Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model.
Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model.
复制标题
DOI：
10.1016/j.ccr.2009.04.001
复制
发表时间：
2009-06-02
期刊：
影响因子：
50.3
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Wang Y;Yang J;Zheng H;Tomasek GJ;Zhang P;McKeever PE;Lee EY;Zhu Y
最近的研究已经确定了在人类胶质母细胞瘤中改变的基因和核心通路。然而，这些胶质母细胞瘤基因的改变单独和合作转化脑细胞的机制仍然知之甚少。此外，胶质母细胞瘤的起源细胞在很大程度上是难以捉摸的。通过将p53框内缺失突变靶向大脑，我们发现p53缺陷对成年脑细胞没有显著的生长优势，但似乎诱导了驱动胶质瘤发生的合作致癌改变的多效性积累。我们的数据表明，可检测水平的突变型p53蛋白的积累首先发生在脑室下区（SVZ）的神经干细胞中，随后在SVZ相关区域中表达突变型p53的Olig 2 + transit-amplifying祖细胞样细胞的扩增启动胶质瘤形成。胶质母细胞瘤是星形细胞胶质瘤中最恶性的形式，也是成人中最常见的原发性脑癌。胶质母细胞瘤的预后差强调迫切需要更好地了解疾病的发病机制。我们证明，p53缺陷可以与不同的促有丝分裂信号通路，以诱导恶性胶质瘤。 例如，Nf 1肿瘤抑制因子的失活、促分裂原活化蛋白激酶的活化或磷脂酰肌醇-3-OH激酶途径的活化不是必需的，但可以促进p53介导的胶质瘤形成。此外，突变型p53蛋白的表达被鉴定为胶质瘤细胞在所有阶段的标志物。对具有可检测水平的突变型p53表达的脑细胞的分析为神经干细胞和过渡扩增祖细胞在p53介导的胶质瘤发生中的作用提供了重要的见解。
Recent studies have identified genes and core pathways that are altered in human glioblastoma. However, the mechanisms by which alterations of these glioblastoma genes singly and cooperatively transform brain cells remain poorly understood. Further, the cell-of-origin of glioblastoma is largely elusive. By targeting a p53 in-frame deletion mutation to the brain, we show that p53 deficiency provides no significant growth advantage to adult brain cells, but appears to induce pleiotropic accumulation of cooperative oncogenic alterations driving gliomagenesis. Our data show that accumulation of a detectable level of mutant p53 proteins occurs first in neural stem cells in the subventricular zone (SVZ) and that subsequent expansion of mutant p53-expressing Olig2+ transit-amplifying progenitor-like cells in the SVZ-associated areas initiates glioma formation. Glioblastoma is the most malignant form of astrocytic gliomas and the most common primary brain cancer in adults. The poor prognosis of glioblastoma emphasizes the urgent need for a greater understanding of disease pathogenesis. We demonstrate that p53 deficiency can cooperate with diverse mitogenic signaling pathways to induce malignant glioma. For example, inactivation of the Nf1 tumor suppressor, activation of mitogen-activated protein kinase, or activation of phosphatidylinositol-3-OH kinase pathways are not essential, but can promote p53-mediated glioma formation. Furthermore, expression of mutant p53 proteins is identified as a marker for glioma cells in all stages. Analysis of brain cells with a detectable level of mutant p53 expression provides important insights into the role of neural stem cells and transit-amplifying progenitors in p53-mediated gliomagenesis.
登录
查看更多内容
影响因子：
56.9
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
通讯作者：
PAVLETICH, NP
影响因子：
30.8
作者：
Reilly, KM;Loisel, DA;Jacks, T
通讯作者：
Jacks, T
影响因子：
7.5
作者：
Merkle, Florian T.;Alvarez-Buylla, Arturo
通讯作者：
Alvarez-Buylla, Arturo
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A