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首页> 外文期刊>Cell cycle >The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma.
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The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma.

机译：CDK抑制剂p18Ink4c是髓母细胞瘤中的肿瘤抑制因子。

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor which is thought to originate from cerebellar granule cell precursors (CGNPs) that fail to properly exit the cell cycle and differentiate. Although mutations in the Sonic Hedgehog (Shh) signaling pathway occur in 30% of cases, genetic alterations that account for MB formation in most patients have not yet been identified. We recently determined that the cyclin D-dependent kinase inhibitor, p18(Ink4c), is expressed as CGNPs exit the cell cycle, suggesting that this protein might play a central role in arresting the proliferation of these cells and in timing their subsequent migration and differentiation. In mice, disruption of Ink4c collaborates independently with loss of p53 or with inactivation of the gene (Ptc1) encoding the Shh receptor, Patched, to induce MB formation. Whereas loss of both Ink4c alleles is required for MB formation in a p53-null background, Ink4c is haplo-insufficient for tumor suppression in a Ptc(1+/-) background. Moreover, MBs derived from Ptc(1+/-) mice that lack one or two Ink4c alleles retain wild-type p53. Methylation of the INK4C (CDKN2C) promoter and complete loss of p18(INK4C) protein expression were detected in a significant fraction of human MBs again pointing toward a role for INK4C in suppression of MB formation.
机译：髓母细胞瘤（MB）是最常见的小儿脑恶性肿瘤，被认为起源于小脑颗粒细胞前体（CGNP），它们无法正确退出细胞周期并分化。尽管在30％的病例中发生了Sonic Hedgehog（Shh）信号传导途径的突变，但尚未发现大多数患者中MB形成的遗传改变。我们最近确定，当CGNPs退出细胞周期时，细胞周期蛋白D依赖性激酶抑制剂p18（Ink4c）被表达，表明该蛋白可能在阻止这些细胞的增殖以及确定其随后的迁移和分化时起着核心作用。 。在小鼠中，Ink4c的破坏与p53的丧失或编码Shh受体的基因（Ptc1）失活协同起作用，从而诱导MB形成。尽管在p53无背景下MB形成需要两个Ink4c等位基因的缺失，但Ink4c在Ptc（1 +/-）背景下单倍不足以抑制肿瘤。此外，缺乏一个或两个Ink4c等位基因的Ptc（1 +/-）小鼠衍生的MB保留野生型p53。在很大一部分人MB中检测到INK4C（CDKN2C）启动子的甲基化和p18（INK4C）蛋白表达的完全丧失，这再次表明INK4C在抑制MB形成中的作用。

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