Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development
- 1 Departments of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
- 2 Laboratory of Developmental Neurobiology, Rockefeller University, New York, New York 10021, USA
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↵3 These authors contributed equally to this work.
Abstract
Bone morphogenic proteins 2 and 4 (BMP2 and BMP4) inhibit proliferation and induce differentiation of cerebellar granule neuron progenitors (GNPs) and primary GNP-like medulloblastoma (MB) cells. This occurs through rapid proteasome-mediated degradation of Math1 (Atoh1), a transcription factor expressed in proliferating GNPs. Ectopic expression of Atoh1, but not of Sonic hedgehog (Shh)-regulated Gli1 or Mycn, cancels these BMP-mediated effects and restores Shh-dependent proliferation of GNPs and MB cells in vitro and in vivo. Genes regulating the BMP signaling pathway are down-regulated in mouse MBs. Thus, BMPs are potent inhibitors of MB and should be considered as novel therapeutic agents.
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Footnotes
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↵4 Corresponding author.
↵4 E-MAIL martine.roussel{at}stjude.org; FAX (901) 495-2381.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1636408.
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- Received November 21, 2007.
- Accepted January 16, 2008.
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Freely available online through the Genes & Development Open Access option.
- Copyright © 2008, Cold Spring Harbor Laboratory Press