Biology subjects

Elvis-Offiah, U. B.

Publications and source records attributed to Elvis-Offiah, U. B..

2 recordsLinked to original sources

bioRxiv2026

Extracellular signalling regulates gastrin transcription through site-specific phosphorylation and nuclear redistribution of Menin

The multiple endocrine neoplasia type 1 (MEN1) gene encodes Menin, a nuclear scaffold protein and tumor suppressor that regulates transcription. It is frequently mutated in endocrine neoplasia. MEN1-gastrinomas are aggressive neuroendocrine tumors (NETs) that arise predominantly in the submucosal Brunners glands of the duodenum, an organelle rich in extracellular growth factors. Many duodenal NETs retain wild-type MEN1 allele and nuclear Menin, suggesting post-translational inactivation of its tumor-suppressor function. The Menin C-terminal domain (CTD) contains a conserved phosphorylation site at Ser487 within the first of three nuclear localization signals (NLS1-3). We hypothesized that extracellular signaling regulates Menin by phosphorylating the CTD at Ser487 blocking its nuclear localization. Using CTD deletion mapping, site-directed mutagenesis, and kinase activation in gastric cell lines, we show that loss of NLS1-3 reduces Menins nuclear localization, stability, and repression of GASTRIN. Cell stimulation by epiregulin, forskolin, or phorbol ester induced Menin Ser487 phosphorylation and its nuclear translocation, relieving repression of GASTRIN. The phospho-mimetic S487D mutant remained cytoplasmic and phenocopied CTD deletion of NLS1-3 sustaining de-repression of GASTRIN. These findings showed that Ser487 phosphorylation restricts nuclear accumulation of Menin and functionally links extracellular signaling to post-translational modification of Menin that ultimately contributes to transcriptional derepression and neuroendocrine tumorigenesis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=127 HEIGHT=200 SRC="FIGDIR/small/717082v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f96df4org.highwire.dtl.DTLVardef@a1db4borg.highwire.dtl.DTLVardef@4435f9org.highwire.dtl.DTLVardef@3373b3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Clinically defined mutations in MEN1 alter its tumor-suppressive function through increased menin turnover

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 three clinical MEN1 mutations (R516fs, E235K, and A541T) recently identified in a cohort of ten patients with GEP-NETs. We evaluated the subcellular localization and half-lives of these mutated menin variants in Men1-null mouse embryo fibroblast cells and in hormone-expressing human gastric adenocarcinoma and murine enteroendocrine 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 variants exhibited severe defects in total and subcellular expression of menin, and this was consistent with reduced half-lives of these mutants. Mutated menin variants 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. ImplicationClinically defined germline and somatic MEN1 mutations confer pathogenicity by destabilizing nuclear menin expression.

cancer biology↗