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Lookup NU author(s): Dr Christopher Calabrese, Professor Steven CliffordORCiD, Dr Richard Gilbertson
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Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway and TP53 inactivation (approximately 25% and 10% of cases, respectively). However, mouse models of MB, regardless of their initiating lesions, generally depend upon p53 inactivation for rapid onset and high penetrance. The gene encoding the cyclin-dependent kinase inhibitor p18(Ink4c) is transiently expressed in mouse cerebellar granule neuronal precursor cells (GNPs) as they exit the cell division cycle and differentiate. Coinactivation of Ink4c and p53 provided cultured GNPs with an additive proliferative advantage, either in the presence or absence of Shh, and induced MB with low penetrance but with greatly increased incidence following postnatal irradiation. In contrast, mice lacking one or two functional Ink4c alleles and one copy of Patched (Ptc1) encoding the Shh receptor rapidly developed MBs that retained wild-type p53. In tumor cells purified from double heterozygotes, the wild-type Ptc1 allele, but not Ink4c, was inactivated. Therefore, when combined with Ptc1 mutation, Ink4c is haploinsufficient for tumor suppression. Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18(INK4C) protein expression was extinguished in 14 of 73 cases. Hence, p18(INK4C) loss may contribute to MB formation in children.
Author(s): Uziel T, Zindy F, Xie S, Lee Y, Forget A, Magdaleno S, Rehg JE, Calabrese CR, Solecki D, Eberhart CG, Sherr SE, Plimmer S, Clifford SC, Hatten ME, McKinnon PJ, Gilbertson RJ, Curran T, Sherr CJ, Roussel MF
Publication type: Article
Publication status: Published
Journal: Genes & Development
Year: 2005
Volume: 19
Issue: 22
Pages: 2656-67
Print publication date: 15/11/2005
ISSN (print): 0890-9369
ISSN (electronic): 1549-5477
Publisher: Cold Spring Harbor Laboratory Press
URL: http://dx.doi.org/10.1101/gad.1368605
DOI: 10.1101/gad.1368605
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