# Transcriptional Control of Gastrin

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $393,675

## Abstract

Abstract
Multiple endocrine neoplasia type 1 (MEN1) develops in different endocrine tissues (e.g., pituitary, pancreas,
thyroid) and encodes the nuclear scaffold protein menin. Endocrine tumors of the gastrointestinal tract
including gastric carcinoids, pancreatic neuroendocrine tumors (pNETs) and gastrinomas, exhibit missense
and nonsense mutations in the MEN1 locus, which causes loss of menin function, e.g., de-repression of gastrin
gene expression. Typically, hypergastrinemia in the setting of MEN1-related gastrinomas develop primarily in
the duodenum and less so in the pancreas. Therefore, the impetus for the current proposal is to understand
the origin of gastrin expressing cells in the submucosa in the context of menin. Recent results have revealed
that the submucosal gastrin-expressing cells in the duodenum are of neural crest and not epithelial cell origin
(glial fibrillary acidic protein, GFAP+), as observed for the archived MEN1 duodenal gastrinomas, which are
also GFAP+. The central hypothesis to be tested is that autocrine or paracrine factors, promote menin
nuclear export and proteasome degradation culminating in induction of gastrin gene expression. A genetically-
engineered mouse model that develops hypergastrinemia and carcinoid tumors is used here to study the role
of nuclear menin on gastrin expression. Aim 1 will define the conditions that regulate the nuclear export of
menin required to induce gastrin gene expression. Aim 2 will study the role of small molecule inhibitors that
suppress gastrin gene expression by restricting menin translocation. A central feature of the approach is the
use of a unique mouse model that exhibits the major clinical features of gastrinomas including gastrin-
expressing cells in the lamina propria of the duodenum, hypergastrinemia and gastric carcinoids. The
combination of acid suppression and genetic background (VillinCre:Men1FL/FL;Sst-/-) was sufficient to induce a
16-fold increase in circulating gastrin above WT control levels. Enteric glial cells will be treated with gastrin and
ErbB ligands to study their effect on the nuclear export and import of menin. Leptomycin B and MG132 will be
used to study the two-step loss of menin from the nucleus and then the cell by menin proteasome degradation
in response to growth factor stimulation. Mass spectroscopy of the GFAP+ enteric glial cells with or without
treatment will be performed to analyze the types of protein-protein interactions of menin in the nucleus versus
the cytoplasm after growth factor treatment as well as mapping the phosphopeptide domains targeted by
signaling pathways. Archived specimens of human duodenal and pancreatic gastrinomas will be characterized
and their tumor DNA sequenced to correlate patient phenotype with the mutant menin genotype. Cell lines will
be used to transfect epitope-tagged WT and mutant menin to study their function at baseline and in response
to growth factors. The effect of small molecules such as octreotide and...

## Key facts

- **NIH application ID:** 10225425
- **Project number:** 5R01DK045729-27
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JUANITA L. MERCHANT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,675
- **Award type:** 5
- **Project period:** 1993-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225425

## Citation

> US National Institutes of Health, RePORTER application 10225425, Transcriptional Control of Gastrin (5R01DK045729-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225425. Licensed CC0.

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