SuperMEN1 pp 59-67 | Cite as

Role of Menin in Bone Development

  • Hiroshi Kaji
  • Lucie Canaffand
  • Geoffrey N. Hendy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 668)


Menin function is related to transcriptional regulation and cell cycle control and it physicallyand functionally interacts with osteotropic transcription factors, such as Smad1/5, Smad3, Runx2 and JunD. Menin promotes the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage, mediated by interactions between menin and the BMP signaling molecules, Smad1/S, or Runx2. On the other hand, in mature osteoblasts the interaction of menin and the TGF-β/Smad3 pathway counteracts the BMP-2/Smad1/S- and Runx2-induced transcriptional activities leading to inhibition of late stage osteoblast differentiation. Moreover, menin suppresses osteoblast maturation partly by inhibiting the differentiation actions of JunD. In conclusion, menin plays an important role in osteoblastogenesis and osteoblast differentiation.


Mesenchymal Stem Cell Transform Growth Factor Osteoblast Differentiation Multiple Endocrine Neoplasia Type Osteoblast Lineage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2:389–406.CrossRefPubMedGoogle Scholar
  2. 2.
    Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs and Cbfa1. Endocr Rev 2000; 21:393–411.CrossRefPubMedGoogle Scholar
  3. 3.
    Stewart C, Parente F, Piehl F et al. Characterization of the mouse Men 1 gene and its expression during development. Oncogene 1998; 17:2485–93.CrossRefPubMedGoogle Scholar
  4. 4.
    Crabtree JS, Scacheri PC, Ward JM et al. A mouse model of multiple endocrine neoplasia type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 2001; 98:1118–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Bertolino P, Tong WM, Galendo D et al. Heterozygous men 1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol 2003; 17:1880–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Kaji H, Canaff L, Lebrun JJ et al. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type β signaling. Proc Natl Acad Sci USA 2001; 98:3837–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Hu PP, Datto MB, Wang XF. Molecular mechanisms of transforming growth factor-S signaling. Endocr Rev 1998; 19:349–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Yakicier MC, Irmak MB, Romano A et al. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999; 18:4879–83.CrossRefPubMedGoogle Scholar
  9. 9.
    Agarwal SK, Guru SC, Heppner C et al. Menin interacts with the API transcription factor JunD and represses JunD-activated transcription. Cell 1999; 96:143–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Gobl AE, Berg M, Lopez-Egido LR et al. Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. Biochim Biophys Acta 1999; 1447:51–6.PubMedGoogle Scholar
  11. 11.
    Kim H, Lee JE, Cho EJ et al. Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. Cancer Res 2003; 63:6135–9.PubMedGoogle Scholar
  12. 12.
    Yazgan O, Pfarr CM. Differential binding of the menin tumor suppressor protein to JunD isoforms. Cancer Res 2001; 61:916–20.PubMedGoogle Scholar
  13. 13.
    Kaji H, Canaff L, Goltzman D et al. Cell cycle regulation of menin expression. Cancer Res 1999; 59:5097–101.PubMedGoogle Scholar
  14. 14.
    Pfarr CM, Mechta F, Spyrou G et al. Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by rase Cell 1994; 76:747–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Agarwal SK, Novotny EA, Crabtree JS et al. Transcriptional factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc Natl Acad Sci USA 2003; 100:10770–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Ikeo Y, Yumita W, Sakurai A et al. JunD-menin interaction regulates c-Jun-mediated AP-1 transactivation. Endocr J 2004; 51:333–42.CrossRefPubMedGoogle Scholar
  17. 17.
    Wozney JM, Rosen V, Celeste A J et al. Novel regulators of bone formation: Molecular clones and activities. Science 1988; 242: 1528–34.CrossRefPubMedGoogle Scholar
  18. 18.
    Janssens K, ten Dijke P, Janssens S et al. Transforming growth factor-β1 to the bone. Endocr Rev 2005; 26:743–74.CrossRefPubMedGoogle Scholar
  19. 19.
    Sowa H, Kaji H, Yamaguchi T et al. Smad3 promotes alkaline phosphatase activity and mineralization of osteoblastic MC3T3-E1 cells. J Bone Miner Res 2002; 17:1190–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Sowa H, Kaji H, Yamaguchi T et al. Activations of ERK1/2 and JNK by transforming growth factor β negatively regulate Smad3-induced alkaline phosphatase activity and mineralization in mouse osteoblastic cells. J Biol Chem 2002; 277:36024–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Komori T, Yagi H, Nomura S et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89:755–64.CrossRefPubMedGoogle Scholar
  22. 22.
    Nakashima K, Zhou X, Kunkel G et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002; 108:17–29.CrossRefPubMedGoogle Scholar
  23. 23.
    Nashio Y, Dong Y, Paris M et al. Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 2006; 372:62–70.CrossRefGoogle Scholar
  24. 24.
    Wang X, Kua HY, Hu Y et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis and bone remodeling. J Cell Biol 2006; 172:115–125.CrossRefPubMedGoogle Scholar
  25. 25.
    Lengner CJ, Steinman HA, Gagnon J et al. Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol 2006; 172:909–921.CrossRefPubMedGoogle Scholar
  26. 26.
    Bodine PVN, Komm BS. Wnt signaling and osteoblastogenesis. Rev Endocr Metab Discord 2006; 7:33–39.CrossRefGoogle Scholar
  27. 27.
    Tobimatsu T, Kaji H, Sowa H et al. Parathyroid hormone increases β-catenin levels through Smad3 in mouse osteoblastic cells. Endocrinol 2006: 147:2583–2590.CrossRefGoogle Scholar
  28. 28.
    Grigoriadis A, Schellander K, Wang ZQ et al. Osteoblasts are target cells for transformation in c-fos transgenic mice. J Cell Biol 1993; 122:685–701.CrossRefPubMedGoogle Scholar
  29. 29.
    Castellazzi M, Spyrou G, La Vista N et al. Overexpression of c-jun, junB, or junD affects cell growth differently. Proc Natl Acad Sci USA 1991; 88:8890–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Jochum W, David JP, Elliott C et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med 2000; 6:980–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Sabarakos G, Sims NA, Chen J et al. Overexpression of DeltaFosB transcription factorts) increases bone formation and inhibits adipogenesis. Nat Med 2000; 6:985–90.CrossRefGoogle Scholar
  32. 32.
    Kenner L, Hoebertz A, Beil T et al. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 2004; 164:613–23.CrossRefPubMedGoogle Scholar
  33. 33.
    Granet C, Vico AG, Alexandre C et al. MAP and src kinases control the induction of AP-1 members in response to changes in mechanical environment in osteoblastic cells. Cell Signal 2002; 14:679–688.CrossRefPubMedGoogle Scholar
  34. 34.
    Varghese S, Rydziel S, Canalis E. Basicfibroblast growth factor stimulates collagenase-3 promoter activity in osteoblasts through an activator prorein-Lbinding site. Endocrinology 2000; 141:2185–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Winchester SK, Selvamurugan N, D’Alonzo RC et al. Developmental regulation of collagenase-3 mRNA in normal, differentiating osteoblasts through the activator protein-1 and the runt domain binding sites. J Biol Chem 2000; 275:23310–8.CrossRefPubMedGoogle Scholar
  36. 36.
    McCabe LR, Banerjee C, Knudu R et al. Developmental expression and activities of specific fos and jun proteins are functionally related to osteoblast maturation: role of Fra-2 and JunD during differentiation. Endocrinology 1996; 137:4398–408.CrossRefPubMedGoogle Scholar
  37. 37.
    Tohjima E, Inoue D, Yamamoto N et al. Decreased AP-1 activity and interleukin-11 expression by bone marrow stromal cells may be associated with impaired bone formation in aged mice. J Bone Miner Res 2003; 18:1461–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Sowa H, Kaji H, Canaff L et al. 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. J Biol Chem 2003; 278:21058–69.CrossRefPubMedGoogle Scholar
  39. 39.
    Sowa H, Kaji H, Hendy GN et al. Menin is required for bone morphogenetic protein 2-and transforming growth factor β-regulated osteoblastic differentiation through interaction with Smads and Runx2. J Biol Chem 2004; 279:40267–75.CrossRefPubMedGoogle Scholar
  40. 40.
    Naito J, Kaji H, Sowa H et al. Menin suppresses osteoblast differentiation by antagonizing the AP-1 factor, JunD. J Biol Chem 2005; 280:4785–4791.CrossRefPubMedGoogle Scholar
  41. 41.
    Lofller KA, Biondi CA, Gartside MG et al. Lack of augmentation of tumor spectrum or sensitivity in dual heterozygous Men1 and Rb1 knockout mice. Oncogene 2007; 26:4009–17.CrossRefGoogle Scholar
  42. 42.
    Dreijerink KMA, Mulder KW, Winkler GS et al. Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Res 2006; 66:4929–35.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen YX, Yan J, Keeshan K et al. The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Proc Natl Acad Sci USA 2006; 103:1018–23.CrossRefPubMedGoogle Scholar
  44. 44.
    Hughes CM, Rosenblatt-Rosen O, Milne TA et al. Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus. Mol Cell 2004; 13:587–97.CrossRefPubMedGoogle Scholar
  45. 45.
    Yokoyama A, Wang Z, Wysocka J et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol 2004; 24:5639–49.CrossRefPubMedGoogle Scholar
  46. 46.
    Papaconstantinou M, Wu Y, Pretorius HK et al. Menin is a regulator of the stress response in drosophila melanogaster. Mol Cell Biol 2005; 25:9960–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Ping LA, Schnepp RW, Petersen CD et al. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. Endocrinology 2004; 145:3443–50.CrossRefGoogle Scholar
  48. 48.
    Lin SY, Elledge SJ. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 2003; 113:881–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Schnepp RW, Mao H, Sykes SM et al. Menin induces apoptosis in murine embryonic fibroblasts. J Biol Chem 2004; 279:10685–91.CrossRefPubMedGoogle Scholar
  50. 50.
    Engleka KA, Wu M, Zhang M et al. Menin is required in cranial neural crest for palatogenesis and perinatal viability. Dev Biol 2007; 311:524–37.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Hiroshi Kaji
    • 1
  • Lucie Canaffand
    • 2
    • 3
  • Geoffrey N. Hendy
    • 4
  1. 1.Division of Diabetes, Metabolism and Endocrinology, Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan
  2. 2.Departments of Medicine Physiology and Human GeneticsMcGill University Royal Victoria HospitalMontrealCanada
  3. 3.Calcium Research Laboratory and Hormones and Cancer Research UnitRoyal Victoria HospitalMontrealCanada
  4. 4.Calcium Research LaboratoryRoyal Victoria HospitalMontrealCanada

Personalised recommendations