Uziel Tamar, Zindy Frederique, Xie Suqing, Lee Youngsoo, Forget Antoine, Magdaleno Susan, Rehg Jerold E, Calabrese Christopher, Solecki David, Eberhart Charles G, Sherr Sarah E, Plimmer Sarah, Clifford Steven C, Hatten Mary E, McKinnon Peter J, Gilbertson Richard J, Curran Tom, Sherr Charles J, Roussel Martine F
Department of Tumor Cell Biology and Genetics, Memphis, Tennessee 38105, USA.
Genes Dev. 2005 Nov 15;19(22):2656-67. doi: 10.1101/gad.1368605. Epub 2005 Oct 31.
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.
人类髓母细胞瘤（MB）中反复出现的基因改变包括音猬因子（SHH）信号通路的突变和TP53失活（分别约占病例的25%和10%）。然而，MB的小鼠模型，无论其起始病变如何，通常都依赖于p53失活来实现快速发病和高侵袭性。编码细胞周期蛋白依赖性激酶抑制剂p18（Ink4c）的基因在小鼠小脑颗粒神经元前体细胞（GNP）退出细胞分裂周期并分化时短暂表达。Ink4c和p53的共同失活为培养的GNP提供了额外的增殖优势，无论是否存在Shh，并诱导产生低侵袭性的MB，但在出生后照射后发病率大大增加。相比之下，缺乏一个或两个功能性Ink4c等位基因以及一个编码Shh受体的patched（Ptc1）拷贝的小鼠迅速发展出保留野生型p53的MB。在从双杂合子中纯化的肿瘤细胞中，野生型Ptc1等位基因而非Ink4c被失活。因此，当与Ptc1突变结合时，Ink4c在肿瘤抑制方面是单倍体不足的。在23例人类MB中有4例观察到INK4C（CDKN2C）的甲基化，在73例中有14例p18（INK4C）蛋白表达消失。因此，p18（INK4C）缺失可能导致儿童MB的形成。
