Bromberg Kenneth D, Ma'ayan Avi, Neves Susana R, Iyengar Ravi
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Science. 2008 May 16;320(5878):903-9. doi: 10.1126/science.1152662.
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.
大麻素受体1（CB1R）调节神经元分化。为了理解控制CB1R诱导的神经突生长的信号网络中决策背后的逻辑，我们分析了细胞刺激后数百种转录因子的激活情况。我们通过将CB1R与23种激活的转录因子相连，构建了一个计算机信号网络。对该网络的统计分析预测乳腺癌1蛋白BRCA1在神经元分化中起作用，以及一条从CB1R通过磷酸肌醇3激酶到转录因子配对盒6（PAX6）的新途径。这两个预测均通过实验得到证实。使用激酶药理学抑制剂的转录因子激活实验结果揭示了一个由部分“或”门调节激酶的网络组织，这些激酶堆叠在控制转录因子的“与”门之上，共同允许在CB1R诱导的神经突生长中进行分布式决策。
