TY - JOUR
T1 - Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3
AU - Farioli-Vecchioli, Stefano
AU - Tanori, Mirella
AU - Micheli, Laura
AU - Mancuso, Mariateresa
AU - Leonardi, Luca
AU - Saran, Anna
AU - Ciotti, Maria Teresa
AU - Ferretti, Elisabetta
AU - Gulino, Alberto
AU - Pazzaglia, Simonetta
AU - Tirone, Felice
PY - 2007/7
Y1 - 2007/7
N2 - 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 ∼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.
AB - 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 ∼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.
KW - Cyclin D1
KW - Math1
KW - Neurogenesis
KW - Tumor suppressor gene
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U2 - 10.1096/fj.06-7548com
DO - 10.1096/fj.06-7548com
M3 - Article
C2 - 17371797
AN - SCOPUS:34347392096
VL - 21
SP - 2215
EP - 2225
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 9
ER -