Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth
Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth
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DOI：
10.1126/science.1152662
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发表时间：
2008-05-16
期刊：
影响因子：
56.9
通讯作者：
Iyengar, Ravi
中科院分区：
文献类型：
--
作者：
Bromberg, Kenneth D.;Ma'ayan, Avi;Iyengar, Ravi
大麻素受体1(CB1R)调节神经元分化。为了理解控制CB1R诱导的轴突生长的信号网络中决策的逻辑，我们描述了细胞刺激后数百个转录因子的激活情况。我们通过将CB1R与23个激活的转录因子连接起来，构建了一个内电子信号网络。对这个网络的统计分析预测了乳腺癌1蛋白BRCA1在神经元分化中的作用，以及从CB1R通过磷酸肌醇3-激酶到转录因子配对框6(PAX6)的新途径。这两个预测都得到了实验的证实。使用药物激酶抑制剂的转录因子激活实验结果显示，部分OR门调控蛋白的网络组织堆积在控制转录因子的AND门之上，这些门共同允许在CB1R诱导的轴突生长中进行分布式决策。
Cannabinoid receptor 1 (CB1R) regulates neuronal differentiation. To understand the logic underlying decision-making in the signaling network controlling CB1R-induced neurite outgrowth, we profiled the activation of several hundred transcription factors after cell stimulation. We assembled an in silico signaling network by connecting CB1R to 23 activated transcription factors. Statistical analyses of this network predicted a role for the breast cancer 1 protein BRCA1 in neuronal differentiation and a new pathway from CB1R through phosphoinositol 3-kinase to the transcription factor paired box 6 (PAX6). Both predictions were experimentally confirmed. Results of transcription factor activation experiments that used pharmacological inhibitors of kinases revealed a network organization of partial OR gates regulating kinases stacked above AND gates that control transcription factors, which together allow for distributed decision-making in CB1R-induced neurite outgrowth.