. We will test the notion that increasing production of
misfolded proteins, combined with proteasome blockage, may be highly effective in killing cancer cells.
Collectively, these aims will address critical issues pertaining to protein homeostasis and oncogenic
transformation, and will likely provide valuable information for the development of effective therapies.

## Key facts

- **NIH application ID:** 10088426
- **Project number:** 5R01CA243520-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Eric J Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $453,169
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088426

## Citation

> US National Institutes of Health, RePORTER application 10088426, A novel protein quality control system and its role in tumorigenesis (5R01CA243520-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10088426. Licensed CC0.

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