Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development.
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.
Zhao
Haotian
H
Departments of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Ayrault
Olivier
O
Zindy
Frederique
F
Kim
Jee-Hae
JH
Roussel
Martine F
MF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071676:Zinc Finger Protein GLI1
D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1; C500943:Atoh1 protein, mouse; C498520:Gli1 protein, mouse; C459801:MYCN protein, human; C465570:Shh protein, mouse