title: The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation.
abstract: 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.
authors.affiliation: Department of Tumor Cell Biology and Genetics, Memphis, Tennessee 38105, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Uziel
authors.forename: Frederique
authors.initials: F
authors.lastname: Zindy
authors.forename: Suqing
authors.initials: S
authors.lastname: Xie
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Antoine
authors.initials: A
authors.lastname: Forget
authors.forename: Susan
authors.initials: S
authors.lastname: Magdaleno
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.forename: David
authors.initials: D
authors.lastname: Solecki
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Sherr
authors.forename: Sarah
authors.initials: S
authors.lastname: Plimmer
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hatten
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Sherr
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins; D006801:Humans; D008527:Medulloblastoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C493971:CDKN2C protein, human; C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53