# Roles of heat shock transcriptional factor 1 in cell proliferation independent of the heat shock response

> **NIH NIH R35** · NEW YORK MEDICAL COLLEGE · 2024 · $410,000

## Abstract

Abstract: The heat shock transcriptional factor 1 (HSF1) plays central roles in cellular protein
homeostasis (proteostasis), and is precisely regulated for organismal health. HSF1 is activated by
proteotoxic stresses in the cytosol and nucleus, and induces the conserved protective response called
the heat shock response (HSR). HSF1 is also activated in specific physiological conditions to regulate
development, reproduction, longevity and energy metabolism. Conversely, aberrant activation of
HSF1 supports malignancy. While the transcriptome and regulatory mechanisms for HSF1 in the HSR
have been extensively studied, significant knowledge gaps exist for programmed activation of HSF1 in
physiology and dysregulation of HSF1 in diseases. Specifically, it is poorly understood: 1> why HSF1
is essential for certain cell types or cellular states and dispensable for others, and 2> what
mechanisms determine HSF1's regulons and activities in those physiological and pathological
conditions. My lab has established animal and cell models to address these questions. Taking the
nematode C. elegans as a model and the genetic tools we newly developed, we have found that
HSF1 is required in the germline for progenitor cell proliferation in a manner uncoupled from the HSR,
and this requisite is dictated by IGF-1/PI3K signaling. We will explore how the IGF-1/PI3K pathway
regulates HSF1 functions in germ cells by cell-autonomous and non-autonomous mechanisms.
Meanwhile, we are using cancer cell lines to understand HSF1's roles in abnormal cell proliferation,
where the transcriptional program of HSF1 is known to be distinct from the HSR. We have recently
identified epistatic interactors of HSF1 in proliferation and survival through CRISPR screens in
prostate cancer cells. Guided by the results, we will study the roles of HSF1 in cell-cycle progression
and its regulation by the replication-coupled nucleosome assembly factor CHAF1B. Through these
studies, we expect to uncover the context-dependent requirements for HSF1, and identify the
mechanisms that specify the unique transcriptional programs of HSF1 in germline development and
uncontrolled cancer cell proliferation from those of the canonical HSR. Our research will establish a
framework for future studies on HSF1 in other physiological processes, and shed light on potential
therapeutic strategies that target the specific regulatory pathways of HSF1 in cancer.

## Key facts

- **NIH application ID:** 10914013
- **Project number:** 5R35GM138364-05
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** Jian Li
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2020-09-02 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914013

## Citation

> US National Institutes of Health, RePORTER application 10914013, Roles of heat shock transcriptional factor 1 in cell proliferation independent of the heat shock response (5R35GM138364-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914013. Licensed CC0.

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