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.

The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells

An Erratum to this article was published on 01 September 2000

Abstract

Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown1,2,3,4,5,6. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 710) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST–VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST–VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST–VP16 mediated by adenovirus vectors (Ad.REST–VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST–VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST–VP16.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Medulloblastoma cells contain high levels of endogenous REST/NRSF activity that can be countered by REST–VP16.
Figure 2: Ad.REST–VP16 activates neural differentiation marker genes but does not alter the expression of neural stem cell genes in Daoy cells.
Figure 3: Adenovirus-mediated expression of REST–VP16 triggers apoptosis in Daoy cells.
Figure 4: REST–VP16 inhibits growth of established medulloblastoma tumors in nude mice.

References

  1. 1

    Fuller, G.N. in Pediatric Neoplasia: Morphology and Biology (ed. David M. Parham) 153–204 (Lippincott-Ravel, Philadelphia, 1996).

    Google Scholar 

  2. 2

    Provias, J.P., and Becker, L. E. Cellular and molecular pathology of medulloblastoma. J. Neurooncol. 29, 35 –43 (1996).

    CAS  Article  Google Scholar 

  3. 3

    He, X.M. et al. Phenotypic analysis of four human medulloblastoma cell lines and transplantable xenografts. J. Neuropathol. Exp. Neurol. 48, 48–68 (1989).

    CAS  Article  Google Scholar 

  4. 4

    Whelan, H.T., Krouwer, H.G., Schmidt, M.H., Reichert, K.W. & Kovnar, E.H. Current therapy and new perspectives in the treatment of medulloblastoma. Pediatr. Neurol. 18, 103–115 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Goussia, A.C., Bruner, J.M., Kyritsis, A.P., Agnantis, N.K. & Fuller, G.N. Cytogenetic and molecular genetic abnormalities in primitive neuroectodermal tumors of the central nervous system . Anticancer Res. 20, 65– 74 (2000).

    CAS  PubMed  Google Scholar 

  6. 6

    Adesina, A.M., Nalbantoglu, J. & Cavenee, W.K. p53 gene mutation and mdm2 gene amplification are uncommon in medulloblastoma. Cancer Res. 54, 5649–5651 (1994).

    CAS  PubMed  Google Scholar 

  7. 7

    Chong, J.A. et al. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949 –957 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Schoenherr, C.J. & Anderson, D.J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360– 1363 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Schoenherr, C.J., Paquette, A.J. & Anderson, D.J. Identification of potential target genes for the neuron-restrictive silencer factor. Proc. Natl. Acad. Sci. USA 93, 9881–9886 (1996).

    CAS  Article  Google Scholar 

  10. 10

    Tapia-Ramirez, J., Eggen, B.J., Peral-Rubio, M.J., Toledo-Aral, J.J. & Mandel, G. A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter. Proc. Natl. Acad. Sci. USA 94, 1177–1182 (1997).

    CAS  Article  Google Scholar 

  11. 11

    Tohyama, T. et al. Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab. Invest. 66, 303–313 (1992).

    CAS  PubMed  Google Scholar 

  12. 12

    Andres, M.E. et al. CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc. Natl. Acad. Sci. USA 96, 9873–9878 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Huang, Y., Meyers, S.J. & Dingledine . Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nature Neurosci. 2, 867 –872 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Grimes, J.A. et al. The co-repressor mSin3A is a functional component of the REST–CoREST repressor complex. J. Biol. Chem. 31, 9461 –9467 (2000).

    Article  Google Scholar 

  15. 15

    Majumder, S., Zhao, Z., Kaneko, K. & DePamphilis, M.L. Developmental acquisition of enhancer function requires a unique coactivator activity. EMBO J. 16, 1721–1731 ( 1997).

    CAS  Article  Google Scholar 

  16. 16

    Chen, Z.F., Paquette, A.J. & Anderson, D.J. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nature Genet. 20, 136–142 ( 1998).

    CAS  Article  Google Scholar 

  17. 17

    Jacobsen, P.F., Jenkyn, D.J. & Papadimitriou, J.M. Establishment of a human medulloblastoma cell line and its heterotransplantation into nude mice. J. Neuropathol. Exp. Neurol. 44, 472–485 ( 1985).

    CAS  Article  Google Scholar 

  18. 18

    Hollstein M., Sidransky, D., Vogelstein, B. & Harris, C.C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    CAS  Article  Google Scholar 

  19. 19

    Harris, C.C. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J. Natl. Cancer Inst. 88, 1442–1455 (1996)

    CAS  Article  Google Scholar 

  20. 20

    Raffel, C., Thomas, G.A., Tishler, D.M., Lassoff, S. & Allen, J.C. Absence of p53 mutations in childhood central nervous system primitive neuroectodermal tumors. Neurosurgery 33, 301–306 ( 1993).

    CAS  Article  Google Scholar 

  21. 21

    Xie, J. et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57, 2369– 2372 (1997).

    CAS  PubMed  Google Scholar 

  22. 22

    Goodrich, L.V., Milenkovic, L., Higgins, K.M. & Scott, M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 ( 1997).

    CAS  Article  Google Scholar 

  23. 23

    Perrimon, N. & McMahon, A.P. Negative feedback mechanisms and their roles during pattern formation. Cell 97, 13–16 (1999).

    CAS  Article  Google Scholar 

  24. 24

    McMahon, A.P. More surprises in the hedgehog signaling pathway. Cell 100, 185–188 (2000).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank G. Mandel for her gift of pREST-Express, p73, pBS.REST and pSDK7; T. Kanda and G. Wahl for pH2BGFP-N1; C. Gomez-Manzano, J. Rossi, G. Lewandowicz and L. Wu for technical help, J.Yung for proof-reading and G. Mandeland G. Mandel and K. Smith for their comments. This work was supported in part by grants to S.M. from the Pediatric Brain Tumor Foundation of the United States and the National Institutes of Health (CA51255, GM53454). L.R. was supported by a Translational Research Award from the American Brain Tumor Association.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sadhan Majumder.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lawinger, P., Venugopal, R., Guo, ZS. et al. The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nat Med 6, 826–831 (2000). https://doi.org/10.1038/77565

Download citation

Further reading

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