Advertisement

SuperMEN1 pp 105-115 | Cite as

Functional Studies of Menin through Genetic Manipulation of the Men1 Homolog in Mice

  • Dheepa Balasubramanian
  • Peter C. Scacheri
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 668)

Abstract

To investigate the physiological role of menin, the protein product of the MEN1 gene, several groups have utilized gene targeting strategies to delete one or both copies of the mouse homolog Men1. Mice that arehomozygous null for Men1 die duringembryogenesis. Heterozygous Men1 mice are viable and develop many of the same types of tumors as humans with MEN1. In addition to conventional knockouts of Men1, tissue-specificelimination of menin using ere-lox has been achieved in pancreatic β cells, anterior pituitary, parathyroid, liver, neural crest and bone marrow, with varying results that are dependent on cell context. In this chapter, we compare the phenotypes of the different conventional Men1 knockouts, detail the similarities and differences between Men1 pathogenesis in mice and humans and highlight results from recent crossbreeding studies between Men1 mutants and mice with null mutations in genes within the retinoblastoma pathway, including p18 Inc4c , p27 Kip1 and Rb. In addition, we discuss not only how the Men1 mutants have shed light on the role of menin in endocrine tumor suppression, but also how Men1 mutant mice have helped uncover previously unrecognized roles for menin in development, leukemogenesis and gestational diabetes.

Keywords

Pituitary Adenoma Neural Crest Multiple Endocrine Neoplasia Type Parathyroid Adenoma Parathyroid Tumor 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Knudson AG Jr. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Debelenko LV Brambilla E, Agarwal SK et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 1997; 6:2285–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Farnebo F, Teh BT, Kytola S et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 1998; 83:2627–30.CrossRefPubMedGoogle Scholar
  4. 4.
    Heppner C, Kester MB, Agarwal SK et al. Somatic mutation of the MEN1 gene in parathyroid tumors. Nat Genet 1997; 16:375–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhuang Z, Ezzat SZ, Vortmeyer AO et al. Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res 1997; 57:5446–51.PubMedGoogle Scholar
  6. 6.
    Zhuang Z, Vortmeyer AO, Pack S et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997; 57:4682–6.PubMedGoogle Scholar
  7. 7.
    Agarwal SK, Kennedy PA, Scacheri PC et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm Metab Res 2005; 37:369–74.CrossRefPubMedGoogle Scholar
  8. 8.
    Hughes CM, Rozenblatt-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
  9. 9.
    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
  10. 10.
    Scacheri PC, Davis S, Odom DT et al. Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis. PLoS Genet 2006; 2:e51.CrossRefPubMedGoogle Scholar
  11. 11.
    Karnik SK, Hughes CM, Gu X et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 2005; 102:14659–64.CrossRefPubMedGoogle Scholar
  12. 12.
    Milne TA, Hughes CM, Lloyd R et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 2005; 102:749–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Bertolino P, Tong WM, Galendo D et al. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol 2003; 17:1880–92.CrossRefPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    Lofller KA, Biondi CA, Gartside M et al. Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1. Int J Cancer 2007; 120:259–67.CrossRefGoogle Scholar
  16. 16.
    Guru SC, Crabtree JS, Brown KD et al. Isolation, genomic organization and expression analysis of MenI, the murine homolog of the MEN1 gene. Mamm Genome 1999; 10:592–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Bertolino P, Tong WM, Herrera PL er al. Pancreatic β-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res 2003; 63:4836–41.PubMedGoogle Scholar
  18. 18.
    Biondi CA, Gartside MG, Waring P et al. Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol Cell Biol 2004; 24:3125–3131.CrossRefPubMedGoogle Scholar
  19. 19.
    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
  20. 20.
    Crabtree JS, Scacheri PC, Ward JM er al. Of mice and MEN1: Insulinomas in a conditional mouse knockout. Mol Cell Biol 2003; 23:6075–85.CrossRefPubMedGoogle Scholar
  21. 21.
    Engleka KA, Wu M, Zhang M et al. Menin is required in cranial neural crest for palatogenesis and perinatal viability. Dev Bioi 2007; 311:524–37.CrossRefGoogle Scholar
  22. 22.
    Yokoyama A, Somervaille TC, Smith KS et al. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 2005; 123:207–18.CrossRefPubMedGoogle Scholar
  23. 23.
    Karnik SK, Chen H, McLean GW et al. Menin controls growth of pancreatic f3-cells in pregnant mice and promotes gestational diabetes mellitus. Science 2007; 318:806–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Bai F, Pei XH, Nishikawa T et al. p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. Mol Cell Biol 2007; 27:1495–504.CrossRefPubMedGoogle Scholar
  25. 25.
    Pei XH, Bai F, Smith MD et al. p18Ink4c collaborates with Men1 to constrain lung stem cell expansion and suppress nonsmall-celliung cancers. Cancer Res 2007; 67:3162–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Bertolino P, Radovanovic I, Casse H et al. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mech Dev 2003; 120:549–60.CrossRefPubMedGoogle Scholar
  27. 27.
    Schnepp RW, Chen YX, Wang H et al. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 2006; 66:5707–15.CrossRefPubMedGoogle Scholar
  28. 28.
    Scacheri PC, Kennedy AL, Chin K et al. Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability. Cancer Res 2004; 64:7039–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Libutti SK, Crabtree LS, Lorang D et al. Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism. Cancer Res 2003; 63:8022–8.PubMedGoogle Scholar
  30. 30.
    Scacheri PC, Crabtree JS, Kennedy AL et al. Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1. Mamm Genome 2004; 15:872–7.CrossRefPubMedGoogle Scholar
  31. 31.
    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
  32. 32.
    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
  33. 33.
    Fero ML, Rivkin M, Tasch M et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis and female sterility in p27(Kip1)-deficient mice. Cell 1996; 85:733–44.CrossRefPubMedGoogle Scholar
  34. 34.
    Franklin DS, Godfrey VL, Lee H et al. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 1998; 12:2899–911.CrossRefPubMedGoogle Scholar
  35. 35.
    Kiyokawa H, Kineman RD, Manova-Todorova KO et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 1996; 85:721–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Nakayama K, Ishida N, Shirane M et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia and pituitary tumors. Cell 1996; 85:707–20.CrossRefPubMedGoogle Scholar
  37. 37.
    Franklin DS, Godfrey VL, O’Brien DA et al. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 2000; 20:6147–58.CrossRefPubMedGoogle Scholar
  38. 38.
    Pellegata NS, Quintanilla-Martinez L, Siggelkow H et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 2006; 103:15558–63.CrossRefPubMedGoogle Scholar
  39. 39.
    Rane SG, Dubus P, Mettus RV et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet 1999; 22:44–52.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang X, Gaspard JP, Mizukami Y et al. Overexpression of cyclin D1 in pancreatic β-cells in vivo results in islet hyperplasia without hypoglycemia. Diabetes 2005; 54:712–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Loffer KA, Biondi CA, Gartside MG et al. Lack of augmentation of tumor spectrum or severity in dual heterozygous Men1 and Rb1 knockout mice. Oncogene 2007; 26:4009–17.CrossRefGoogle Scholar
  42. 42.
    Matoso A, Zhou Z, Hayama R et al. Cell lineage-specific interactions between Men 1 and Rb in neuroendocrine neoplasia. Carcinogenesis 2008; 29:620–8.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Dheepa Balasubramanian
    • 1
  • Peter C. Scacheri
    • 1
  1. 1.Department of GeneticsCaseWestern Reserve UniversityClevelandUSA

Personalised recommendations