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RESEARCH PAPER

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

Departments of ¹ Tumor Cell Biology and Genetics, ² Developmental Neurobiology, ³ Pathology, ⁴ Hematology-Oncology, and ⁵ Howard Hughes Medical Institute at St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; ⁶ Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21205, USA; ⁷ Laboratory of Developmental Neurobiology, Rockefeller University, New York, New York 10021, USA; ⁸ Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, United Kingdom

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 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.

[Keywords: Cyclin-dependent kinase inhibitors; haploinsufficiency; sonic hedgehog signaling]

Received May 31, 2005; revised version accepted September 9, 2005.

Supplemental material is available at http://www.genesdev.org.

Note added in proof

We have now performed quantitative PCR analyses of Ptc1 and Ink4c RNA expression in GNP-like tumor cells purified from 30 mouse medulloblastomas. As indicated in Figure 5C, six of six tumors from Ptc1^+/-–Ink4c^+/+ mice, 11 of 14 from Ptc1^+/-–Ink4c^+/- mice, and 10 of 10 from Ptc1^+/-–Ink4c^-/- mice expressed no detectable Ptc1 mRNA. The 30 tumors expressed Math1, and all 20 tumors from Ink4c^+/+ and Ink4c^+/- animals continued to express Ink4c mRNA. Thus, Ink4c is haploinsufficient for tumor suppression, whereas Ptc1 is not.

⁹ These authors contributed equally to this work.

¹⁰ Corresponding author.

E-MAIL martine.roussel{at}stjude.org; FAX (901) 495-2381.

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