Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1.
Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1.
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DOI：
10.1371/journal.pone.0018017
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发表时间：
2011-03-24
期刊：
影响因子：
3.7
通讯作者：
Rao JS
中科院分区：
文献类型：
--
作者：
Velpula KK;Dasari VR;Tsung AJ;Gondi CS;Klopfenstein JD;Mohanam S;Rao JS
细胞周期的正常进程需要细胞周期蛋白的顺序表达。在有丝分裂信号存在或不存在的情况下，细胞周期蛋白D1的快速诱导及其与细胞周期蛋白依赖的激酶的结合，通常被认为是细胞周期通过G1期的限速步骤。在本研究中，人脐血干细胞与胶质母细胞瘤细胞(U251和5310)共培养不仅能诱导G0-G1期阻滞，而且还能减少处于S和G2-M期的细胞数量。Western和FACS分析显示，hUCBSC处理后，细胞周期调节蛋白的表达水平降低。人脐血干细胞抑制细胞周期蛋白D1的活性足以取消CDK4、CDK6、细胞周期蛋白B1、β-连环蛋白的表达水平。我们的免疫沉淀实验表明，hUCBSC处理胶质瘤细胞后，通过使细胞周期蛋白D1/CDK4和细胞周期蛋白D1/CDK6复合体失活而导致细胞周期停滞。观察到hUCBSC与胶质瘤细胞共培养时，G0-G1期增加，而G0-G1期调控蛋白Cyclin D1和CDK4表达减少。我们发现，与hUCBSC共培养时，G0-G1期调控蛋白Cyclin D1和CDK4的减少可能部分地被Cyclin E1的表达所补偿。裸鼠脑移植瘤与细胞周期蛋白D1和CD81抗体的体内共定位实验表明，hUCBSC可降低细胞周期蛋白D1的表达。本文阐明了一种调控胶质瘤细胞周期进程的模型，在该模型中，hUCBSC通过介导细胞周期停滞在G0-G1期来控制细胞周期蛋白D1的诱导，并协同其伴侣激酶CDK4和CDK6。
The normal progression of the cell cycle requires sequential expression of cyclins. Rapid induction of cyclin D1 and its associated binding with cyclin-dependent kinases, in the presence or absence of mitogenic signals, often is considered a rate-limiting step during cell cycle progression through the G1 phase. In the present study, human umbilical cord blood stem cells (hUCBSC) in co-cultures with glioblastoma cells (U251 and 5310) not only induced G0-G1 phase arrest, but also reduced the number of cells at S and G2-M phases of cell cycle. Cell cycle regulatory proteins showed decreased expression levels upon treatment with hUCBSC as revealed by Western and FACS analyses. Inhibition of cyclin D1 activity by hUCBSC treatment is sufficient to abolish the expression levels of Cdk 4, Cdk 6, cyclin B1, β-Catenin levels. Our immuno precipitation experiments present evidence that, treatment of glioma cells with hUCBSC leads to the arrest of cell-cycle progression through inactivation of both cyclin D1/Cdk 4 and cyclin D1/Cdk 6 complexes. It is observed that hUCBSC, when co-cultured with glioma cells, caused an increased G0-G1 phase despite the reduction of G0-G1 regulatory proteins cyclin D1 and Cdk 4. We found that this reduction of G0-G1 regulatory proteins, cyclin D1 and Cdk 4 may be in part compensated by the expression of cyclin E1, when co-cultured with hUCBSC. Co-localization experiments under in vivo conditions in nude mice brain xenografts with cyclin D1 and CD81 antibodies demonstrated, decreased expression of cyclin D1 in the presence of hUCBSC. This paper elucidates a model to regulate glioma cell cycle progression in which hUCBSC acts to control cyclin D1 induction and in concert its partner kinases, Cdk 4 and Cdk 6 by mediating cell cycle arrest at G0-G1 phase.
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影响因子：
3.7
作者：
Dasari VR;Kaur K;Velpula KK;Gujrati M;Fassett D;Klopfenstein JD;Dinh DH;Rao JS
通讯作者：
Rao JS
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8
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