Disease relevance of MEN1

• MEN1 (Menin) gene-disease database  
• Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown [1].
• Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and the anterior pituitary [2].
• In contrast, a low incidence of deletions involving the MEN1 gene was found in sporadic pituitary adenomas [3].
• Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets [4].
• Specific clonal alterations involving somatic mutation and/or deletion of both MEN1 alleles have been demonstrated in about 15-20% of sporadic parathyroid adenomas [5].
• We detected a loss of heterozygosity (LOH) at chromosome 11q in the removed tumours, including gastrinoma, insulinoma and parathyroid adenoma from two probands of MEN1 families [6].
• Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development [7].

High impact information on MEN1

• MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors [8].
• Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts [8].
• Furthermore, menin is essential for maintenance of MLL-associated but not other oncogene induced myeloid transformation [8].
• These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers [8].
• The third, the tumor suppressor Menin, is a direct repressor of hTERT [9].

Chemical compound and disease context of MEN1

• Menin-mediated repression is relieved by the histone deacetylase inhibitor trichostatin A, indicating that deacetylation of histones is an essential component of this repression mechanism, as has recently been demonstrated for the retinoblastoma protein [10].
• A 63-year-old female presented with the extremely rare occurrence of an aldosterone-secreting adrenocortical adenoma as part of the syndrome of multiple endocrine neoplasia type 1 (MEN1) [11].
• METHODS: Comparative genomic hybridization (CGH), loss of heterozygosity (LOH) and multiple endocrine neoplasia type 1 gene (MEN1) mutation analysis were used to analyze twelve parathyroid tumors from nine patients with lithium-associated HPT [12].
• MEN13346 and MEN13031 (pKi = 9.7and 9.5, pA2 = 8.2 and 7.9, pKB = 7.9 and 8.5, respectively) were 10- to 30-fold less active in vivo than MEN1 1270, without improving the discrimination between BK-induced BC and hypotension after either systemic or topical administration [13].
• Further examinations established multiple endocrine neoplasia type 1 (MEN1) with a germline mutation at codon 1153 (T->A) in exon 7, causing an amino-acid change, from isoleucine to asparagine (Ile348Asn), in the MEN1 gene [14].

Biological context of MEN1

• All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele [1].
• We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10) [1].
• Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene [1].
• The MEN1 gene contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript [2].
• The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified [15].

Anatomical context of MEN1

• Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary [15].
• We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations [16].
• The gene for multiple endocrine neoplasia type 1 (MEN1), an inherited predisposition to neuroendocrine neoplasm of the parathyroid glands, the pancreatic islet parenchyma, and the anterior pituitary gland, was recently mapped to chromosome 11q13 based on genetic linkage in families [3].
• Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues [16].
• MEN1 RNA and corresponding protein levels were all reduced after siRNA transfection of HeLa cells, although the degree of inhibition mediated by individual siRNAs varied [17].

Associations of MEN1 with chemical compounds

• The MEN1 locus has been localized by family studies to 11q13, flanked by markers PGA and D11S97 [18].
• RESULTS: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363 [19].
• Analysis of germline DNA in the proband showed a missense mutation (GGC-->GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D) [20].
• In rat pituitary GH3 cells stably expressing menin, both PRL gene expression/secretion and thymidine incorporation into DNA were inhibited as compared with mock-transfected cells [21].
• A 6-bp deletion that resulted in the loss of two proline residues at codons 479 and 480 in exon 12 was found in one MEN1 patient [22].

Physical interactions of MEN1

• Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components [23].
• Here we show that menin specifically interacts with FANCD2, a protein encoded by a gene involved in DNA repair and mutated in patients with an inherited cancer-prone syndrome, Fanconi anemia [24].
• Here, we show that point mutations in three individual NLSs, NLS1, NLS2, and a novel accessory NLS, NLSa, do not block nuclear translocation, but compromise the ability of menin to repress expression of the endogenous insulin-like growth factor binding protein-2 (IGFBP-2) gene [25].
• Over expressing active CHK1 (1-365) increased chromatin-bound menin, similar to UV [26].
• Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription [27].

Enzymatic interactions of MEN1

• Four small families with a family history of hyperparathyroidism without clear-cut MEN-1 features were screened for a MEN1 mutation [28].

Co-localisations of MEN1

• Endogenous menin is colocalized with GFAP and vimentin in glioma cells as determined by confocal microscopy [29].

Regulatory relationships of MEN1

• These observations suggest that menin inhibits hPRL promoter activity and cell proliferation, raising the possibility that menin might play an important role in the tumorigenesis of prolactinoma [21].
• Northern studies have revealed that FKBP2 is expressed in those tissues predisposed to hyperplasia in MEN1; however, single-strand conformation polymorphism analysis and direct sequencing of DNAs from affected members of MEN1 kindreds and sporadic tumour DNAs have been performed and no mutations have been found [30].
• Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism [10].
• Early diagnosis of pancreatic endocrine tumours in MEN-1 is enhanced by the use of a standardized meal stimulation test with measurements of serum PP and gastrin response [31].
• Cdx4 and menin co-regulate hoxa9 expression in hematopoietic cells [32].

Other interactions of MEN1

• We have identified a germ-line nonsense mutation in the human CDKN1B gene in a MEN1 mutation-negative patient presenting with pituitary and parathyroid tumors [33].
• The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies [34].
• These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis [23].
• We can now exclude PLCB3 from candidacy as the MEN1 gene [35].
• The nearest proximal and distal markers that show recombination with the disease are D11S822 and GSTP1, respectively, thereby narrowing the candidate region for MEN1 by 50% on the distal side [18].

Analytical, diagnostic and therapeutic context of MEN1

• The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis [2].
• In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis [36].
• To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data [36].
• RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp) [37].
• The histogenesis of pancreatic islet cell tumors was investigated by morphological identification of putative precursor lesions in pancreatic tissue from patients with multiple endocrine neoplasia type 1 (MEN1), tissue microdissection, and genetic analysis [38].

References