# Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $328,355

## Abstract

Protein homeostasis (proteostasis), or the proper folding and function of the proteome, is vital for cellular and
organismal health. Critical to proteostasis is an evolutionarily ancient cytoprotective mechanism originally
characterized in cells subjected to elevated temperatures. This mechanism, termed the Heat Shock Response
(HSR), is now known to protect against many diverse sources of proteotoxic stress. A hallmark of the HSR is the
profound transcriptional induction of molecular chaperones known as heat shock proteins (HSPs), a process
regulated by the transcription factor Heat Shock Factor 1 (HSF1). Because this rapid and robust transcriptional
induction can be provoked by simply increasing temperature, the HSR has been used as a model system in the
gene expression field for decades. As such, the processes that govern HSF1 activation and transcriptional
regulation upon heat shock have been extensively studied. However, evidence accumulating over the last
decade has revealed a more complicated picture of HSF1 function. We have found that in cancer, HSF1 directly
regulates the transcription of genes involved in cellular processes which extend far beyond protein folding, in a
manner distinct from the classic HSR. This has been mirrored in studies of HSF1 in other physiological contexts,
such as in the tumor microenvironment and in organismal development. The mechanisms which enable HSF1's
regulatory plasticity, and the underlying logic that connects the disparate set of HSF1-regulated genes with
HSF1's role in proteostasis, is not well understood. Here we propose to use cancer as a as a model system to
study the mechanisms that underlie HSF1's non-canonical regulatory roles. Through a series of unbiased proteomic
and genetic screens we identify a factor critical for HSF1 in this distinct physiological context, and a surprising
multifaceted role for a non-canonical HSF1 target gene in feedback regulation of HSF1 and the HSR. To investigate
these mechanisms, we will integrate sophisticated technologies in the field of transcription regulation with
established biochemical, genetic and genomic methods. Our studies will provide the knowledge required for the
development of therapeutic interventions that promote or inhibit specific programs directed by HSF1. Ultimately,
this may enable us to modulate HSF1's non-canonical programs which are implicated in an ever-expanding array
of disease states.

## Key facts

- **NIH application ID:** 10693802
- **Project number:** 5R01GM144617-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marc Mendillo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $328,355
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693802

## Citation

> US National Institutes of Health, RePORTER application 10693802, Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses (5R01GM144617-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693802. Licensed CC0.

---

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