Journal
SCIENCE
Volume 320, Issue 5878, Pages 903-909Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1152662
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Funding
- NCI NIH HHS [T32 CA088796, T32 CA88796, 5R24 CA095823-04, R24 CA095823] Funding Source: Medline
- NCRR NIH HHS [1 S10 RR0 9145-01] Funding Source: Medline
- NIGMS NIH HHS [P50 GM071558-020007, P50 GM071558-030007, R01 GM054508, P50 GM071558-01A2, R01 GM054508-21, P50 GM071558-02, GM072853, R01 GM072853-04, GM54508, P50 GM071558, R01 GM072853, P50 GM071558-01A20007] Funding Source: Medline
- PHS HHS [P50-071558] Funding Source: Medline
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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.
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