The CREB family of transcription factors participates in a variety of cellular functions including energy homeostasis. Recently, a new family of CREB coactivators, called TORCs, has been identified. TORCs translocate to the nucleus in response to cAMP and calcium signals, where they potentiate cellular gene expression via a direct interaction with CREB. Drosophila has a single TORC family member, dTORC, which can act as a bone fide member of the TORC family in cell culture coactivation assays. TORC1 +/- mice are hyperphagic, gain more weight than wild type littermates and show hyperinsulinemia. Similarly, dTORC mutant flies show increased food intake, altered glycogen and triglyceride stores, and also show sensitivity to starvation. These phenotypes can be rescued by supplying dTORC in the nervous system, indicating that neuronal dTORC activity is critical for regulation of appetite and energy stores. This proposal aims to use Drosophila to understand how TORC proteins function in these processes. The domains of dTORC that are conserved between mammals and Drosophila will be tested for function. Since dTORC is active in the insulin-producing cells of the fly brain and mutant dTORC flies have phenotypes expected from alteration of the insulin pathway, the hypothesis that dTORC regulates insulin expression and signaling will be tested. Tests for genetic interactions with insulin signaling pathway components will be carried out. The time course of changes in dTORC phosphorylation state and nuclear shuttling in response to feeding and fasting will be examined. In addition to insulin signaling, other components involved in satiety and energy stores are likely to be controlled by dTORC and mammalian TORCs. By capitalizing on a dTORC overexpression phenotype in the eye, a screen for genes that enhance or suppress the phenotype will be carried out. These genes may encode components of the dTORC signaling pathway, and by extension the pathway for mammalian TORCs as well.
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