Small-molecule blocks malignant astrocyte proliferation and induces neuronal gene expression.
Small-molecule blocks malignant astrocyte proliferation and induces neuronal gene expression.
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DOI：
10.1016/j.diff.2011.02.005
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发表时间：
2011-04
期刊：
影响因子：
2.9
通讯作者：
Hsieh, Jenny
中科院分区：
文献类型：
--
作者：
Zhang, Ling;Li, Peng;Hsu, Tiffany;Aguilar, Hector R.;Frantz, Doug E.;Schneider, Jay W.;Bachoo, Robert M.;Hsieh, Jenny
在中枢神经系统（CNS）中，神经干细胞（NSCs）分化为神经元、星形胶质细胞和少突胶质细胞，这些细胞系在正常情况下被认为是单向的和不可逆的。一组明确的转录因子的引入已被证明可以直接将终末分化的细胞转化为多能干细胞，从而强化了保持细胞身份是一个主动过程的概念。事实上，最近的研究强调，肿瘤抑制基因（tsg），如Ink4a/Arf和p53，控制了有效重编程的障碍，留下了相同的tsg是否维持分化状态的问题。在恶性肿瘤或脑损伤期间，成熟星形胶质细胞已被报道在一定程度上重新表达神经元基因并重新获得神经发生潜能，但由于有限的细胞模型或工具来探索这一过程，因此很少有研究解决潜在的机制。在这里，我们使用合成的小分子（异恶唑）来证明高度恶性表达Ink4a/Arf-/-的egfrviii；Pten-/-星形胶质细胞下调星形胶质细胞特性，重新进入细胞周期，上调神经元基因表达。作为附带发现，异恶唑小分子在体外阻断肿瘤细胞增殖，这种表型可能与神经元基因表达的激活有关。同样，组蛋白去乙酰化酶抑制剂诱导神经元基因表达和与神经元表型相关的形态学改变，表明参与了表观遗传介导的基因激活。我们的研究评估了星形胶质细胞去分化潜能的特定遗传途径的贡献，并揭示了一种新的药理工具来探索星形胶质细胞的可塑性，这可能为重编程和抗肿瘤策略带来见解。
In the central nervous system (CNS), neural stem cells (NSCs) differentiate into neurons, astrocytes, and oligodendrocytes - these cell lineages are considered unidirectional and irreversible under normal conditions. The introduction of a defined set of transcription factors has been shown to directly convert terminally differentiated cells into pluripotent stem cells, reinforcing the notion that preserving cellular identity is an active process. Indeed, recent studies highlight that tumor suppressor genes (TSGs) such as Ink4a/Arf and p53, control the barrier to efficient reprogramming, leaving open the question whether the same TSGs function to maintain the differentiated state. During malignancy or following brain injury, mature astrocytes have been reported to re-express neuronal genes and re-gain neurogenic potential to a certain degree, yet few studies have addressed the underlying mechanisms due to a limited number of cellular models or tools to probe this process. Here, we use a synthetic small-molecule (isoxazole) to demonstrate that highly malignant EGFRvIII-expressing Ink4a/Arf-/-; Pten-/- astrocytes down-regulated their astrocyte character, re-entered the cell cycle, and upregulated neuronal gene expression. As a collateral discovery, isoxazole small-molecules blocked tumor cell proliferation in vitro, a phenotype likely coupled to activation of neuronal gene expression. Similarly, histone deacetylase inhibitors induced neuronal gene expression and morphologic changes associated with the neuronal phenotype, suggesting the involvement of epigenetic-mediated gene activation. Our study assesses the contribution of specific genetic pathways underlying the de-differentiation potential of astrocytes and uncovers a novel pharmacological tool to explore astrocyte plasticity, which may bring insight to reprogramming and anti-tumor strategies.
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影响因子：
9.8
作者：
Heinrich C;Blum R;Gascón S;Masserdotti G;Tripathi P;Sánchez R;Tiedt S;Schroeder T;Götz M;Berninger B
通讯作者：
Berninger B
DOI：
10.1083/jcb.200308101
发表时间：
2004-01-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hsieh J;Aimone JB;Kaspar BK;Kuwabara T;Nakashima K;Gage FH
通讯作者：
Gage FH
影响因子：
13.9
作者：
Kriegstein A;Alvarez-Buylla A
通讯作者：
Alvarez-Buylla A
影响因子：
64.8
作者：
KOH, J;ENDERS, GH;HARLOW, E
通讯作者：
HARLOW, E
影响因子：
50.3
作者：
Bachoo, RM;Maher, EA;DePinho, RA
通讯作者：
DePinho, RA