# Nrf1-dependent Proteotoxic Stress Response

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $326,025

## Abstract

ABSTRACT
 Proteotoxic stress or inhibition of cellular proteasome activity by proteasome
inhibitor drugs sets in motion an evolutionarily conserved pathway that directs the de
novo synthesis of proteasomes as a compensatory response. Our previous studies
established the transcription factor Nrf1 as a key player in this stress-response pathway.
Nrf1, by its ability to bind to the anti-oxidant response elements typically found in the
regulatory regions of proteasome genes, induces their expression in response to
proteasome inhibition. As an endoplasmic reticulum (ER)-bound transcription factor with
a bulk of its polypeptide in the lumen, Nrf1 activation involves its retrotranslocation into
the cytosol in a manner that depends on the ATPase p97/VCP. This is followed by
proteolytic processing and subsequent mobilization of the transcriptionally active form of
Nrf1 to the nucleus. Further understanding of the Nrf1 pathway could shed light on the
intricate mechanisms by which cells cope with proteotoxic stress.
 In the first two aims, we propose to dissect the functional output and the
mechanism of activation of Nrf1 pathway and explore various factors that assist in
mobilizing this transcription factor from the lumen of the ER all the way to the nucleus.
Using the information gleaned from the above two aims and using genetic and chemical
tools, in the third aim, we propose to test if inhibition of Nrf1 pathway leads to increased
efficacy of proteasome inhibitor treatment in cancer cells. Thus, the proposed line of
work is important not only from a basic research stand-point of furthering Nrf1 biology; it
is also significant from a translational perspective as well, since it has the potential to
illuminate novel strategies to modulate the cellular protein clearance pathways in various
human diseases.

## Key facts

- **NIH application ID:** 9898396
- **Project number:** 5R01GM132396-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Senthil Kumar Radhakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,025
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898396

## Citation

> US National Institutes of Health, RePORTER application 9898396, Nrf1-dependent Proteotoxic Stress Response (5R01GM132396-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898396. Licensed CC0.

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