# Role of MED1 in the AR-dependent transcription in advanced prostate cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $371,719

## Abstract

Project Summary:
Advanced metastatic castration-resistant prostate cancer (CRPC) is an aggressive disease with high mortality
rate, primarily resulting from the transcriptional addiction driven by Androgen Receptor (AR) signaling. The
evolutionarily conserved multi-subunit Mediator complex plays a central role in the regulation of transcription by
virtue of its ability to functionally bridge gene-specific transcription factors with the RNA polymerase II-
associated basal transcription machinery. MED1 is a key component of the Mediator complex and is
responsible for targeting and anchoring the complex to a broad range of nuclear receptors, including AR. We
have identified phosphorylation of MED1 catalyzed by CDK7 transcriptional kinase is required for its interaction
with AR and as a rate-limiting step in AR-mediated transcription. The underlying hypothesis of this proposal is
that the CDK7 mediated phosphorylation of MED1 is necessary for the formation and stability of MED1-AR
complex at the chromatin in both naïve and anti-androgen refractory CRPC which could be targeted by CDK7
specific inhibitors. The goals of this grant application are to investigate the mechanistic basis of MED1-AR
interaction further, and evaluate the CDK7 specific inhibitors in reversing the AR-dependent transcriptional
addiction in advanced prostate cancer. The three specific aims of the projects are:
Specific Aim 1: Investigate the role of p-MED1 in hyper-activation of AR-signaling
Specific Aim 2: Investigate the mechanism of increased p-MED1 in enzalutamide refractory PCa.
Specific Aim 3: Establish the efficacy of CDK7 inhibitor in clinically relevant naïve and refractory CRPC
models in vivo.

## Key facts

- **NIH application ID:** 10356845
- **Project number:** 5R01CA249210-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Irfan Ahmed Asangani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $371,719
- **Award type:** 5
- **Project period:** 2020-03-06 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356845

## Citation

> US National Institutes of Health, RePORTER application 10356845, Role of MED1 in the AR-dependent transcription in advanced prostate cancer (5R01CA249210-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356845. Licensed CC0.

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