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Analysis of p27Kip1 Expression in Insulinomas Developed in Pancreatic β-cell Specific Men1 Mutant Mice

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Abstract

Multiple Endocrine Neoplasia type 1 (MEN1) is a hereditary disease characterised by the occurrence of multiple endocrine tumours. The biological functions of the responsible gene, MEN1, and its encoded protein, menin, remain so far largely elusive. The recent generation of Men1 mutant mice by our group and other laboratories provides powerful tools allowing for the identification of cellular and molecular events that occur after gene disruption. Interestingly, it has been recently reported that p27Kip1 expression is regulated by menin and that decreased p27Kip1 expression can be found in MEN1 insulinomas and parathyroid adenomas. In order to address whether and when p27Kip1 expression alters during insulinoma development in pancreatic β-cell-specific Men1 mutant mice, we analysed p27Kip1 expression in islet lesions from mutant mice at different ages. Our data revealed that p27Kip1 protein expression was reduced in 40 out of 52 (77%) insulinomas analysed, whereas the remaining 12 insulinomas (23%) did not show altered p27Kip1 expression. No difference between the insulinomas with and without decreased p27Kip1 expression could be observed in terms of histological features or menin inactivation. Furthermore, our analysis on hyperplastic and dysplastic islets developed in young mutant mice showed the lack of detectable alteration in p27Kip1 expression, despite evident loss of menin expression in a substantial proportion of islet cells. Our work confirms the altered p27Kip1 expression reported in tumours from MEN1 patients, whereas it suggests that other molecular events may also participate in the tumorigenesis process initiated by the Men1 gene inactivation.

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Abbreviations

Cre:

causes recombination

MEN1:

multiple endocrine neoplasia type 1

Rip:

rat insulin promoter

References

  1. RV Thakker (1995) Multiple endocrine neoplasia type 1 LJ Groot ParticleDe G Besser J Jameson (Eds) et al. Endocrinology Saunders Philadelphia 2815–31

    Google Scholar 

  2. SK Agarwal MB Kester LV Debelenko et al. (1997) ArticleTitleGermline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states Hum Mol Genet 6 1169–75 Occurrence Handle10.1093/hmg/6.7.1169 Occurrence Handle1:STN:280:ByiA2MflvFc%3D Occurrence Handle9215689

    Article  CAS  PubMed  Google Scholar 

  3. JH Bassett SA Forbes AA Pannett et al. (1998) ArticleTitleCharacterization of mutations in patients with multiple endocrine neoplasia type 1 Am J Hum Genet 62 232–44 Occurrence Handle10.1086/301729 Occurrence Handle1:CAS:528:DyaK1cXhslGjs70%3D Occurrence Handle9463336

    Article  CAS  PubMed  Google Scholar 

  4. S Giraud CX Zhang O Serova-Sinilnikova et al. (1998) ArticleTitleGerm-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders Am J Hum Genet 63 455–67 Occurrence Handle10.1086/301953 Occurrence Handle1:CAS:528:DyaK1cXlslWrtbc%3D Occurrence Handle9683585

    Article  CAS  PubMed  Google Scholar 

  5. F Farnebo BT Teh S Kytola et al. (1998) ArticleTitleAlterations of the MEN1 gene in sporadic parathyroid tumors J Clin Endocrinol Metab 83 2627–30 Occurrence Handle10.1210/jc.83.8.2627 Occurrence Handle1:CAS:528:DyaK1cXltlWntL4%3D Occurrence Handle9709922

    Article  CAS  PubMed  Google Scholar 

  6. Z Zhuang AO Vortmeyer S Pack et al. (1997) ArticleTitleSomatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas Cancer Res 57 4682–86 Occurrence Handle1:CAS:528:DyaK2sXnt12gtbo%3D Occurrence Handle9354421

    CAS  PubMed  Google Scholar 

  7. KM Schulte M Mengel M Heinze et al. (2000) ArticleTitleComplete sequencing and messenger ribonucleic acid expression analysis of the MENI gene in adrenal cancer1 J Clin Endocrinol Metab 85 IssueID1 441–8 Occurrence Handle10.1210/jc.85.1.441 Occurrence Handle1:CAS:528:DC%2BD3cXjtl2ktQ%3D%3D Occurrence Handle10634422

    Article  CAS  PubMed  Google Scholar 

  8. C Tanaka K Takehiko P Yang et al. (1998) ArticleTitleAnalysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of the MEN1 gene in sporadic pituitary adenomas J Clin Endocrinol Metab 83 IssueID8 2631–34 Occurrence Handle1:CAS:528:DyaK1cXltlWntb8%3D Occurrence Handle9709923

    CAS  PubMed  Google Scholar 

  9. SK Agarwal SC Guru C Heppner et al. (1999) ArticleTitleMenin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription Cell 96 143–52 Occurrence Handle10.1016/S0092-8674(00)80967-8 Occurrence Handle1:CAS:528:DyaK1MXmslansA%3D%3D Occurrence Handle9989505

    Article  CAS  PubMed  Google Scholar 

  10. H Kaji L Canaff JJ Lebrun et al. (2001) ArticleTitleInactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling Proc Natl Acad Sci USA 98 3837–42 Occurrence Handle10.1073/pnas.061358098 Occurrence Handle1:CAS:528:DC%2BD3MXis1Khsrc%3D Occurrence Handle11274402

    Article  CAS  PubMed  Google Scholar 

  11. J Naito H Kaji H Sowa et al. (2003) ArticleTitleInactivation 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 278 IssueID23 21058–69

    Google Scholar 

  12. N Ohkura M Kishi T Tsukada et al. (2001) ArticleTitleMenin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23 Biochem Biophys Res Commun 282 1206–10 Occurrence Handle10.1006/bbrc.2001.4723 Occurrence Handle1:CAS:528:DC%2BD3MXis1eqt74%3D Occurrence Handle11302744

    Article  CAS  PubMed  Google Scholar 

  13. IH Lemmens L Forsberg AA Pannett et al. (2001) ArticleTitleMenin interacts directly with the homeobox-containing protein Pem Biochem Biophys Res Commun 286 426–31 Occurrence Handle10.1006/bbrc.2001.5405 Occurrence Handle1:CAS:528:DC%2BD3MXlvVejtLw%3D Occurrence Handle11500056

    Article  CAS  PubMed  Google Scholar 

  14. C Heppner KY Bilimoria SK Agarwal et al. (2001) ArticleTitleThe tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation Oncogene 20 4917–25 Occurrence Handle10.1038/sj.onc.1204529 Occurrence Handle1:CAS:528:DC%2BD3MXmtlCksrw%3D Occurrence Handle11526476

    Article  CAS  PubMed  Google Scholar 

  15. SY Lin SJ Elledge (2003) ArticleTitleMultiple tumor suppressor pathways negatively regulate telomerase Cell 113 881–9 Occurrence Handle10.1016/S0092-8674(03)00430-6 Occurrence Handle1:CAS:528:DC%2BD3sXlsVSjtbk%3D Occurrence Handle12837246

    Article  CAS  PubMed  Google Scholar 

  16. Y Sayo K Murao H Imachi et al. (2002) ArticleTitleThe multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells Endocrinology 143 IssueID6 2437–40 Occurrence Handle10.1210/en.143.6.2437 Occurrence Handle1:CAS:528:DC%2BD38XjvFKju7w%3D Occurrence Handle12021209

    Article  CAS  PubMed  Google Scholar 

  17. H Namihira M Sato K Murao et al. (2002) ArticleTitleThe multiple endocrine neoplasia type 1 gene product, menin, inhibits the human prolactin promoter activity J Mol Endocrinol 29 IssueID3 297–304 Occurrence Handle10.1677/jme.0.0290297 Occurrence Handle1:CAS:528:DC%2BD3sXnsVGltLk%3D Occurrence Handle12459032

    Article  CAS  PubMed  Google Scholar 

  18. M Fromaget C Vercherat CX Zhang et al. (2003) ArticleTitleFunctional characterization of a promoter region in the human MEN1 tumor suppressor gene J Mol Biol 333 IssueID1 87–102 Occurrence Handle10.1016/j.jmb.2003.08.001 Occurrence Handle1:CAS:528:DC%2BD3sXnsVWrtLw%3D Occurrence Handle14516745

    Article  CAS  PubMed  Google Scholar 

  19. KE Sukhodolets AB Hickman S Agarwal et al. (2003) ArticleTitleThe 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene Mol Cell Biol 23 IssueID2 493–509 Occurrence Handle10.1128/MCB.23.2.493-509.2003 Occurrence Handle1:CAS:528:DC%2BD3sXjslWrug%3D%3D Occurrence Handle12509449

    Article  CAS  PubMed  Google Scholar 

  20. H Kim JE Lee EJ Cho et al. (2003) ArticleTitleMenin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex Cancer Res 63 IssueID19 6135–9 Occurrence Handle1:CAS:528:DC%2BD3sXotV2jtLk%3D Occurrence Handle14559791

    CAS  PubMed  Google Scholar 

  21. CM Hughes CM Rozenblatt-Rosen O Milne et al. (2004) ArticleTitleMenin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus Mol Cell 13 IssueID4 587–97 Occurrence Handle10.1016/S1097-2765(04)00081-4 Occurrence Handle1:CAS:528:DC%2BD2cXitV2gtr0%3D Occurrence Handle14992727

    Article  CAS  PubMed  Google Scholar 

  22. A Yokoyama Z Wang J Wysocka et al. (2004) ArticleTitleLeukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression Mol Cell Biol 24 IssueID13 5639–49 Occurrence Handle10.1128/MCB.24.13.5639-5649.2004 Occurrence Handle1:CAS:528:DC%2BD2cXls1aqsb8%3D Occurrence Handle15199122

    Article  CAS  PubMed  Google Scholar 

  23. JS Crabtree PC Scacheri JM Ward et al. (2001) ArticleTitleA mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors Proc Natl Acad Sci USA 98 1118–23 Occurrence Handle10.1073/pnas.98.3.1118 Occurrence Handle1:CAS:528:DC%2BD3MXht1Smsbc%3D Occurrence Handle11158604

    Article  CAS  PubMed  Google Scholar 

  24. P Bertolino T Wei-Min D Galendo et al. (2003) ArticleTitleHeterozygous Men1 mutant mice develop a range of endocrine tumors mimicking Multiple Endocrine Neoplasia type 1 Mol Endocrinol 17 IssueID9 1880–92 Occurrence Handle10.1210/me.2003-0154 Occurrence Handle1:CAS:528:DC%2BD3sXntFyls70%3D Occurrence Handle12819299

    Article  CAS  PubMed  Google Scholar 

  25. CA Biondi GG Michael P Waring et al. (2004) ArticleTitleConditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues MCB 24 IssueID8 3125–31 Occurrence Handle1:CAS:528:DC%2BD2cXjtFKjsbw%3D Occurrence Handle15060136

    CAS  PubMed  Google Scholar 

  26. P Bertolino T Wei-Min PL Herrera et al. (2003) ArticleTitlePancreatic β-cell-specific ablation of the Multiple Endocrine Neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice Cancer Res 63 IssueID16 4836–41 Occurrence Handle1:CAS:528:DC%2BD3sXms12nsr0%3D Occurrence Handle12941803

    CAS  PubMed  Google Scholar 

  27. JS Crabtree PC Scacheri JM Ward et al. (2003) ArticleTitleOf mice and MEN1: Insulinomas in a conditional mouse knockout Mol Cell Biol 23 IssueID17 6075–85 Occurrence Handle10.1128/MCB.23.17.6075-6085.2003 Occurrence Handle1:CAS:528:DC%2BD3sXms1Ohtrs%3D Occurrence Handle12917331

    Article  CAS  PubMed  Google Scholar 

  28. SK Libutti JS Crabtree D Lorang et al. (2003) ArticleTitleParathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism Cancer Res 63 IssueID22 8022–8 Occurrence Handle1:CAS:528:DC%2BD3sXptFOltbo%3D Occurrence Handle14633735

    CAS  PubMed  Google Scholar 

  29. TA Milne C Hughes R Lloyd et al. (2005) ArticleTitleMenin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors Proc Natl Acad Sci USA 102 IssueID3 749–54 Occurrence Handle10.1073/pnas.0408836102 Occurrence Handle1:CAS:528:DC%2BD2MXis1CqsLo%3D Occurrence Handle15640349

    Article  CAS  PubMed  Google Scholar 

  30. V Wautot S Khodaei L Frappart et al. (2000) ArticleTitleExpression analysis of endogenous menin, the product of the multiple endocrine neoplasia type 1 gene, in cell lines and human tissues Int J Cancer 85 877–81 Occurrence Handle10.1002/(SICI)1097-0215(20000315)85:6<877::AID-IJC23>3.0.CO;2-F Occurrence Handle1:CAS:528:DC%2BD3cXitVehsL8%3D Occurrence Handle10709111

    Article  CAS  PubMed  Google Scholar 

  31. DS Franklin VL Godfrey DA O’Brien et al. (2000) ArticleTitleFunctional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity Mol Cell Biol 16 6147–58

    Google Scholar 

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Author notes

  1. Philippe Bertolino

    Present address: Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Retzius väg 8, 17177, Stockholm, Sweden

Authors and Affiliations

  1. Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon 1, 69373, Lyon, France

    Sandra Fontanière, Huguette Casse, Philippe Bertolino & Chang Xian Zhang

  2. Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon 1, 8 Avenue Rockfeller, 69373, Lyon Cedex 08, France

    Chang Xian Zhang

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  1. Sandra Fontanière
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  2. Huguette Casse
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  4. Chang Xian Zhang
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Correspondence to Chang Xian Zhang.

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These two authors contributed equally to this work.

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Fontanière, S., Casse, H., Bertolino, P. et al. Analysis of p27Kip1 Expression in Insulinomas Developed in Pancreatic β-cell Specific Men1 Mutant Mice. Familial Cancer 5, 49–54 (2006). https://doi.org/10.1007/s10689-005-2575-3

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