Animal models of multiple endocrine neoplasia

Wiedemann, Tobias; Pellegata, Natalia S.

doi:10.1016/j.mce.2015.07.004

Cited by 19 publications

(31 citation statements)

References 73 publications

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“…The MEN4 syndrome is due to germ line mutations in the CDKN1B locus, [31, 32]. To determine whether gastrin-driven carcinoids in our study correlated with p27 Kip1 levels, we studied p27 Kip1 protein expression in the polyps excised from omeprazole treated Men1 ΔIEC ; Sst −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Deletion ofMen1andsomatostatininduces hypergastrinemia and gastric carcinoids

Sundaresan

Kang

Hayes

et al. 2016

Gut

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Gastric carcinoids are slow growing neuroendocrine tumors arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumors arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumors. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal. Objective To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines. Design: The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27Kip1 was tested on the human AGSE and mouse STC-1 cell lines. Results The combination of conditional Men1 deletion in the absence of somatostatin lead to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27Kip1 both in vivo and in gastrin-treated cell lines. Loss of p27Kip1 was also observed in human gastric carcinoids arising in the setting of atrophic gastritis. Conclusion Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27Kip1 cellular location and stability.

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Section: Resultsmentioning

confidence: 99%

Deletion ofMen1andsomatostatininduces hypergastrinemia and gastric carcinoids

Sundaresan

Kang

Hayes

et al. 2016

Gut

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“…Less than 50% of MEN1 gastrinomas develop loss of heterozygosity (LOH) suggesting that other mechanisms contribute to loss of WT menin protein function 8, 10, 11 . Although MEN1 is the locus most frequently mutated in the germline of subjects with pancreatic neuroendocrine tumors (pNETS) 12 and gastrinomas 8 , deletion of Men1 in mice does not result in gastrinomas suggesting synergy with other gene loci 2, 13–16 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…The current structural and molecular understanding of the RET ATP-binding and kinase domains and RET ligand-binding sequences, as well as the complexes formed by RET interactions with its ligands and co-receptors are of particular interest as we look to the next generation of RET-targeted therapeutics including small-molecule peptide mimetic inhibitors and synthetic blocking antibodies. Moving to preclinical evaluations, powerful murine models for RET have shown us how RET contributes to tumorigenesis and have been valuable tools in characterizing and validating RET-targeted agents (Wiedemann & Pellegata 2016, Vitale et al 2017. However, Tirtha Das and Ross Cagan also make a strong plea for the complementary value of 'Non-mammalian models of multiple endocrine neoplasia type 2', and their contribution to the understanding of RET function (Das & Cagan 2018).…”

Section: Perspectives From the Benchmentioning

confidence: 99%

The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2

Moodley

Weber

Mulligan

2018

Endocrine-Related Cancer

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The association of medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO) that we now recognize as multiple endocrine neoplasia type 2 (MEN2) (Fig. 1) was first reported by John Sipple in 1961 (Sipple 1961), but over 30 years passed before the cause of this inherited cancer syndrome was identified as mutations of the rearranged during transfection (RET) receptor tyrosine kinase (Donis-Keller et al. 1993, Mulligan et al. 1993. In the ensuing 25 years, RET mutation detection has changed our approaches to MEN2 risk prediction, diagnosis, management and treatment and has greatly improved disease outcomes and quality of life for patients and families with the disease. Moreover, advances in research and technology and better understanding of the disease are pushing the barrier toward earlier, less intensive, personalized care.The identification of activating RET point mutations as the cause of MEN2 represented a novel paradigm for the origins of hereditary cancers, which had previously been exclusively linked to tumor suppressors. As MEN2 mutations activate or enhance RET kinase function, there were relatively few unique mutations (Fig. 2), which simplified detection and interpretation. This has led to our current abilities to predict disease course and optimize management based on the specific RET mutation observed (Wells et al. 2015).

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Animal models of multiple endocrine neoplasia

Cited by 19 publications

References 73 publications

Deletion ofMen1andsomatostatininduces hypergastrinemia and gastric carcinoids

Deletion ofMen1andsomatostatininduces hypergastrinemia and gastric carcinoids

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

The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2

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