Abstract
Medulloblastoma, the most common brain tumor in childhood, appears to originate from cerebellar granule cell precursors (GCPs), located in the external granular layer (EGL) of the cerebellum. The antiproliferative gene PC3 (Tis21/BTG2) promotes cerebellar neurogenesis by inducing GCPs to shift from proliferation to differentiation. To assess whether PC3 can prevent the neoplastic transformation of GCPs and medulloblastoma development, we crossed transgenic mice conditionally expressing PC3 (TgPC3) in GCPs with Patched1 heterozygous mice (Ptc(+/-)), a model of medulloblastoma pathogenesis characterized by hyperactivation of the Sonic Hedgehog pathway. Perinatal up-regulation of PC3 in Ptc(+/-)/TgPC3 mice results in a decrease of medulloblastoma incidence of approximately 40% and in a marked reduction of preneoplastic abnormalities, such as hyperplastic EGL areas and lesions. Moreover, overexpression of cyclin D1, hyperproliferation, and defective differentiation--observed in Ptc(+/-) GCPs--are restored to normality in Ptc(+/-)/TgPC3 mice. The PC3-mediated inhibition of cyclin D1 expression correlates with recruitment of PC3 to the cyclin D1 promoter, which is accompanied by histone deacetylation. Remarkably, down-regulation of PC3 is observed in preneoplastic lesions, as well as in human and murine medulloblastomas. As a whole, this indicates that PC3 may prevent medulloblastoma development by controlling cell cycle and promoting differentiation of GCPs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Basal Cell Nevus Syndrome / genetics
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cell Division / genetics
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Cell Division / physiology
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Cell Transformation, Neoplastic / genetics
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Cerebellar Cortex / abnormalities
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Cerebellar Cortex / embryology
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / prevention & control*
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Choristoma / genetics
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Chromatin Immunoprecipitation
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Cyclin D
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Cyclins / biosynthesis
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Cyclins / genetics
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Genes, Tumor Suppressor*
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Hedgehog Proteins / physiology
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Heterozygote
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / physiology*
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Medulloblastoma / genetics
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Medulloblastoma / prevention & control*
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Mice
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Mice, Transgenic
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Neoplastic Syndromes, Hereditary / genetics
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Neoplastic Syndromes, Hereditary / prevention & control
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Neurons / pathology
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PC12 Cells / chemistry
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Patched Receptors
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Patched-1 Receptor
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Precancerous Conditions / genetics
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Promoter Regions, Genetic
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Protein Processing, Post-Translational
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RNA, Neoplasm / genetics
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Rats
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Recombinant Fusion Proteins / physiology
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Tumor Suppressor Proteins
Substances
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BTG2 protein, rat
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Cyclin D
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Cyclins
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Hedgehog Proteins
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Histones
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Immediate-Early Proteins
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Ptch1 protein, mouse
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Ptch1 protein, rat
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RNA, Neoplasm
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Receptors, Cell Surface
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Recombinant Fusion Proteins
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Shh protein, mouse
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Tumor Suppressor Proteins
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Histone Deacetylases