Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly
Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly
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DOI：
10.1177/08830738050200041101
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发表时间：
2005-04-01
影响因子：
1.9
通讯作者：
Crino, PB
中科院分区：
文献类型：
--
作者：
Crino, PB
我的实验室最近证实，在局灶性皮质发育不良和半侧巨脑症的气球样细胞中存在核糖体S6蛋白磷酸化的选择性表达，但上游激酶磷酸化 - p70S6激酶无表达。磷酸化 - p70S6激酶激活的两种蛋白，磷酸化 - STAT3和磷酸化 - 4EBP1，在气球样细胞中未被检测到。在半侧巨脑症标本中使用互补DNA阵列，我们发现细胞周期蛋白D1和c - myc信使核糖核酸（RNAs）表达增加。细胞周期蛋白D1和c - myc基因的表达由β - 连环蛋白转录激活。蛋白质印迹分析表明半侧巨脑皮质中非磷酸化β - 连环蛋白水平升高。在半侧巨脑症中检测到Ser33、Ser37和Thr41磷酸化 - β - 连环蛋白水平降低，这些位点已知由糖原合成酶激酶3磷酸化，并且对β - 连环蛋白失活至关重要。细胞周期蛋白D - 1和c - myc信使RNAs转录增强、转录活性β - 连环蛋白增加以及Ser33/Ser37/Thr41磷酸化 - β - 连环蛋白减少，表明在半侧巨脑症中Wnt - 1/β - 连环蛋白级联被激活，这可能导致大脑发育过程中异常的细胞增殖和半球增大。磷酸化 - S6和β - 连环蛋白的激活增强提示了两种汇聚的细胞通路，它们可能在局灶性皮质发育不良和半侧巨脑症的发病机制中起关键作用。
My laboratory recently demonstrated that there is selective expression of phosphoribosomal S6 protein in balloon cells in focal cortical dysplasia and hemimegalencephaly but no expression of the upstream kinase, phospho-p70S6 kinase. Two proteins activated by phospho-p70S6 kinase, phospho-STAT3 and phospho-4EBP1, were not detected in balloon cells. Using complementary DNA arrays in hemimegalencephaly specimens, we found increased expression of cyclin D1 and c-myc messenger ribonucleic acids (RNAs). Expression of cyclin D1 and c-myc genes is transcriptionally activated by beta-catenin. Western analysis demonstrated increased levels of nonphosphorylated beta-catenin in hemimegalencephalic cortex. Reduced levels of Ser33, Ser37, and Thr41 phospho-beta-catenin, sites known to be phosphorylated by glycogen synthase kinase 3 and to be essential for beta-catenin inactivation, were detected in hemimegalencephaly. Enhanced transcription of cyclin D-1 and c-myc messenger RNAs, increased transcriptionally active beta-catenin, and decreased Ser33/Ser37/Thr41 phospho-beta-catenin suggest activation of the Wnt-1/beta-catenin cascade in hemimegalencephaly, which can lead to aberrant cell proliferation and hemispheric enlargement during brain development. Enhanced activation of phospho-S6 and beta-catenin suggests two converging cell pathways that can be pivotal in the pathogenesis of focal cortical dysplasia and hemimegalencephaly.