# Regulation of endometrial proliferation by the PGRMC family

> **NIH NIH R01** · UNIVERSITY OF WYOMING · 2024 · $321,875

## Abstract

Project Summary/Abstract
 Progesterone receptor membrane component (PGRMC) 1 and PGRMC2 are thought to mediate
progesterone actions. Our lab recently floxed the murine Pgrmc1 and Pgrmc2 genes in an effort to evaluate the
function of these genes in the context of female fertility. Mutagenesis studies using Pgr-Cre mice revealed that
Pgrmc1 and Pgrmc2 are essential for female fertility in that conditional ablation of each gene results in subfertility
that progresses to premature reproductive senescence. Despite being a purported progesterone receptor,
endometrial PGRMC1 expression is actually highest during the proliferative, estradiol (E2)-dominated phase of
the menstrual cycle in humans and primates. The evolutionary origin of the PGRMC family predates the
appearance of sterols as signaling molecules by at least 300 million years. As such, it is now becoming clear
that PGRMCs have both progesterone-dependent and progesterone-independent functions. An evaluation of
estrogenic responses in Pgrmc1d/d, Pgrmc2d/d, and Pgrmc1/2d/d mice revealed that PGRMC proteins are
fundamentally required for E2-induced endometrial epithelial cell proliferation. Furthermore, we determined that
PGRMC1 expression is elevated in human endometrial cancer. Consistent with these findings, human
endometrial xenograft tumors derived from PGRMC1 over-expressing cells grow faster and are more resistant
to chemotherapy treatment. Recent proteomic efforts in our lab have established that PGRMC1 interacts with
three principal groups of proteins, and these include glycolytic enzymes, RNA-binding proteins and proteins
involved in the initiation of translation. Estrogen is known to induce an endometrial Warburg-like glycolytic effect.
Our central hypothesis is that PGRMC family members help coordinate E2-induced endometrial cell proliferation
through their interactions with RNA-binding proteins and by establishing a Warburg-like aerobic glycolytic state
to ensure that sufficient anabolic carbon-based building materials are available for proliferation and expansion
of the tissue during the proliferative phase of the menstrual/estrous cycle. A linked component of this hypothesis
is that PGRMC family members regulate mRNA processing that favors Warburg-like glycolysis. Through the use
of proteomics, primary cell cultures, mouse models designed for evaluating endometrial epithelial cell
proliferation in vivo, development of a novel transgenic mouse, and RNA-seq/CLIP-seq analysis, this hypothesis
will be tested in the following Specific Aims: 1) evaluate the consequences of PGRMC1 over-expression on
female fertility and development of endometrial hyperplasia and cancer; 2) demonstrate that PGRMC1
contributes to E2-induced proliferation by establishing a Warburg-like glycolytic effect in endometrial epithelial
cells; and 3) demonstrate that PGRMC1 mediates at least some of the proliferative actions of E2 in endometrial
epithelial cells through its interactions with RNA-binding proteins th...

## Key facts

- **NIH application ID:** 10810663
- **Project number:** 5R01HD102386-04
- **Recipient organization:** UNIVERSITY OF WYOMING
- **Principal Investigator:** James K Pru
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $321,875
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810663

## Citation

> US National Institutes of Health, RePORTER application 10810663, Regulation of endometrial proliferation by the PGRMC family (5R01HD102386-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10810663. Licensed CC0.

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