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

in Genes & development by 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

TLDR

  • The study found that a protein called p18(INK4C) is important for preventing cancer in the brain. When this protein is missing or not working properly, it can lead to a type of cancer called medulloblastoma. The study also found that combining the loss of p18(INK4C) with another protein called p53 can make cancer cells grow faster and more likely to develop. This could be a potential way to treat medulloblastoma in the future.

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.

Overview

  • The study investigates the role of cyclin-dependent kinase inhibitor p18(Ink4c) in recurrent genetic alterations in human medulloblastoma (MB).
  • The study compares the outcomes observed under different experimental conditions, specifically the combination of Ink4c and p53 inactivation versus the lack of functional Ink4c alleles and one copy of Patched (Ptc1) encoding the Shh receptor.

Comparative Analysis & Findings

  • 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.

Implications and Future Directions

  • The study highlights the importance of p18(INK4C) loss in MB formation and suggests that targeting p18(INK4C) may be a potential therapeutic approach for MB. Future research should focus on developing targeted therapies for p18(INK4C) loss and exploring the role of p18(INK4C) in other cancers.
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