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RNAi screening for kinases and phosphatases identifies FoxO regulators

Mattila, Jaakko, Kallijärvi, Jukka, Puig, Oscar
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.39 pp. 14873-14878
Drosophila, RNA interference, energy, genome, glycogen synthase kinases, insulin, longevity, mammals, metabolism, mitogen-activated protein kinase, protein kinase C, proteins, screening, signal transduction, stress tolerance, tau-protein kinase, transcription (genetics), transcription factors
Forkhead box class O (FoxO) transcription factors are key regulators of growth, metabolism, life span, and stress resistance. FoxOs integrate signals from different pathways and guide the cellular response to varying energy and stress conditions. FoxOs are modulated by several signaling pathways, e.g., the insulin-TOR signaling pathway and the stress induced JNK signaling pathway. Here, we report a genome wide RNAi screen of kinases and phosphatases aiming to find regulators of dFoxO activity in Drosophila S2 cells. By using a combination of transcriptional activity and localization assays we identified several enzymes that modulate dFoxO transcriptional activity, intracellular localization and/or protein stability. Importantly, several currently known dFoxO regulators were found in the screening, confirming the validity of our approach. In addition, several interesting new regulators were identified, including protein kinase C and glycogen synthase kinase 3β, two proteins with important roles in insulin signaling. Furthermore, several mammalian orthologs of the proteins identified in Drosophila also regulate FOXO activity in mammalian cells. Our results contribute to a comprehensive understanding of FoxO regulatory processes.