Menin and JunD regulate gastrin gene expression through proximal DNA elements

Mensah-Osman, Edith; Veniaminova, Natalia A.; Merchant, Juanita L.

doi:10.1152/ajpgi.00160.2011

Cited by 21 publications

(38 citation statements)

References 44 publications

(55 reference statements)

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“…We previously showed that menin suppresses gastrin gene expression and that reducing menin expression is sufficient to induce gastrin expression (23). Therefore, we hypothesize in this study that loss of menin expression will be sufficient to induce gastrin expression.…”

mentioning

confidence: 60%

Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia

Veniaminova

Hayes

Varney

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Antral gastrin is the hormone known to stimulate acid secretion and proliferation of the gastric corpus epithelium. Patients with mutations in the multiple endocrine neoplasia type 1 (MEN1) locus, which encodes the protein menin, develop pituitary hyperplasia, insulinomas, and gastrinomas in the duodenum. We previously hypothesized that loss of menin leads to derepression of the gastrin gene and hypergastrinemia. Indeed, we show that menin represses JunD induction of gastrin in vitro. Therefore, we examined whether conditional deletion of Men1 (Villin-Cre and Lgr5-EGFP-IRES-CreERT2), with subsequent loss of menin from the gastrointestinal epithelium, increases gastrin expression. We found that epithelium-specific deletion of Men1 using Villin-Cre increased plasma gastrin, antral G cell numbers, and gastrin expression in the antrum, but not the duodenum. Moreover, the mice were hypochlorhydric by 12 mo of age, and gastric somatostatin mRNA levels were reduced. However, duodenal mRNA levels of the cyclin-dependent kinase inhibitor p27Kip1 were decreased, and cell proliferation determined by Ki67 staining was increased. About 11% of the menin-deficient mice developed antral tumors that were negative for gastrin; however, gastrinomas were not observed, even at 12 mo of age. No gastrinomas were observed with conditional deletion of Men1 in the Lgr5 stem cells 5 mo after Cre induction. In summary, epithelium-specific deletion of the Men1 locus resulted in hypergastrinemia due to antral G cell hyperplasia and a hyperproliferative epithelium, but no gastrinomas. This result suggests that additional mutations in gene targets other than the Men1 locus are required to produce gastrin-secreting tumors.somatostatin; p27

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mentioning

confidence: 60%

Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia

Veniaminova

Hayes

Varney

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This hypothesis was confirmed by the demonstration that downregulation of MTF1 expression did not inhibit activation of gastrin promoter activity by Zn 2C ions. The Sp1 transcription factor, which plays a central role in gastrin expression (Merchant et al 1995, Tillotson 1999, Mensah-Osman et al 2011, was also eliminated from contention in the current study. The epithelial-mesenchymal transition (EMT) in cancer cells endows them with invasiveness and stem cell characteristics which in turn make them more aggressive and resistant to chemotherapy.…”

Section: Discussionmentioning

confidence: 84%

“…A dual role of the zinc finger transcription factor ZBP-89 has been proposed as, depending on the conditions, it can either stimulate or repress gastrin expression (Merchant 2000, Holley-Guthrie et al 2005. The observation that various proteins mediate gastrin transcription via interaction with the Sp1 transcription factor indicates that Sp1 plays a central regulatory role in gastrin expression (Merchant et al 1995, Tillotson 1999, Mensah-Osman et al 2011. Interestingly, gastrin acting via the CCK2R can upregulate its own transcription, and this upregulation is independent of Sp1 binding (Kovac et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

Xiao

Kovac

Chang

et al. 2014

Journal of Molecular Endocrinology

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Gastrin and its precursors act as growth factors for the normal and neoplastic gastrointestinal mucosa. As the hypoxia mimetic cobalt chloride upregulates the gastrin gene, the effect of other metal ions on gastrin promoter activity was investigated. Gastrin mRNA was measured by real-time PCR, gastrin peptides by RIA, and gastrin promoter activity by dual-luciferase reporter assay. Exposure to Zn 2C ions increased gastrin mRNA concentrations in the human gastric adenocarcinoma cell line AGS in a dose-dependent manner, with a maximum stimulation of 55G14-fold at 100 mM (P!0.05). . Deletional mutation of the gastrin promoter identified an 11 bp DNA sequence, which contained an E-box motif, as necessary for Zn 2C -dependent gastrin induction. The fact that E-box binding transcription factors play a crucial role in the epithelial-mesenchymal transition (EMT), together with our observation that Zn 2C ions upregulate the gastrin gene in AGS cells by an E-box-dependent mechanism, suggests that Zn 2C ions may induce an EMT, and that gastrin may be involved in the transition.

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“…Deacetylation of histones at promoters of target genes is associated with downregulation of gene transcription. GAST (gastrin) was identified as a potential target of menin/mSin3A/HDAC complexes (Mensah-Osman et al 2011).…”

Section: Menin As An Epigenetic Repressor Of Gene Transcriptionmentioning

confidence: 99%

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

Pieterman¹,

Conemans²,

Dreijerink³

et al. 2014

Endocrine-Related Cancer

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Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

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Menin and JunD regulate gastrin gene expression through proximal DNA elements

Cited by 21 publications

References 44 publications

Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia

Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

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