p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.
p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.
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DOI：
10.1038/nature07443
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发表时间：
2008-10-23
期刊：
影响因子：
64.8
通讯作者：
DePinho, Ronald A.
中科院分区：
文献类型：
--
作者：
Zheng, Hongwu;Ying, Haoqiang;Yan, Haiyan;Kimmelman, Alec C.;Hiller, David J.;Chen, An-Jou;Perry, Samuel R.;Tonon, Giovanni;Chu, Gerald C.;Ding, Zhihu;Stommel, Jayne M.;Dunn, Katherine L.;Wiedemeyer, Ruprecht;You, Mingjian J.;Brennan, Cameron;Wang, Y. Alan;Ligon, Keith L.;Wong, Wing H.;Chin, Lynda;DePinho, Ronald A.
胶质母细胞瘤 (GBM) 是一种高度致命的脑肿瘤，是具有不同临床病史和分子特征的两种亚型之一。原发性 GBM 亚型急性表现为高度疾病，通常含有 EGFR、Pten 和 Ink4a/Arf 突变，而继发性 GBM 亚型是由低度疾病的缓慢进展演变而来，通常具有 PDGF 和 p53 事件。在这里，我们发现，小鼠中枢神经系统中 p53 和 Pten 的中枢神经系统特异性缺失会产生一种渗透性急性发作的高级恶性神经胶质瘤表型，其临床、病理和分子水平与人类原发性 GBM 具有惊人的相似性。这一基因观察促进了人类原发性 GBM 中的 p53 和 Pten 突变分析，证明了 p53 意外频繁的失活突变以及预期的 Pten 突变。综合转录组分析、计算机启动子分析和小鼠神经干细胞 (NSC) 的功能研究证实，p53 和 Pten 的双重（而非单一）失活可促进具有高更新潜力的未分化状态，并驱动 c-Myc 水平及其相关特征升高。功能研究证实，c-Myc 活性的增加是 p53-Pten null NSC 以及源自该模型的肿瘤神经球 (TNS) 分化受损和增强更新的重要因素。 c-Myc 还可以维持 p53-Pten null TNS 强大的致瘤潜力。这些小鼠模型研究与人类原发性 GBM 中的确认性转录组/启动子研究一起，验证了人类原发性 GBM 中常见肿瘤抑制突变谱的致病作用，并将 c-Myc 确立为 p53 和 Pten 在调节正常和恶性干/祖细胞分化、自我更新和致瘤潜力中合作作用的关键靶标。
Glioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, Pten and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and Pten mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected Pten mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya
影响因子：
50.3
作者：
Bachoo, RM;Maher, EA;DePinho, RA
通讯作者：
DePinho, RA