The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells (original) (raw)

Nature Medicine volume 6, pages 826–831 (2000)Cite this article

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. 7–10) 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.

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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.

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Author notes

  1. Patrick Lawinger, Radjendirane Venugopal and Zong-Sheng Guo: P.L., R.V. and Z.-S.G. contributed equally to this study.

Authors and Affiliations

  1. Brain Tumor Center, The University of Texas MD Anderson Cancer Center,, 1515 Holcombe Boulevard, Box 316, Houston, 77005, Texas, USA
    Patrick Lawinger, Radjendirane Venugopal, Anand Immaneni, Devjani Sengupta, Wenying Lu, Luca Rastelli, Ana Marin Dias Carneiro, Victor Levin, Gregory N. Fuller & Sadhan Majumder
  2. Surgery Branch, National Cancer Institute,, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA
    Zong-Sheng Guo
  3. Genzyme Transgenics Corporation,, 1 Mountain Road, Framingham, 01710, Massachusetts, USA
    Yann Echelard

Authors

  1. Patrick Lawinger
  2. Radjendirane Venugopal
  3. Zong-Sheng Guo
  4. Anand Immaneni
  5. Devjani Sengupta
  6. Wenying Lu
  7. Luca Rastelli
  8. Ana Marin Dias Carneiro
  9. Victor Levin
  10. Gregory N. Fuller
  11. Yann Echelard
  12. Sadhan Majumder

Corresponding author

Correspondence toSadhan Majumder.

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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

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