Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched.
Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched.
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DOI：
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发表时间：
2001
期刊：
影响因子：
11.2
通讯作者：
C. Wetmore;D. Eberhart;T. Curran
中科院分区：
文献类型：
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作者：
C. Wetmore;D. Eberhart;T. Curran
脑恶性肿瘤是儿童中最常见的实体瘤，导致显着的死亡率和发病率。人们对最常见的恶性儿童脑肿瘤——髓母细胞瘤的分子基础知之甚少。遗传性和散发性髓母细胞瘤亚群中已报道了多种基因的突变，包括果蝇节段极性基因的人类同源物补丁（PTCH）、腺瘤性息肉病大肠杆菌基因（APC）、β-连环蛋白和p53。小鼠中一种 Ptc 等位基因失活导致髓母细胞瘤的发病率为 14%。在此，我们报告缺乏 p53 的 Ptc 杂合子小鼠中髓母细胞瘤的发病率显着增加 (>95%) 并加速发展（12 周龄之前）。 Ptc+/- 小鼠中肿瘤发生的加速是 p53 缺失所特有的，因为在携带 APC (Min+/-) 突变的 Ptc+/- 小鼠或缺乏 p19ARF 的 Ptc+/- 小鼠中没有观察到肿瘤发生率的变化。因此，p53 缺失和 Ptc 杂合性之间存在特定的相互作用，导致髓母细胞瘤。这可能是与 p53 功能丧失相关的基因组不稳定性增加的结果，p53 功能丧失可能会提高二次突变的获得率。 Ptc+/- p53-/- 小鼠为研究髓母细胞瘤的分子基础和评估自发性内源性脑肿瘤的治疗干预策略的功效提供了有用的模型。
Brain malignancies represent the most common solid tumors in children, and they are responsible for significant mortality and morbidity. The molecular basis of the most common malignant pediatric brain tumor, medulloblastoma, is poorly understood. Mutations in several genes including the human homologue of the Drosophila segment polarity gene, patched (PTCH), the adenomatous polyposis coli gene (APC), beta-catenin, and p53 have been reported in subsets of hereditary and sporadic medulloblastoma. Inactivation of one Ptc allele in mice results in a 14% incidence of medulloblastoma. Here, we report a dramatic increase in the incidence (>95%) and accelerated development (prior to 12 weeks of age) of medulloblastoma in mice heterozygous for Ptc that lack p53. The acceleration of tumorigenesis in Ptc+/- mice is specific for loss of p53, because no change in tumor incidence was observed in Ptc+/- mice carrying a mutation in APC (Min+/-) or in Ptc+/- mice deficient in p19ARF. Thus, there is a specific interaction between p53 loss and heterozygosity of Ptc that results in medulloblastoma. This may be a consequence of increased genomic instability associated with loss of p53 function that may enhance the rate of acquisition of secondary mutations. Ptc+/- p53-/- mice provide a useful model for investigation of the molecular bases of medulloblastoma and for evaluation of the efficacy of therapeutic intervention strategies in a spontaneously arising endogenous brain tumor.