Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells

Abstract

Background The Multiple Endocrine Neoplasia, type 1 (MEN1) locus encodes the nuclear tumor suppressor protein menin. MEN1 mutations frequently cause neuroendocrine tumors (NETs) such as gastrinomas, remarkable for their predominant duodenal location and local metastasis at the time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner’s glands. We show here that loss of menin in enteric glial cells induces gastrin expression. Aim To determine how menin regulates gastrin gene expression and induces the generation of submucosal gastrin-expressing cell hyperplasia. Methods Primary enteric glial cultures were generated from the Villin-Cre:Men1FL/FL:Sst−/− mice with or without inhibition of gastric acid using omeprazole. In addition, primary enteric glial cells from wild type mice were treated with gastrin and were separated into nuclear and cytoplasmic fractions. Forskolin and H89 treatments were used to activate or inhibit protein kinase A activity. Immunoprecipitation with menin or ubiquitin was used to demonstrate posttranslational modification of menin. Primary glial cells were treated with Leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. Results Gfap+ enteric glial cells expressed gastrin de novo through a feedforward PKA-dependent mechanism. Gastrin-induced nuclear export of menin through Cckbr-mediated PKA activation. Once exported menin was ubiquitinated and degraded by the proteasome. Gfap and other enteric glial markers co-localized with gastrin in human duodenal gastrinomas. Conclusion Collectively, these results suggest that MEN1-associated gastrinomas, which develop in the submucosa might arise from enteric glial cells through hormone-dependent PKA signaling that abrogates menin function leading to hypergastrinemia and associated sequelae.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids—What Is the Relationship?

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Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer

“…Despite these important functions, however, their impact on the development of colorectal cancer (CRC) has not been well investigated. Nevertheless, a number of observations suggest that these cells may be involved in modulating tumor development, as they are implicated in the origin of gastrinomas (18), they can produce inflammatory molecules (19)(20)(21), and their tissue organization is disrupted in human neoplasias (13,22). Moreover, megacolon, which can develop following ablation of the ganglia in the gut, appears to protect against carcinogenesis (23,24).…”

Enteric Glia: S100, GFAP, and Beyond

“…A recent exciting study has shown the colocalization of gastrin with several glial markers such as GFAP, p75 (low‐affinity neurotrophin receptor), and S100b in duodenal gastrinomas (Sundaresan et al, ). Therefore, EGCs or their precursors might be transformed to cancer stem cells.…”