# Characterizing a Common Degradation Pathway for Nuclear Hormone Receptors

> **NIH NIH DP5** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $447,500

## Abstract

PROJECT SUMMARY / ABSTRACT
Nuclear hormone receptors (NRs) are among the most widely targeted proteins in malignancy as they drive a
number of common cancers. Hormones directly bind to NRs, leading to downstream transcriptional signaling.
Some of the most common cancers (breast and prostate) are a result of aberrant NR signaling (estrogen and
androgen receptor, respectively), and are treated using NR-targeting drugs like selective estrogen receptor
modulators (SERMs) and degraders (SERDs). Other NRs, including glucocorticoid and thyroid receptors, are
targeted in other diseases. Still others are orphan receptors or have yet to be therapeutically targeted.
 My research focuses on an important yet unanswered aspect of NR biology. It is known that hormone
binding to NRs leads to transcriptional activation, followed by NR protein degradation. NR degradation regulates
its transcriptional activity, but the mechanism of NR degradation and its effects on NR signaling remains not well
characterized and is a central question in the field of NR biology. Understanding this phenomenon is clinically
important: widely prescribed drugs for breast and prostate cancer work via binding and degrading specific NRs.
I have recently discovered that, after hormone binding to NRs, the HECT E3 ubiquitin ligase UBR5 binds to and
degrades NRs. Importantly, I found that multiple NRs are degraded by UBR5, delineating a common degradation
mechanism of at least a large subset of NRs. We discovered that UBR5 regulates NRs following ligand activation
by binding to the same site as nuclear co-activators (NCOA), which facilitate NR induced transcription, resulting
in direct competition on chromatin. UBR5 therefore is not only a regulator of NR protein stability, but of
transcription. However, we and others have observed that NRs can undergo ligand induced degradation without
ligand induced activation, implying that NRs discriminate between NCOA and UBR5 binding; characterization
and control of these interactions would lead to a specific induction of NR activation or degradation (or both),
leading to significant therapeutic control over physiologic or disease processes reliant on hormone signaling.
 My goal is to characterize UBR5's role as a transcriptional regulator by direct degradation on chromatin
and by doing so, enable an understanding of the pathways of nuclear hormone activation and degradation. If
successful, this may enable the rational design of hormone derivatives that can decouple NR activation and
degradation, allowing for control over hormone receptor signaling. The research proposed here also will yield
basic insight into chromatin and transcriptional regulation, and ubiquitin E3 ligase biology. To achieve this long-
term goal, we must first develop: a characterization of the biochemical interactions between UBR5 and its NR
substrates (Aim 1), a better understanding of UBR5's regulatory capabilities over NR transcriptional activities
(Aim 2), and a broader character...

## Key facts

- **NIH application ID:** 10933400
- **Project number:** 5DP5OD036132-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jonathan Michael Tsai
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,500
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933400

## Citation

> US National Institutes of Health, RePORTER application 10933400, Characterizing a Common Degradation Pathway for Nuclear Hormone Receptors (5DP5OD036132-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933400. Licensed CC0.

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