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

Tamar Uziel, Frederique Zindy, Suqing Xie, Youngsoo Lee, Antoine Forget, Susan Magdaleno, Jerold E. Rehg, Christopher Calabrese, David Solecki, Charles G. Eberhart, Sarah E. Sherr, Sarah Plimmer, Steven C. Clifford, Mary E. Hatten, Peter J. McKinnon, Richard J. Gilbertson, Tom Curran, Charles J. Sherr, Martine F. Roussel

Research output: Contribution to journalArticlepeer-review

Abstract

Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway and TP53 inactivation (∼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 p18Ink4c 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 p18INK4C protein expression was extinguished in 14 of 73 cases. Hence, p18INK4C loss may contribute to MB formation in children.

Original languageEnglish (US)
Pages (from-to)2656-2667
Number of pages12
JournalGenes and Development
Volume19
Issue number22
DOIs
StatePublished - Nov 15 2005

Keywords

  • Cyclin-dependent kinase inhibitors
  • Haploinsufficiency
  • Sonic hedgehog signaling

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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