Nature Medicine
6, 826 - 831 (2000)
doi:10.1038/77565
The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma
cellsPatrick Lawinger1, 4, Radjendirane Venugopal1, 4, Zong-Sheng Guo2, 4, Anand Immaneni1, Devjani Sengupta1, Wenying Lu1, Luca Rastelli1, Ana Marin Dias Carneiro1, Victor Levin1, Gregory N. Fuller1, Yann Echelard3
& Sadhan Majumder11
Brain Tumor Center, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard, Box 316,
Houston, Texas 77005, USA
2
Surgery Branch, National Cancer Institute,
9000 Rockville Pike, Bethesda, Maryland
20892, USA
3
Genzyme Transgenics Corporation, 1 Mountain
Road, Framingham, Massachusetts 01710,
USA
4
P.L., R.V. and Z.-S.G. contributed equally to this study.
Correspondence should be addressed to Sadhan Majumder majumder@mdanderson.orgMedulloblastoma 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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