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Gene Review

MEN1  -  multiple endocrine neoplasia I

Homo sapiens

Synonyms: MEAI, Menin, SCG2
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Disease relevance of MEN1


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


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


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


Co-localisations of MEN1


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].


  1. Somatic mutation of the MEN1 gene in parathyroid tumours. Heppner, C., Kester, M.B., Agarwal, S.K., Debelenko, L.V., Emmert-Buck, M.R., Guru, S.C., Manickam, P., Olufemi, S.E., Skarulis, M.C., Doppman, J.L., Alexander, R.H., Kim, Y.S., Saggar, S.K., Lubensky, I.A., Zhuang, Z., Liotta, L.A., Chandrasekharappa, S.C., Collins, F.S., Spiegel, A.M., Burns, A.L., Marx, S.J. Nat. Genet. (1997) [Pubmed]
  2. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Chandrasekharappa, S.C., Guru, S.C., Manickam, P., Olufemi, S.E., Collins, F.S., Emmert-Buck, M.R., Debelenko, L.V., Zhuang, Z., Lubensky, I.A., Liotta, L.A., Crabtree, J.S., Wang, Y., Roe, B.A., Weisemann, J., Boguski, M.S., Agarwal, S.K., Kester, M.B., Kim, Y.S., Heppner, C., Dong, Q., Spiegel, A.M., Burns, A.L., Marx, S.J. Science (1997) [Pubmed]
  3. Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Byström, C., Larsson, C., Blomberg, C., Sandelin, K., Falkmer, U., Skogseid, B., Oberg, K., Werner, S., Nordenskjöld, M. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  4. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Milne, T.A., Hughes, C.M., Lloyd, R., Yang, Z., Rozenblatt-Rosen, O., Dou, Y., Schnepp, R.W., Krankel, C., Livolsi, V.A., Gibbs, D., Hua, X., Roeder, R.G., Meyerson, M., Hess, J.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. Molecular pathogenesis of primary hyperparathyroidism. Arnold, A., Shattuck, T.M., Mallya, S.M., Krebs, L.J., Costa, J., Gallagher, J., Wild, Y., Saucier, K. J. Bone Miner. Res. (2002) [Pubmed]
  6. MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1. Jiang, X.H., Lu, J.L., Cui, B., Zhao, Y.J., Wang, W.Q., Liu, J.M., Fang, W.Q., Cao, Y.N., Ge, Y., Zhang, C.X., Casse, H., Li, X.Y., Ning, G. Endocr. Relat. Cancer (2007) [Pubmed]
  7. Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas. Perren, A., Anlauf, M., Henopp, T., Rudolph, T., Schmitt, A., Raffel, A., Gimm, O., Weihe, E., Knoefel, W.T., Dralle, H., Heitz, P.U., Komminoth, P., Klöppel, G. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  8. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Yokoyama, A., Somervaille, T.C., Smith, K.S., Rozenblatt-Rosen, O., Meyerson, M., Cleary, M.L. Cell (2005) [Pubmed]
  9. Multiple tumor suppressor pathways negatively regulate telomerase. Lin, S.Y., Elledge, S.J. Cell (2003) [Pubmed]
  10. Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. Gobl, A.E., Berg, M., Lopez-Egido, J.R., Oberg, K., Skogseid, B., Westin, G. Biochim. Biophys. Acta (1999) [Pubmed]
  11. Aldosterone-secreting adrenal adenoma as part of multiple endocrine neoplasia type 1 (MEN1): loss of heterozygosity for polymorphic chromosome 11 deoxyribonucleic acid markers, including the MEN1 locus. Beckers, A., Abs, R., Willems, P.J., van der Auwera, B., Kovacs, K., Reznik, M., Stevenaert, A. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  12. Genetic analysis of lithium-associated parathyroid tumors. Dwight, T., Kytölä, S., Teh, B.T., Theodosopoulos, G., Richardson, A.L., Philips, J., Twigg, S., Delbridge, L., Marsh, D.J., Nelson, A.E., Larsson, C., Robinson, B.G. Eur. J. Endocrinol. (2002) [Pubmed]
  13. In vitro and in vivo activity of analogues of the kinin B2 receptor antagonist MEN1 1270. Meini, S., Lecci, A., Carini, F., Tramontana, M., Giuliani, S., Maggi, C.A., Ricci, R., Fabbri, G., Anichini, B., Harmat, N., Rizzi, A., Camarda, V., Regoli, D., Quartara, L. Can. J. Physiol. Pharmacol. (2002) [Pubmed]
  14. Primary peripancreatic lymph node gastrinoma in a woman with MEN1. Zhou, H., Schweikert, H.U., Wolff, M., Fischer, H.P. Journal of hepato-biliary-pancreatic surgery. (2006) [Pubmed]
  15. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Bassett, J.H., Forbes, S.A., Pannett, A.A., Lloyd, S.E., Christie, P.T., Wooding, C., Harding, B., Besser, G.M., Edwards, C.R., Monson, J.P., Sampson, J., Wass, J.A., Wheeler, M.H., Thakker, R.V. Am. J. Hum. Genet. (1998) [Pubmed]
  16. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Giraud, S., Zhang, C.X., Serova-Sinilnikova, O., Wautot, V., Salandre, J., Buisson, N., Waterlot, C., Bauters, C., Porchet, N., Aubert, J.P., Emy, P., Cadiot, G., Delemer, B., Chabre, O., Niccoli, P., Leprat, F., Duron, F., Emperauger, B., Cougard, P., Goudet, P., Sarfati, E., Riou, J.P., Guichard, S., Rodier, M., Meyrier, A., Caron, P., Vantyghem, M.C., Assayag, M., Peix, J.L., Pugeat, M., Rohmer, V., Vallotton, M., Lenoir, G., Gaudray, P., Proye, C., Conte-Devolx, B., Chanson, P., Shugart, Y.Y., Goldgar, D., Murat, A., Calender, A. Am. J. Hum. Genet. (1998) [Pubmed]
  17. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Scacheri, P.C., Rozenblatt-Rosen, O., Caplen, N.J., Wolfsberg, T.G., Umayam, L., Lee, J.C., Hughes, C.M., Shanmugam, K.S., Bhattacharjee, A., Meyerson, M., Collins, F.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. Mapping eight new polymorphisms in 11q13 in the vicinity of multiple endocrine neoplasia type 1: identification of a new distal recombinant. Smith, C.M., Wells, S.A., Gerhard, D.S. Hum. Genet. (1995) [Pubmed]
  19. Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant? Miedlich, S., Lohmann, T., Schneyer, U., Lamesch, P., Paschke, R. Eur. J. Endocrinol. (2001) [Pubmed]
  20. A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism. Honda, M., Tsukada, T., Tanaka, H., Maruyama, K., Yamaguchi, K., Obara, T., Yamaji, T., Ishibashi, M. Eur. J. Endocrinol. (2000) [Pubmed]
  21. The multiple endocrine neoplasia type 1 gene product, menin, inhibits the human prolactin promoter activity. Namihira, H., Sato, M., Murao, K., Cao, W.M., Matsubara, S., Imachi, H., Niimi, M., Dobashi, H., Wong, N.C., Ishida, T. J. Mol. Endocrinol. (2002) [Pubmed]
  22. Exclusion of ZFM1 as a candidate gene for multiple endocrine neoplasia type 1 (MEN1). Lloyd, S.E., Pang, J.T., Pearce, S.H., Leigh, S.E., Thakker, R.V. Hum. Genet. (1997) [Pubmed]
  23. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Yokoyama, A., Wang, Z., Wysocka, J., Sanyal, M., Aufiero, D.J., Kitabayashi, I., Herr, W., Cleary, M.L. Mol. Cell. Biol. (2004) [Pubmed]
  24. Menin associates with FANCD2, a protein involved in repair of DNA damage. Jin, S., Mao, H., Schnepp, R.W., Sykes, S.M., Silva, A.C., D'Andrea, A.D., Hua, X. Cancer Res. (2003) [Pubmed]
  25. Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. La, P., Desmond, A., Hou, Z., Silva, A.C., Schnepp, R.W., Hua, X. Oncogene (2006) [Pubmed]
  26. Menin localizes to chromatin through an ATR-CHK1 mediated pathway after UV-induced DNA damage. Farley, S.M., Chen, G., Guo, S., Wang, M., A, J., Lee, F., Lee, F., Sawicki, M. J. Surg. Res. (2006) [Pubmed]
  27. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Agarwal, S.K., Guru, S.C., Heppner, C., Erdos, M.R., Collins, R.M., Park, S.Y., Saggar, S., Chandrasekharappa, S.C., Collins, F.S., Spiegel, A.M., Marx, S.J., Burns, A.L. Cell (1999) [Pubmed]
  28. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. Perrier, N.D., Villablanca, A., Larsson, C., Wong, M., Ituarte, P., Teh, B.T., Clark, O.H. World journal of surgery. (2002) [Pubmed]
  29. Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity. Lopez-Egido, J., Cunningham, J., Berg, M., Oberg, K., Bongcam-Rudloff, E., Gobl, A. Exp. Cell Res. (2002) [Pubmed]
  30. Exclusion of the 13-kDa rapamycin binding protein gene (FKBP2) as a candidate gene for multiple endocrine neoplasia type 1. Grimmond, S., Weber, G., Larsson, C., Walters, M., Teh, B., Shepherd, J., Nordenskjold, M., Hayward, N. Hum. Genet. (1995) [Pubmed]
  31. The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1. Oberg, K., Skogseid, B. J. Intern. Med. (1998) [Pubmed]
  32. Cdx4 and menin co-regulate hoxa9 expression in hematopoietic cells. Yan, J., Chen, Y.X., Desmond, A., Silva, A., Yang, Y., Wang, H., Hua, X. PLoS ONE (2006) [Pubmed]
  33. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Pellegata, N.S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., H??fler, H., Fend, F., Graw, J., Atkinson, M.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  34. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Lemmens, I., Van de Ven, W.J., Kas, K., Zhang, C.X., Giraud, S., Wautot, V., Buisson, N., De Witte, K., Salandre, J., Lenoir, G., Pugeat, M., Calender, A., Parente, F., Quincey, D., Gaudray, P., De Wit, M.J., Lips, C.J., Höppener, J.W., Khodaei, S., Grant, A.L., Weber, G., Kytölä, S., Teh, B.T., Farnebo, F., Thakker, R.V. Hum. Mol. Genet. (1997) [Pubmed]
  35. Exclusion of the phosphoinositide-specific phospholipase C beta 3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1. Weber, G., Grimmond, S., Lagercrantz, J., Friedman, E., Phelan, C., Carson, E., Hayward, N., Jacobovitz, O., Nordenskjöld, M., Larsson, C. Hum. Genet. (1997) [Pubmed]
  36. Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene. Kas, K., Weber, G., Merregaert, J., Michiels, L., Sandelin, K., Skogseid, B., Thompson, N., Nordenskjöld, M., Larsson, C., Friedman, E. Hum. Mol. Genet. (1993) [Pubmed]
  37. Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism. Carrasco, C.A., González, A.A., Carvajal, C.A., Campusano, C., Oestreicher, E., Arteaga, E., Wohllk, N., Fardella, C.E. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  38. Non-islet origin of pancreatic islet cell tumors. Vortmeyer, A.O., Huang, S., Lubensky, I., Zhuang, Z. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
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