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.

  • Letter
  • Published:

Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice

Abstract

Gliomas are the most common primary malignant brain tumours and are classified into four clinical grades1, with the most aggressive tumours being grade 4 astrocytomas (also known as glioblastoma multiforme; GBM). Frequent genetic alterations in GBMs (refs 25) result in stimulation of common signal transduction pathways involving Ras, Akt and other proteins6,7,8,9,10. It is not known which of these pathways, if any, are sufficient to induce GBM formation. Here we transfer, in a tissue-specific manner, genes encoding activated forms of Ras and Akt to astrocytes and neural progenitors in mice. We found that although neither activated Ras nor Akt alone is sufficient to induce GBM formation, the combination of activated Ras and Akt induces high-grade gliomas with the histological features of human GBMs. These tumours appear to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs (ref. 11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Gross characteristics of glioblastomas induced by infection of Ntv-a mice with RCAS-Kras and RCAS-Akt.
Figure 2: Microscopic appearance of glioblastomas induced by the combination of Ras and Akt.
Figure 3: Mouse glioblastomas express Gfap, nestin, virally transduced Akt and Ras.
Figure 4: AKT activity is elevated in most human GBMs.

Similar content being viewed by others

References

  1. Kleihues, P., Burger, P.C. & Scheithauer, B.W. Histological Typing Of Tumours Of The Central Nervous System (Springer, Berlin, Heidelberg, New York, 1993 ).

    Book  Google Scholar 

  2. Hermanson, M. et al. Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor a receptor expression in human gliomas . Cancer Res. 56, 164–171 (1996).

    CAS  PubMed  Google Scholar 

  3. Antoniades, H.N., Galanopoulos, T., Neville-Golden, J. & Maxwell, M. Expression of insulin like growth factors I and II and their receptor mRNAs in primary human astrocytomas and meningiomas; in vivo studies using in situ hybridization and immunocytochemistry. Int. J. Cancer. 50, 215–222 (1992).

    Article  CAS  Google Scholar 

  4. Gross, J.L. et al. Basic fibroblast growth factor: a potential autocrine regulator of human glioma cell growth. J. Neurosci. Res. 27, 689–696 (1990).

    Article  CAS  Google Scholar 

  5. Schlegel, J. et al. Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behavior in human glioblastoma. Int. J. Cancer 56, 72–77 (1994).

    Article  CAS  Google Scholar 

  6. Feldkamp, M.M., Lau, N. & Guha, A. Signal transduction pathways and their relevance in human astrocytomas. J. Neurooncol. 35, 223–248 (1997).

    Article  CAS  Google Scholar 

  7. Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89, 693–702 (1997).

    Article  CAS  Google Scholar 

  8. Kulik, G. & Webber, M.J. Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol. Cell. Biol. 18, 6711–6718 (1998).

    Article  CAS  Google Scholar 

  9. Kim, B., Cheng, H.L., Margolis, B. & Feldman, E.L. Insulin receptor substrate 2 and shc play different roles in insulin-like growth factor I signaling. J. Biol. Chem. 273, 34543–34550 (1998).

    Article  CAS  Google Scholar 

  10. Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling Cell 80, 225– 236 (1995).

    Article  CAS  Google Scholar 

  11. Guha, A., Feldkamp, M.M., Lau, N., Boss, G. & Pawson, A. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15, 2755– 2765 (1997).

    Article  CAS  Google Scholar 

  12. Holland, E.C. & Varmus, H.E. Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc. Natl Acad. Sci. USA 95, 1218 –1223 (1998).

    Article  CAS  Google Scholar 

  13. Holland, E.C., Hively, W.P., DePinho, R.A. & Varmus, H.E. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell cycle arrest pathways to induce gliomas in mice. Genes Dev. 12, 3675–3685 ( 1998).

    Article  CAS  Google Scholar 

  14. Aoki, M., Batista, O., Bellacosta, A., Tsichlis, P. & Vogt, P.K. The AKT kinase: molecular determinants of oncogenicity. Proc. Natl Acad. Sci. USA 25, 14950–14955 (1998).

    Article  Google Scholar 

  15. Li, J. et al. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 58 , 5667–5672 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H. Varmus for input on the project and manuscript; T. Jacks for the mutant K-ras cDNA; G. Fisher for the RCAS-Kras vector; D. Foster for the DF-1 cells; D. Fults for his input on the project; and P. Vogt for the RCAS-Akt vector. This work was partially supported by Cancer Center Support (CORE) Grant CA16672. E.C.H. is a recipient of a grant from the Bullock Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric C. Holland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holland, E., Celestino, J., Dai, C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25, 55–57 (2000). https://doi.org/10.1038/75596

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/75596

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing