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The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation

Lookup NU author(s): Dr Christopher Calabrese, Professor Steven Clifford, 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.

Publication metadata

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


DOI: 10.1101/gad.1368605


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