Disease relevance of Men1

• Gene expression profiling in insulinomas of Men1 {beta}-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic {beta}-cell tumorigenesis [1].
• Menin also alters the structure of the chromatin surrounding the promoter of the IGFBP-2 gene, as demonstrated by the deoxyribonuclease I hypersensitivity assay [2].
• The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells [3].
• Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months [4].
• Here, we show that loss of Men1 gene function in the parathyroid glands of mice results in histological changes consistent with parathyroid neoplasia as well as systemic hypercalcemia [5].

High impact information on Men1

• Mutations in the extracellular cysteine-rich domain of Ret have been identified previously in patients with multiple endocrine neoplasia type 2A, and a targeted mutation in the tyrosine kinase domain of the same gene produces intestinal aganglionosis and kidney agenesis in homozygous transgenic mice [6].
• This menin-associated complex methylates histone H3 on lysine 4 [7].
• C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B [8].
• Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and Hoxa9 expression [9].
• The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression [9].

Chemical compound and disease context of Men1

• Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype [10].
• MET mutation M1268T was located in a codon highly conserved among receptor tyrosine kinases, and homologous to the codon mutated in multiple endocrine neoplasia type 2B, and many cases of sporadic medullary carcinoma of the thyroid gland (Ret M918T) [11].

Biological context of Men1

• Combined mutations of p27(-)(/)(-) and Men1(+/)(-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth [12].
• The tumor suppressor gene Men1, which is frequently mutated in MEN1 patients, encodes the nuclear protein menin [13].
• Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells [3].
• Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis [14].
• However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts [14].

Anatomical context of Men1

• Compared with their corresponding single mutant littermates, the p18(-)(/)(-); Men1(+/)(-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas [12].
• To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic beta-cells [1].
• In adult mice both Men1 and Pem yielded strong signals in testis, Sertoli cells and particularly in seminiferous tubules [15].
• Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count [9].
• By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas [3].

Associations of Men1 with chemical compounds

• Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms [16].
• Stable inactivation of menin in MC3T3-E1 cells increased ALP activity, mineralization, and the expression of type I collagen and OCN [17].
• Multiple Endocrine Neoplasia Type 1 Interacts with Forkhead Transcription Factor CHES1 in DNA Damage Response [18].
• Repair by Src kinase of function-impaired RET with multiple endocrine neoplasia type 2A mutation with substitutions of tyrosines in the COOH-terminal kinase domain for phenylalanine [19].
• In this study, we found that the expression of mouse CD109 gene was upregulated in NIH3T3 cells expressing RET tyrosine kinase with a multiple endocrine neoplasia 2B mutation [20].

Physical interactions of Men1

• Thus, our study has identified that menin interacts with Pem, and the high expression of these proteins in the testis suggests a role in spermatogenesis [15].
• Menin interacts directly with the homeobox-containing protein Pem [15].
• Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro [9].

Regulatory relationships of Men1

• Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2 [2].
• Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c [21].
• The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor [22].
• In addition, we detected BMK1 activation in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A mutation [23].

Other interactions of Men1

• These data indicate that menin inactivation specifically inhibits the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage, mediated by menin and Smad1/5 interactions [17].
• Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter [24].
• Analyses of JunD and menin effects on proliferation, morphology, and cyclin D1 in stable cell lines unmasked an unexpected growth promoting activity of JunD [24].
• Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation [25].
• Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease [26].

Analytical, diagnostic and therapeutic context of Men1

• By RNA in situ hybridization and Northern analysis the spatiotemporal expression pattern of Men1 was determined during mouse development [27].
• By 5' RACE and RT-PCR four alternative splice variants were identified, indicating a 5' heterogeneity of Men1 similar to the human counterpart [28].
• In order to identify menin-interacting proteins we used a yeast two-hybrid assay to screen a 12.5-dpc mouse embryo library with partial menin encompassing amino acids 278 to 476 [15].
• To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach [29].
• We found that overexpression of menin in an inducible cell culture system down-regulated the proximal promoter [30].

References