Data from Clinically defined mutations in MEN1 alter its tumor-suppressive function through increased menin turnover
Year: 2023
Type: other
Abstract: Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NETs) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure–function relationship of clinical Multiple Endocrine Neoplasia, type 1 (MEN1) mutations in the absence of a complete loss of heterozygosity at both loci. Here, we determined whether clinical MEN1 mutations render nuclear menin unstable and lead to its functional inactivation. We studied the structural and functional implications of two clinical MEN1 mutations (R516fs, E235K) and a third variant (A541T) recently identified in ten patients with GEP-NETs. We evaluated the subcellular localization and half-lives of the mutants and variant in Men1-null mouse embryo fibroblast cells and in hormone-expressing human gastric adenocarcinoma and neuroendocrine tumor cell lines. Loss of menin function was assessed by cell proliferation and gastrin gene expression assays. Lastly, we evaluated the effect of the small molecule compound MI-503 on stabilizing nuclear menin expression and function in vitro and in a previously reported mouse model of gastric NET development. Both the R516fs and E235K mutants exhibited severe defects in total and subcellular expression of menin, and this was consistent with reduced half-lives of these mutants. Mutated menin proteins exhibited loss of function in suppressing tumor cell proliferation and gastrin expression. Treatment with MI-503 rescued nuclear menin expression and attenuated hypergastrinemia and gastric hyperplasia in NET-bearing mice. Clinically defined MEN1 mutations and a germline variant confer pathogenicity by destabilizing nuclear menin expression.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4382937500