Effect of doublecortin on self-renewal and differentiation in brain tumor stem cells.
Effect of doublecortin on self-renewal and differentiation in brain tumor stem cells.
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双皮质素对脑肿瘤干细胞自我更新和分化的影响。
DOI：
10.1111/j.1349-7006.2011.01952.x
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发表时间：
2011-07
期刊：
影响因子：
5.7
通讯作者：
Chopp M
中科院分区：
文献类型：
--
作者：
Santra M;Santra S;Buller B;Santra K;Nallani A;Chopp M
对来自神经胶质瘤患者样品的Affy探针数据的分析结合患者Kaplan-Meier存活图表明神经胶质瘤抑制基因双皮质素（DCX）的表达有利于神经胶质瘤患者存活。从培养中的神经球形成，延时显微镜视频记录和肿瘤异种移植，我们表明，DCX合成显着减少脑肿瘤干细胞（BTSC）的自我更新在人类原发性胶质瘤（YU-PG，HF 66）细胞从切除的人类胶质瘤标本和U87细胞在体外和体内。延时显微镜录像显示，用DCX和neurabin II双重转染YU-PG、HF 66和U87细胞导致细胞周期不完整，胞质分裂失败，即由一个母体BTSC分裂为三个子细胞的内有丝分裂。辛伐他汀（10 nM）处理来自YU-PG、HF 66和U87细胞的DCX+neurabin II+ BTSC后，c-jun NH 2-末端激酶1（JNK 1）的活化诱导终末分化为神经元样细胞。TUNEL染色结果显示JNK 1的激活仅在DCX和neurabin II双转染的BTSC中诱导凋亡，而在YU-PG、HF 66和U87细胞的单转染BTSC中不诱导凋亡。Western blot分析显示，在YU-PG、HF 66和U87 BTSC中，DCX转染后半胱天冬酶原-3被诱导，辛伐他汀处理后被激活。连续免疫沉淀和Western印迹数据显示，DCX合成阻断蛋白磷酸酶-1（PP 1）/caspase-3蛋白-蛋白相互作用，并增加PP 1-DCX相互作用。这些数据表明，DCX合成通过新的JNK 1/neurabin II/DCX/PP 1/caspase-3途径诱导BTSC的凋亡。
Analysis of Affymetrix Probe data from glioma patient samples in conjuction with patient Kaplan-Meier Survival Plot indicate that expression of a glioma suppressor gene doublecortin (DCX) favors glioma patient survival. From neurosphere formation in culture, Time-Lapse Microscopy video recording and tumor xenograft, we show that DCX synthesis significantly reduces self-renewal of brain tumor stem cells (BTSCs) in human primary glioma (YU-PG, HF66) cells from surgically-removed human glioma specimens and U87 cells in vitro and in vivo. Time-Lapse Microscopic video recording revealed that double transfection of YU-PG, HF66 and U87 cells with DCX and neurabin II caused incomplete cell cycle with failure of cytokinesis, i.e. endomitosis by dividing into three daughter cells from one mother BTSC. Activation of c-jun NH2-terminal kinase 1 (JNK1) after simvastatin (10nM) treatment of DCX+neurabin II+ BTSCs from YU-PG, HF66 and U87 cells induced terminal differentiation into neuron-like cells. TUNEL staining data demonstrated that JNK1 activation also induced apoptosis only in double transfected BTSCs with DCX and neurabin II, but not in single transfected BTSCs from YU-PG, HF66 and U87 cells. Western blot analysis showed that procaspase-3 was induced after DCX transfection and activated after simvastatin treatment in YU-PG, HF66 and U87 BTSCs. Sequential immunoprecipitation and Western blot data revealed that DCX synthesis blocked protein phosphatase-1 (PP1)/caspase-3 protein-protein interaction and increased PP1-DCX interaction. These data demonstrate that DCX synthesis induces apoptosis in BTSCs via a novel JNK1/neurabin II/DCX/PP1/caspase-3 pathway.
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DOI：
10.1083/jcb.200303138
发表时间：
2003-05-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ackerley S;Thornhill P;Grierson AJ;Brownlees J;Anderton BH;Leigh PN;Shaw CE;Miller CC
通讯作者：
Miller CC
影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
影响因子：
64.8
作者：
Ricci-Vitiani, Lucia;Pallini, Roberto;De Maria, Ruggero
通讯作者：
De Maria, Ruggero
影响因子：
2.7
作者：
Akiyama-Oda, Y;Hotta, Y;Oda, H
通讯作者：
Oda, H
影响因子：
5.3
作者：
Ozduman, Koray;Wollmann, Guido;Van den Pol, Anthony N.
通讯作者：
Van den Pol, Anthony N.