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Gene Review

Men1  -  multiple endocrine neoplasia 1

Mus musculus

Synonyms: AW045611, Menin, menin
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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


Chemical compound and disease context of Men1


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


Associations of Men1 with chemical compounds


Physical interactions of Men1


Regulatory relationships of Men1


Other interactions of Men1


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].


  1. Gene expression profiling in insulinomas of Men1 {beta}-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic {beta}-cell tumorigenesis. Fontani??re, S., Tost, J., Wierinckx, A., Lachuer, J., Lu, J., Hussein, N., Busato, F., Gut, I., Wang, Z.Q., Zhang, C.X. Endocr. Relat. Cancer (2006) [Pubmed]
  2. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. La, P., Schnepp, R.W., D Petersen, C., C Silva, A., Hua, X. Endocrinology (2004) [Pubmed]
  3. Of mice and MEN1: Insulinomas in a conditional mouse knockout. Crabtree, J.S., Scacheri, P.C., Ward, J.M., McNally, S.R., Swain, G.P., Montagna, C., Hager, J.H., Hanahan, D., Edlund, H., Magnuson, M.A., Garrett-Beal, L., Burns, A.L., Ried, T., Chandrasekharappa, S.C., Marx, S.J., Spiegel, A.M., Collins, F.S. Mol. Cell. Biol. (2003) [Pubmed]
  4. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Biondi, C.A., Gartside, M.G., Waring, P., Loffler, K.A., Stark, M.S., Magnuson, M.A., Kay, G.F., Hayward, N.K. Mol. Cell. Biol. (2004) [Pubmed]
  5. Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism. Libutti, S.K., Crabtree, J.S., Lorang, D., Burns, A.L., Mazzanti, C., Hewitt, S.M., O'Connor, S., Ward, J.M., Emmert-Buck, M.R., Remaley, A., Miller, M., Turner, E., Alexander, H.R., Arnold, A., Marx, S.J., Collins, F.S., Spiegel, A.M. Cancer Res. (2003) [Pubmed]
  6. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Romeo, G., Ronchetto, P., Luo, Y., Barone, V., Seri, M., Ceccherini, I., Pasini, B., Bocciardi, R., Lerone, M., Kääriäinen, H. Nature (1994) [Pubmed]
  7. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Hughes, C.M., Rozenblatt-Rosen, O., Milne, T.A., Copeland, T.D., Levine, S.S., Lee, J.C., Hayes, D.N., Shanmugam, K.S., Bhattacharjee, A., Biondi, C.A., Kay, G.F., Hayward, N.K., Hess, J.L., Meyerson, M. Mol. Cell (2004) [Pubmed]
  8. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. Smith-Hicks, C.L., Sizer, K.C., Powers, J.F., Tischler, A.S., Costantini, F. EMBO J. (2000) [Pubmed]
  9. The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Chen, Y.X., Yan, J., Keeshan, K., Tubbs, A.T., Wang, H., Silva, A., Brown, E.J., Hess, J.L., Pear, W.S., Hua, X. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Ito, S., Iwashita, T., Asai, N., Murakami, H., Iwata, Y., Sobue, G., Takahashi, M. Cancer Res. (1997) [Pubmed]
  11. Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src. Nakaigawa, N., Weirich, G., Schmidt, L., Zbar, B. Oncogene (2000) [Pubmed]
  12. p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors. Bai, F., Pei, X.H., Nishikawa, T., Smith, M.D., Xiong, Y. Mol. Cell. Biol. (2007) [Pubmed]
  13. Menin induces apoptosis in murine embryonic fibroblasts. Schnepp, R.W., Mao, H., Sykes, S.M., Zong, W.X., Silva, A., La, P., Hua, X. J. Biol. Chem. (2004) [Pubmed]
  14. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Bertolino, P., Radovanovic, I., Casse, H., Aguzzi, A., Wang, Z.Q., Zhang, C.X. Mech. Dev. (2003) [Pubmed]
  15. Menin interacts directly with the homeobox-containing protein Pem. Lemmens, I.H., Forsberg, L., Pannett, A.A., Meyen, E., Piehl, F., Turner, J.J., Van de Ven, W.J., Thakker, R.V., Larsson, C., Kas, K. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  16. Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Bertolino, P., Tong, W.M., Herrera, P.L., Casse, H., Zhang, C.X., Wang, Z.Q. Cancer Res. (2003) [Pubmed]
  17. Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage. Sowa, H., Kaji, H., Canaff, L., Hendy, G.N., Tsukamoto, T., Yamaguchi, T., Miyazono, K., Sugimoto, T., Chihara, K. J. Biol. Chem. (2003) [Pubmed]
  18. Multiple Endocrine Neoplasia Type 1 Interacts with Forkhead Transcription Factor CHES1 in DNA Damage Response. Busygina, V., Kottemann, M.C., Scott, K.L., Plon, S.E., Bale, A.E. Cancer Res. (2006) [Pubmed]
  19. 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. Kato, M., Takeda, K., Kawamoto, Y., Iwashita, T., Akhand, A.A., Senga, T., Yamamoto, M., Sobue, G., Hamaguchi, M., Takahashi, M., Nakashima, I. Cancer Res. (2002) [Pubmed]
  20. Expression of CD109 in human cancer. Hashimoto, M., Ichihara, M., Watanabe, T., Kawai, K., Koshikawa, K., Yuasa, N., Takahashi, T., Yatabe, Y., Murakumo, Y., Zhang, J.M., Nimura, Y., Takahashi, M. Oncogene (2004) [Pubmed]
  21. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Karnik, S.K., Hughes, C.M., Gu, X., Rozenblatt-Rosen, O., McLean, G.W., Xiong, Y., Meyerson, M., Kim, S.K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor. Pandit, S.D., Donis-Keller, H., Iwamoto, T., Tomich, J.M., Pike, L.J. J. Biol. Chem. (1996) [Pubmed]
  23. Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation. Hayashi, Y., Iwashita, T., Murakamai, H., Kato, Y., Kawai, K., Kurokawa, K., Tohnai, I., Ueda, M., Takahashi, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  24. Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Agarwal, S.K., Novotny, E.A., Crabtree, J.S., Weitzman, J.B., Yaniv, M., Burns, A.L., Chandrasekharappa, S.C., Collins, F.S., Spiegel, A.M., Marx, S.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  25. Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. Kawai, K., Iwashita, T., Murakami, H., Hiraiwa, N., Yoshiki, A., Kusakabe, M., Ono, K., Iida, K., Nakayama, A., Takahashi, M. Cancer Res. (2000) [Pubmed]
  26. Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease. Carlomagno, F., Melillo, R.M., Visconti, R., Salvatore, G., De Vita, G., Lupoli, G., Yu, Y., Jing, S., Vecchio, G., Fusco, A., Santoro, M. Endocrinology (1998) [Pubmed]
  27. Characterization of the mouse Men1 gene and its expression during development. Stewart, C., Parente, F., Piehl, F., Farnebo, F., Quincey, D., Silins, G., Bergman, L., Carle, G.F., Lemmens, I., Grimmond, S., Xian, C.Z., Khodei, S., Teh, B.T., Lagercrantz, J., Siggers, P., Calender, A., Van de Vem, V., Kas, K., Weber, G., Hayward, N., Gaudray, P., Larsson, C. Oncogene (1998) [Pubmed]
  28. Differential expression of multiple alternative spliceforms of the Men1 tumor suppressor gene in mouse. Forsberg, L., Zablewska, B., Piehl, F., Weber, G., Lagercrantz, S., Gaudray, P., Höög, C., Larsson, C. Int. J. Mol. Med. (2001) [Pubmed]
  29. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Bertolino, P., Tong, W.M., Galendo, D., Wang, Z.Q., Zhang, C.X. Mol. Endocrinol. (2003) [Pubmed]
  30. Transcription regulation of the multiple endocrine neoplasia type 1 gene in human and mouse. Zablewska, B., Bylund, L., Mandic, S.A., Fromaget, M., Gaudray, P., Weber, G. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
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