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.

  • Short Communication
  • Published:

Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/−p53−/− compound mutant mice

Oncogene volume 25, pages 1816–1820 (2006)Cite this article

Abstract

Germline mutations in the LKB1 gene are responsible for Peutz–Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomas and increasing risk of cancer. Mice with Lkb1+/− mutation develop gastric hamartomas after >20 weeks of age, and hepatocellular adenomas and carcinomas >30 weeks. It has been reported that, in PJS patients, carcinomas progressed from hamartomas contain p53 mutations, and that LKB1 regulates p53-dependent apoptosis. To investigate the roles of LKB1 and p53 mutations in tumorigenesis, we constructed compound mutant mice of Lkb1 and p53 genes. In the Lkb1+/−p53−/− mice, formation of gastric hamartomas and hepatic tumors was accelerated. However, histopathology of hamartomas was similar between Lkb1+/−p53−/− and Lkb1+/− mice, and Lkb1 genotype remained heterozygous, suggesting that the p53 mutation affected hamartoma initiation. Contrary to the heterozygous hamartomas in the stomach and duodenum, the hepatic adenomas in Lkb1+/−p53−/− mice showed loss of Lkb1 heterozygosity (LOH), suggesting that lack of p53 stimulated Lkb1 LOH and tumor initiation in the liver. Taken together, these results indicate that lack of p53 causes earlier onsets of gastric hamartomas and hepatic tumors in Lkb1+/−p53−/− mice.

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

Similar content being viewed by others

References

  • Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ et al. (2004). Cell 116: 457–466.

  • Bronner MP . (2003). Mod Pathol 16: 359–365.

  • Crowe SE . (2005). Curr Opin Gastroenterol 21: 32–38.

  • Donehower LA . (1996). Semin Cancer Biol 7: 269–278.

  • Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV et al. (1987). N Engl J Med 316: 1511–1514.

  • Gruber SB, Entius MM, Petersen GM, Laken SJ, Longo PA, Boyer R et al. (1998). Cancer Res 58: 5267–5270.

  • Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP et al. (2003). J Biol 2: 28.

  • Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A et al. (1998). Nature 391: 184–187.

  • Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R et al. (1998). Nat Genet 18: 38–43.

  • Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R et al. (2001). Mol Cell 7: 1307–1319.

  • Levine AJ . (1997). Cell 88: 323–331.

  • Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD . (1992). Cell 70: 923–935.

  • Miyaki M, Iijima T, Hosono K, Ishii R, Yasuno M, Mori T et al. (2000). Cancer Res 60: 6311–6313.

  • Miyoshi H, Nakau M, Ishikawa T, Seldin MF, Oshima M, Taketo MM . (2002). Cancer Res 62: 2261–2266.

  • Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H et al. (2004). Cancer Res 64: 7740–7747.

  • Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M, Taketo MM . (2002). Cancer Res 62: 4549–4553.

  • Papageorgiou T, Stratakis CA . (2002). Int J Gynecol Cancer 12: 337–347.

  • Seno H, Oshima M, Taniguchi M, Usami K, Ishikawa T, Chiba T et al. (2002). Int J Oncol 21: 769–774.

  • Spigelman AD, Murday V, Phillips RK . (1989). Gut 30: 1588–1590.

  • Takahashi M, Sakayori M, Takahashi S, Kato T, Kaji M, Kawahara M et al. (2004). J Gastroenterol 39: 1210–1214.

  • Tiainen M, Ylikorkala A, Mäkelä TP . (1999). Proc Natl Acad Sci USA 96: 9248–9251.

  • Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T . (1994). Nat Genet 7: 480–484.

  • Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D et al. (2003). Curr Biol 13: 2004–2008.

Download references

Acknowledgements

We thank Drs Masahiro Aoki and Koji Aoki for fruitful discussions.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto, Japan

    H Takeda, H Miyoshi, Y Kojima, M Oshima & M M Taketo

Authors
  1. H Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M M Taketo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M M Taketo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takeda, H., Miyoshi, H., Kojima, Y. et al. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/−p53−/− compound mutant mice. Oncogene 25, 1816–1820 (2006). https://doi.org/10.1038/sj.onc.1209207

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209207

Keywords

This article is cited by

Search

Advanced search

Quick links