Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stable overexpression of MEN1 suppresses tumorigenicity of RAS

Oncogene volume 18, pages 5936–5942 (1999)Cite this article

Abstract

Although there is indirect genetic evidence that MEN1, the gene for multiple endocrine neoplasia type 1, is a tumor suppressor gene, little is known about the MEN1-encoded protein, menin. Menin was stably overexpressed in a well-characterized murine tumor cell line, (valine-12)-RAS-transformed NIH3T3 cells. Menin overexpression reverted the morphology of the RAS-transformed NIH3T3 cells towards the more flattened and more spread, fibroblastic shape of wild type NIH3T3 cells. The proliferation rate of the RAS-transformed cells in 0.5% calf serum was also slower with menin overexpression. Menin overexpression reduced the RAS-induced clonogenicity in soft agar. Menin also reduced tumor growth after injection of cells in nude mice. In conclusion, stable overexpression of MEN1 suppressed partially the RAS-mediated tumor phenotype in vitro and in vivo. Overexpressed menin protein had biological effects, directly supporting MEN1 gene function as a tumor suppressor.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

MEN1:

multiple endocrine neoplasia type 1

MEN1 :

gene for MEN1

WT:

wild type

R:

RAS-NIH3T3 cells

RMX:

RAS- and MEN1-transfected NIH3T3 cells, with `X' indicating cell line number(s)

AEA and SQV:

antisera against menin, named by codes for the first three amino acids of the synthetic peptide used for immunization

G12V:

normal glycine at amino acid 12, substituted by valine

EM:

Menin (human sequence with poly-histidine added at N-terminus) expressed in E. coli

References

  • Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ and Burns AL. . 1999 Cell 96: 143–152.

    Article  CAS  Google Scholar 

  • Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi S, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL and Marx SJ. . 1997 Hum. Mol. Genet. 6: 1169–1175.

  • Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH and Thakker RC. . 1998 Am. J. Hum. Genet. 62: 232–244.

  • Boni R, Vortmeyer AO, Pack S, Park WS, Burg G, Hofbauer G, Darling T, Liotta L and Zhuang Z. . 1998 J. Invest. Dermatol. 111: 539–540.

  • Chandrasekharappa SC, Guru SC, Manickam P, Olufemi S, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL and Marx SJ. . 1997 Science 276: 404–407.

  • Cox DR. . (1970) In Analysis of Binary Data. Chapman and Hall: London pp. 14–29.

    Google Scholar 

  • Crespo P, Xu N, Simonds WF and Gutkind JS. . 1994 Nature 369: 418–420.

    Article  CAS  Google Scholar 

  • Debelenko LV, Brambilla E, Agarwall SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang ZP, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, EmmertBuck MR. . 1997 Hum. Molec. Genet. 6: 2285–2290.

  • Eliyahu D, Michalovitz D, Eliyahu S, Phnhasi-Kimhi O and Oren M. . 1989 Proc. Natl. Acad. Sci. USA 86: 8763–8767.

  • Finlay CA, Hinds PW and Levine AJ. . 1989 Cell 57: 1083–1093.

    Article  CAS  Google Scholar 

  • Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A and Calender A. . 1998 Am. J. Hum. Genet. 63: 455–467.

  • Guru SC, Agarwal SK, Manickam P, Olufemi SE, Crabtree JS, Weisemann JM, Kester MB, Kim YS, Wang YP, EmmertBuck MR, Liotta LA, Spiegel AM, Boguski MS, Roe BA, Collins FS, Marx SJ, Burns AL and Chandrasekharappa SC. . 1997 Genome Res. 7: 725–735.

  • Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS and Chandrasekharappa SC. . 1998 Proc. Nat. Acad. Sci. USA 95: 1630–1634.

  • Gutkind JS. . 1998 J. Biol. Chem. 273: 1839–1842.

    Article  CAS  Google Scholar 

  • Haber DA, Park S, Maheswaran S, Englert C, Re GG, Hazen-Martin DJ, Sens DA and Garvin AJ. . 1993 Science 262: 2057–2059.

    Article  CAS  Google Scholar 

  • Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppman JL, Alexander RH, Kim YS, Saggar SK, Lubensky IA, Zhuang ZP, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL and Marx SJ. . 1997 Nat. Genet. 16: 375–378.

  • Hollander M and Wolfe DA. . (1973) In Nonparametric Statistical Methods. John Wiley & Sons, New York pp.67–75.

    Google Scholar 

  • Huang H-JS, Yee Y-K, Shew J-K, Chen P-L, Bookstein R, Friedmann T, Lee EY-HP and Lee W-H. . 1988 Science 242: 1563–1566.

    Article  CAS  Google Scholar 

  • Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D and Schlessinger J. . 1997 Cell 89: 693–702.

    Article  CAS  Google Scholar 

  • Kozak M. . 1991 J. Biol. Chem. 266: 19867–19870.

  • Larsson C, Skogseid B, Oberg K, Nakamura Y and Nordenskjold M. . (1988) Nature 332: 85–87.

    Article  CAS  Google Scholar 

  • Luo XN, Reddy JC, Yeyati PL, Idris AH, Hosono S, Haber DA, Licht JD and Atweh GF. . 1995 Oncogene 11: 743–750.

  • Marx SJ. . 1998 In: The Genetic Basis of Human Cancer. Vogelstein B & Kinzler KW (eds). McGraw Hill: New York. pp.489–506.

    Google Scholar 

  • Mu Z, Chin K, Liu J, Lozano G and Chang K. . 1994 Mol. Cell. Biol. 14: 6858–6867.

    Article  CAS  Google Scholar 

  • Murray MJ, Shilo BZ, Shih C, Cowing D, Hsu HW and Weinberg RA. . 1981 Cell 25: 355–361.

    Article  CAS  Google Scholar 

  • Mutch MG, Dilley WG, Sanjurjo F, DeBenedetti MK, Doherty GM, Wells Jr SA, Goodfellow PJ and Larimore TC. . 1999 Hum. Mut. 13: 175–185.

  • Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S and Yaniv M. . 1994 Cell 76: 747–760.

    Article  CAS  Google Scholar 

  • Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, van Gaal L, Verellen C, Koulischer L and Beckers A. . 1999 Hum. Mut. 13: 54–60.

  • Satoh T, Nakafuku M and Kaziro Y. . 1992 J. Biol. Chem. 267: 24149–24152.

  • Solonas M and Escrich E. . 1996 J. Physiol. Biochem. 52: 173–192.

  • Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Menon J, Khir A, Tan T, Chan SP, Zaini A, Khalid BAK, Sandelin K, Thompson N, Brandi M-L, Warth M, Stock J, Leisti J, Cameron D, Shepherd JJ, Öberg K, Nordenskjöld M and Salmela P. . 1998 J. Clin. Endocrinol. Metab. 83: 2621–2626.

  • Vogelstein B and Kinzler KW. . 1993 Trends Genetics. 9: 138–141.

  • Zhou Y, Li J, Xu K, Hu S, Benedict WF and Xu H. . 1994 Proc. Natl. Acad. Sci. USA 91: 4165–4169.

  • Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park W, Agarwal SK, Debelenko LV, Kester MB, Guru SC, Manickam P, Olufemi S, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert-Buck MR, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Jensen RT, Liotta LA and Lubensky IA. . 1997 Cancer Res. 57: 4682–4686.

Download references

Acknowledgements

We thank Drs Haesook Teresa Kim and David Venzon for statistical analyses. We thank Dr J Sylvio Gutkind for reagents and advice.

Author information

Authors and Affiliations

  1. Metabolic Diseases Branch, NIDDK, Bethesda, 20892, Maryland, MD, USA

    Y S Kim, A L Burns, P K Goldsmith, C Heppner, S Y Park, A M Spiegel & S J Marx

  2. Genetics and Molecular Biology Branch, NHGR1, Building 49, Room 3A-14, Bethesda, 20892, Maryland, MD, USA

    S C Chandrasekharappa & F S Collins

Authors
  1. Y S Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A L Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P K Goldsmith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Heppner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Y Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S C Chandrasekharappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F S Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A M Spiegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S J Marx
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, Y., Burns, A., Goldsmith, P. et al. Stable overexpression of MEN1 suppresses tumorigenicity of RAS. Oncogene 18, 5936–5942 (1999). https://doi.org/10.1038/sj.onc.1203005

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203005

Keywords

This article is cited by

Search

Advanced search

Quick links