MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

Abstract

The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues.Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

Evaluating the role of MEN1 gene expression and its clinical significance in breast cancer patients

“…To further investigate epigenetic or polymorphic alteration that could possibly be involved in the anomalous expression of MEN1 in breast tumors, MS-PCR and Sanger sequencing was performed. Mutations in the MEN1 gene can cause menin function to be lost or altered, compromising the normal regulation of cell growth and division [ 9 , 42 ]. The C terminal of MEN1 protein has nucleus localizing sequences that are critical for its nuclear import; however there are very limited instances where MEN 1 mutations in cases of sporadic breast cancer are reported [ 9 , 43 ].…”

Follow-up study of a Colombian family with a novel MEN1 variant and rare ACTH-producing pancreatic neuroendocrine carcinoma

“…For instance, compromised interaction with FANCD2 could impair DNA repair via the Fanconi anemia pathway [30], while disrupted interaction with MLL1 has been associated with parathyroid adenomas [31]. Altered interactions with proteins such as JunD may affect their oncogenic or tumorsuppressing activities, potentially leading to gastrinomas [27,32]. Additionally, the menin-PRMT5…”

Formation and Detection of Gizzerosine in Animal Feed Matrices: Progress and Perspectives

“…A small amount of histamine is released from enterochromaffin-like (ECL) cells in the corpus under normal circumstances. ECL cells activate parietal cells to regulate gastric acid secretion through histamine; the mechanism is shown in Figure . The binding of histamine to the H2 receptor activates adenylate cyclase (AC) to produce cAMP through Gs signaling, , which potently stimulates H + –K + -ATPase activity via the cAMP-dependent protein kinase (PKA) .…”

“…(A) Cellular anatomy of the stomach. (B) Histamine secreted by ECL cells in the corpus binds to H2 receptors on parietal cells, and stimulates AC generating cAMP, activating PKA and inducing the conformational change of H + –K + -ATPase through phosphorylation and dephosphorylation through Gs signal, − which leads to the transfer of H3O + from parietal cells and the inflow of K + from extracellular cells, and the H + secreted into lumen combining with the Cl – in lumen to form gastric acid. , (C) E1 conformation due to ATP dephosphorylation binds hydronium ions (E1-P form) from the cytoplasm of the parietal cells, and conformational changes (E2-P form) occur at the same time, so that H + –K + -ATPase releases H3O + into the lumen and binds to K + from outside the cytoplasm, resulting in catalytic subunit dephosphorylation back to E1 conformation. , K + is released from the ion-binding site into the cytoplasm of parietal cells after ATP binding …”