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Horm Metab Res 2005; 37(6): 369-374
DOI: 10.1055/s-2005-870139
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© Georg Thieme Verlag KG Stuttgart · New York

Menin Molecular Interactions: Insights into Normal Functions and Tumorigenesis

S.  K.  Agarwal1 , P.  A.  Kennedy1 , P.  C.  Scacheri2 , E.  A.  Novotny2 , A.  B.  Hickman1 , A.  Cerrato1 , T.  S.  Rice1 , J.  B.  Moore1 , S.  Rao1 , Y.  Ji2 , C.  Mateo1 , S.  K.  Libutti3 , B.  Oliver1 , S.  C.  Chandrasekharappa2 , A.  L.  Burns1 , F.  S.  Collins2 , A.  M.  Spiegel4 , S.  J.  Marx1
  • 1National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
  • 2National Human Genome Research Institute, NIH, Bethesda, MD, USA
  • 3National Cancer Institute, NIH, Bethesda, MD, USA
  • 4National Institute of Deafness and Communication Disorders, NIH, Bethesda, MD, USA
Further Information

Publication History

Received 10 September 2004

Accepted after revision 5 October 2004

Publication Date:
07 July 2005 (online)

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Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease predisposed by heterozygous germline mutations in the MEN1 tumor suppressor gene. Biallelic loss of MEN1 resulting from small mutation and/or loss of heterozygosity occurs in a large tissue spectrum of MEN1 tumors or non-hereditary tumors. Mouse models of MEN1 underexpression or overexpression have also supported the tumor-suppressor effect of the MEN1 gene. Menin, the 610-amino-acid protein encoded by MEN1, is expressed ubiquitously and found predominantly in the nucleus. Sequence analyses do not reveal motifs of known function other than two nuclear localization sequences. Menin has been found to partner in vitro with a variety of proteins that comprise transcription factors, DNA processing factors, DNA repair proteins, and cytoskeletal proteins. The diverse functions of menin interactors suggest roles for menin in multiple biological pathways. Inactivation of menin switches its JunD partner from a downstream action of growth suppression to growth promotion. This is a plausible mechanism for menin tumorigenesis.

Key words

MEN1 - JunD - MLL - Hox genes - Tumor suppressor - Oncogene - Multiple endocrine neoplasia - Transcription - Partners

References

  • 1 Marx S J. In: The Genetic Basis of Human Cancer. Vogelstein B and Kinzler KW (eds) Multiple endocrine neoplasia type 1. New York; McGraw Hill 2002: 475-450
    Google Scholar
  • 2 Dean P G, van Heerden J A, Farley D R. et al . Are patients with multiple endocrine neoplasia type 1 prone to premature death?.  World J Surg. 2000;  24 1437-1441
    CrossrefPubMedGoogle Scholar
  • 3 Eng C. RET proto-oncogene in the development of human cancer.  J Clin Oncol. 1999;  17 380-393
    CrossrefPubMedGoogle Scholar
  • 4 Yaguchi H, Ohkura N, Takahashi M, Nagamura Y, Kitabayashi I, Tsukada T. Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway.  Mol Cell Biol. 2004;  24 6569-6580
    CrossrefPubMedGoogle Scholar
  • 5 Crabtree J S, Scacheri P C, Ward J M. et al . A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.  Proc Natl Acad Sci USA. 2001;  98 1118-1123
    CrossrefPubMedGoogle Scholar
  • 6 Suphapeetiporn K, Busygina V, Xu T, Bale A E. Drosophila homolog of human multiple endocrine neoplasia type I gene (MEN1) interacts with Jun and Fos in vivo.  Am J Hum Genet,. 2001;  69 (Suppl) 156 (Abstract)
    PubMedGoogle Scholar
  • 7 Cerrato A, Santa Anna A S, Marx S. et al . The Drosophila homolog of the human tumor suppressor gene MEN1 functions in the thoracic closure pathway.  Annual Dros Res Conf. 2002;  43 546C (Abstract)
    PubMedGoogle Scholar
  • 8 Lin S Y, Elledge S J. Multiple tumor suppressor pathways negatively regulate telomerase.  Cell. 2003;  113 881-889
    CrossrefPubMedGoogle Scholar
  • 9 Kim Y S, Burns A L, Goldsmith P K. et al . Stable overexpression of MEN1 suppresses tumorigenicity of RAS.  Oncogene. 1999;  18 5936-5942
    CrossrefPubMedGoogle Scholar
  • 10 Bertolino P, Radovanovic I, Casse H, Aguzzi A, Wang Z Q, Zhang C X. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs.  Mech Dev. 2003;  120 549-560
    CrossrefPubMedGoogle Scholar
  • 11 Bertolino P, Tong W M, Galendo D, Wang Z Q, Zhang C X. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1.  Mol Endocrinol. 2003;  17 1880-1892
    CrossrefPubMedGoogle Scholar
  • 12 Libutti S K, Crabtree J S, Lorang D. et al . Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism.  Cancer Res. 2003;  63 8022-8028
    PubMedGoogle Scholar
  • 13 Crabtree J S, Scacheri P C, Ward J M. et al . Of mice and MEN1: Insulinomas in a conditional mouse knockout.  Mol Cell Biol. 2003;  23 6075-6085
    CrossrefPubMedGoogle Scholar
  • 14 Bertolino P, Tong W M, Herrera P L, Casse H, Zhang C X, Wang Z Q. Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.  Cancer Res. 2003;  63 4836-4841
    PubMedGoogle Scholar
  • 15 Biondi C A, Gartside M G, 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 3125-131
    CrossrefPubMedGoogle Scholar
  • 16 Scacheri P C, Crabtree J S, Kennedy A L. et al .Tissue specificity of a tumor suppressor: homozygous loss of menin is well tolerated in hepatocytes. Ninth international workshop on multiple endocrine neoplasia (MEN 2004) June 20 - 23, 2004 Hyatt Regency Hotel, Bethesda, MD. Hot Topics Abstracts. Page 21
    Google Scholar
  • 17 Agarwal S K, Guru S C, Heppner C. et al . Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.  Cell. 1999;  96 143-152
    CrossrefPubMedGoogle Scholar
  • 18 Gobl A E, Berg M, Lopez-Egido J R, Oberg K, Skogseid B, Westin G. Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism.  Biochim Biophys Acta. 1999;  1447 51-56
    PubMedGoogle Scholar
  • 19 Ikeo Y, Yumita W, Sakurai A, Hashizume K. JunD-menin interaction regulates c-Jun-mediated AP-1 transactivation.  Endocr J. 2004;  51 333-342
    CrossrefPubMedGoogle Scholar
  • 20 Knapp J I, Heppner C, Hickman A B. et al . Identification and characterization of JunD missense mutants that lack menin binding.  Oncogene. 2000;  19 4706-4712
    CrossrefPubMedGoogle Scholar
  • 21 Kim H, Lee J E, Cho E J, Liu J O, Youn H D. Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex.  Cancer Res. 2003;  63 6135-6139
    PubMedGoogle Scholar
  • 22 Mechta-Grigoriou F, Gerald D, Yaniv M. The mammalian Jun proteins: redundancy and specificity.  Oncogene. 2001;  20 2378-2389
    CrossrefPubMedGoogle Scholar
  • 23 Jochum W, Passegue E, Wagner E F. AP-1 in mouse development and tumorigenesis.  Oncogene. 2001;  20 2401-2412
    CrossrefPubMedGoogle Scholar
  • 24 Heppner C, Bilimoria K Y, Agarwal S K. et al . The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation.  Oncogene. 2001;  20 4917-4925
    CrossrefPubMedGoogle Scholar
  • 25 Perkins N D. The Rel/NF-kappa B family: friend and foe.  Trends Biochem Sci.. 2000;  25 434-440
    CrossrefPubMedGoogle Scholar
  • 26 Lemmens I H, Forsberg L, Pannett A A. et al . Menin interacts directly with the homeobox-containing protein Pem.  Biochem Biophys Res Commun. 2001;  286 426-431
    CrossrefPubMedGoogle Scholar
  • 27 Kaji H, Canaff L, Lebrun J J, Goltzman D, Hendy G N. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling.  Proc Natl Acad Sci USA. 2001;  98 3837-3842
    CrossrefPubMedGoogle Scholar
  • 28 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 21 058-21 069
    PubMedGoogle Scholar
  • 29 Sowa H, Kaji H, Hendy G N. et al . Menin is required for BMP-2- and TGF-beta-regulated osteoblastic differentiation through interaction with Smads and Runx2.  J Biol Chem. 2004;  279 40 267-40 275
    PubMedGoogle Scholar
  • 30 Hughes C M, Rozenblatt-Rosen O, Milne T A. et al . Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.  Mol Cell. 2004;  13 587-597
    CrossrefPubMedGoogle Scholar
  • 31 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 5639-5649
    CrossrefPubMedGoogle Scholar
  • 32 Miller T, Krogan N J, Dover J. et al . COMPASS: a complex of proteins associated with a trithorax-related SET domain protein.  Proc Natl Acad Sci USA,. 2001;  98 12 902-12 907
    PubMedGoogle Scholar
  • 33 Rozenblatt-Rosen O, Hughes C M, Nannepaga S J, Shanmugam K S, Copeland T D, Guszczynski T, Resau J H, Meyerson M. The parafibromin tumor suppressor protein is part of a human Paf1 complex.  Mol Cell Biol. 2005;  25 612-620
    CrossrefPubMedGoogle Scholar
  • 34 Krogan N J, Dover J, Wood A. et al . The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation.  Mol Cell. 2003;  11 721-729
    CrossrefPubMedGoogle Scholar
  • 35 Mueller C L, Jaehning J A. Ctr9, Rtf1, and Leo1 are components of the Paf1/RNA polymerase II complex.  Mol Cell Biol. 2002;  22 1971-1980
    CrossrefPubMedGoogle Scholar
  • 36 Carpten J D, Robbins C M, Villablanca A. et al . HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.  Nat Genet. 2002;  32 676-680
    CrossrefPubMedGoogle Scholar
  • 37 Sukhodolets K E, Hickman A B, Agarwal S K. et al . The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene.  Mol Cell Biol. 2003;  23 493-509
    CrossrefPubMedGoogle Scholar
  • 38 Jin S, Mao H, Schnepp R W. et al . Menin associates with FANCD2, a protein involved in repair of DNA damage.  Cancer Res. 2003;  63 4204-4210
    PubMedGoogle Scholar
  • 39 La P, Silva A C, Hou Z. et al . Direct binding of DNA by tumor suppressor menin.  J Biol Chem. 2004;  279 49 045-49 054
    PubMedGoogle Scholar
  • 40 Obungu V H, Lee Burns A, Agarwal S K, Chandrasekharapa S C, Adelstein R S, Marx S J. Menin, a tumor suppressor, associates with nonmuscle myosin II-A heavy chain.  Oncogene. 2003;  22 6347-6358
    CrossrefPubMedGoogle Scholar
  • 41 Lopez-Egido J, Cunningham J, Berg M, Oberg K, Bongcam-Rudloff E, Gobl A. Menin’s interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity.  Exp Cell Res. 2002;  278 175-183
    CrossrefPubMedGoogle Scholar
  • 42 Ohkura N, Kishi M, Tsukada T, Yamaguchi K. Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23.  Biochem Biophys Res Commun. 2001;  282 1206-1210
    CrossrefPubMedGoogle Scholar
  • 43 Yaguchi H, Ohkura N, Tsukada T, Yamaguchi K. Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23.  J Biol Chem. 2002;  277 38 197-381 204
    PubMedGoogle Scholar
  • 44 Stalberg P, Grimfjard P, Santesson M. et al . Transfection of the multiple endocrine neoplasia type 1 gene to a human endocrine pancreatic tumor cell line inhibits cell growth and affects expression of JunD, delta-like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen, and QM/Jif-1.  J Clin Endocrinol Metab. 2004;  89 2326-2337
    CrossrefPubMedGoogle Scholar
  • 45 Agarwal S K, Novotny E A, Crabtree J S. et al . Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter.  Proc Natl Acad Sci USA. 2003;  100 10 770-10 775
    PubMedGoogle Scholar
  • 46 La P, Schnepp R W, Petersen C D, Silva A C, Hua X. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2.  Endocrinology. 2004;  145 3443-3450
    CrossrefPubMedGoogle Scholar
  • 47 Schnepp R W, Mao H, Sykes S M. et al . Menin induces apoptosis in murine embryonic fibroblasts.  J Biol Chem. 2004;  279 10 685-10 691
    PubMedGoogle Scholar
  • 48 Milne T A, Briggs S D, Brock H W. et al . MLL targets SET domain methyltransferase activity to Hox gene promoters.  Mol Cell. 2002;  10 1107-1117
    CrossrefPubMedGoogle Scholar
  • 49 Sayo Y, Murao K, Imachi H. et al . The multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells.  Endocrinology. 2002;  143 2437-2440
    CrossrefPubMedGoogle Scholar
  • 50 Namihira H, Sato M, Murao K. et al . The multiple endocrine neoplasia type 1 gene product, menin, inhibits the human prolactin promoter activity.  J Mol Endocrinol. 2002;  29 297-304
    CrossrefPubMedGoogle Scholar
  • 51 Gallo A, Cuozzo C, Esposito I. et al . Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation.  Oncogene. 2002;  21 6434-6445
    CrossrefPubMedGoogle Scholar
  • 52 Varro A, Hemers E, Archer D. et al . Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: Role of Rho GTPase and menin.  Gastroenterology. 2002;  123 271-280
    CrossrefPubMedGoogle Scholar
  • 53 Yumita W, Ikeo Y, Yamauchi K, Sakurai A, Hashizume K. Suppression of insulin-induced AP-1 transactivation by menin accompanies inhibition of c-Fos induction.  Int J Cancer. 2003;  103 738-744
    CrossrefPubMedGoogle Scholar
  • 54 Lacerte A, Lee E H, Reynaud R. et al . Activin inhibits pituitary prolactin expression and cell growth through Smads, Pit-1 and menin.  Mol Endocrinol. 2004;  18 1558-1569
    CrossrefPubMedGoogle Scholar
  • 55 Hendy G N. Menin and TGF-beta superfamily member signaling via the Smad pathway in pituitary, parathyroid, and osteoblast.  Horm Metab Res. 2005;  37 375-379
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Busygina V, Suphapeetiporn K, Marek L R, Stowers R S, Xu T, Bale A E. Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.  Hum Mol Genet. 2004;  13 2399-2408
    CrossrefPubMedGoogle Scholar
  • 57 Franklin D S, Godfrey V L, O’Brien D A, Deng C, Xiong Y. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity.  Mol Cell Biol. 2000;  20 6147-6158
    CrossrefPubMedGoogle Scholar

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