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:

Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells

Oncogene volume 25, pages 2697–2707 (2006)Cite this article

Abstract

Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates ‘stemness’ in a broad spectrum of stem cell systems.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y . (1998). Mol Cell Biol 18: 1866–1878.

  • Boeuf H, Hauss C, Graeve FD, Baran N, Kedinger C . (1997). J Cell Biol 138: 1207–1217.

  • Brazil DP, Yang ZZ, Hemmings BA . (2004). Trends Biochem Sci 29: 233–242.

  • Burdon T, Smith A, Savatier P . (2002). Trends Cell Biol 12: 432–438.

  • Burdon T, Stracey C, Chambers I, Nichols J, Smith A . (1999). Dev Biol 210: 30–43.

  • Cantley LC . (2002). Science 296: 1655–1657.

  • Chambers I, Smith A . (2004). Oncogene 23: 7150–7160.

  • Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S et al. (2003). Cell 113: 643–655.

  • Daheron L, Opitz SL, Zaehres H, Lensch WM, Andrews PW, Itskovitz-Eldor J et al. (2004). Stem Cells 22: 770–778.

  • Furuya M, Yasuchika K, Mizutani K, Yoshimura Y, Nakatsuji N, Suemori H . (2003). Genesis 37: 180–187.

  • Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA et al. (2001). Science 294: 2186–2189.

  • Hay N, Sonenberg N . (2004). Genes Dev 18: 1926–1945.

  • Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT et al. (2004). Stem Cells 22: 522–530.

  • Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S, Savatier P . (2002). Oncogene 21: 5515–5528.

  • Kielman MF, Rindapaa M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S et al. (2002). Nat Genet 32: 594–605.

  • Kim SJ, Cheon SH, Yoo SJ, Kwon J, Park JH, Kim CG et al. (2005). FEBS Lett 579: 534–540.

  • Kimura T, Ito C, Watanabe S, Takahashi T, Ikawa M, Yomogida K et al. (2003a). Mol Cell Biol 23: 1304–1315.

  • Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N et al. (2003b). Development 130: 1691–1700.

  • Kohn AD, Barthel A, Kovacina KS, Boge A, Wallach B, Summers SA et al. (1998). J Biol Chem 273: 11937–11943.

  • Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, Gotoh Y . (2001). J Biol Chem 276: 32799–32805.

  • Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T et al. (1999). EMBO J 18: 4261–4269.

  • Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K et al. (2003). Cell 113: 631–642.

  • Moon RT, Kohn AD, De Ferrari GV, Kaykas A . (2004). Nat Rev Genet 5: 691–701.

  • Nagata M, Takahashi M, Muramatsu S, Ueda Y, Hanazono Y, Takeuchi K et al. (2003). J Gene Med 5: 921–928.

  • Nakano T, Kodama H, Honjo T . (1996). Science 272: 722–724.

  • Niwa H, Burdon T, Chambers I, Smith A . (1998). Genes Dev 12: 2048–2060.

  • Niwa H, Yamamura K, Miyazaki J . (1991). Gene 108: 193–199.

  • Paling NR, Wheadon H, Bone HK, Welham MJ . (2004). J Biol Chem 279: 48063–48070.

  • Pesce M, Scholer HR . (2001). Stem Cells 19: 271–278.

  • Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H et al. (2004). Proc Natl Acad Sci USA 101: 6027–6032.

  • Saitou M, Barton SC, Surani MA . (2002). Nature 418: 293–300.

  • Sato M, Kimura T, Kurokawa K, Fujita Y, Abe K, Masuhara M et al. (2002). Mech Dev 113: 91–94.

  • Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH . (2004). Nat Med 10: 55–63.

  • Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R et al. (2002). Mol Cell Biol 22: 3842–3851.

  • Stiles B, Groszer M, Wang S, Jiao J, Wu H . (2004). Dev Biol 273: 175–184.

  • Suemori H, Nakatsuji N . (2003). Methods Enzymol 365: 419–429.

  • Sumi T, Fujimoto Y, Nakatsuji N, Suemori H . (2004). Stem Cells 22: 861–872.

  • Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J et al. (1999). Proc Natl Acad Sci USA 96: 6199–6204.

  • Takahashi K, Mitsui K, Yamanaka S . (2003). Nature 423: 541–545.

  • Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA . (2005). Nat Methods 2: 185–190.

  • Ying QL, Nichols J, Chambers I, Smith A . (2003a). Cell 115: 281–292.

  • Ying QL, Stavridis M, Griffiths D, Li M, Smith A . (2003b). Nat Biotechnol 21: 183–186.

Download references

Acknowledgements

We thank Dr H Suemori for generous help of culturing monkey ES cells, and Drs Y Gotoh, T Akiyama, H Niwa, S Takada and S Akira for providing materials and supporting microarray analysis. We also thank Dr E Morii for histological inspection and Ms M Ikeuchi, Y Fujita, T Asada, A Mizokami and A Kawai for assistance. SW is supported by scholarship from the Japanese Society for Promotion of Science. This work is supported in part by grants from the Ministry of Education, Science, Sports and Culture, Support Program for Technology Development on the Basis of Academic Findings (NEDO) and Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan

    S Watanabe, H Umehara & T Nakano

  2. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    K Murayama, T Kimura & T Nakano

  3. Genome Information Research Center, Osaka University, Suita, Osaka, Japan

    M Okabe

Authors
  1. S Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Umehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Murayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Okabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to T Kimura or T Nakano.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watanabe, S., Umehara, H., Murayama, K. et al. Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene 25, 2697–2707 (2006). https://doi.org/10.1038/sj.onc.1209307

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209307

Keywords

This article is cited by

Search

Advanced search

Quick links