Transcriptional Mediators of Growth and Survival Downstream of the Target of Rapamycin (TOR) Pathway. Lauren E. Killip, Savraj Grewal. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.

   Nutrition is essential for growth and survival in animals. The conserved Target-Of-Rapamycin (TOR) kinase signaling pathway is the central nutrient-sensing pathway that controls metabolism to promote either cell growth or survival. When nutrients are abundant, TOR is active and stimulates metabolism to drive cell, tissue and body growth. Upon nutrient deprivation, TOR is inactivated and the animals switch their metabolism to promote survival. Our lab studies mechanisms downstream of TOR that mediate the metabolic switch between growth and survival. One potential mechanism is the regulation of gene expression. We have focused on identifying transcription factors that regulate metabolic gene expression downstream of TOR in Drosophila. One transcription factor required for TOR-dependent growth is DREF. We found that DREF levels are decreased in conditions of reduced TOR signaling and that loss of DREF leads to decreased organismal growth. These effects are due in part to a requirement for DREF function in cell-autonomous growth. We also uncovered a non-autonomous role for DREF activity in the larval fat body where the tissue-specific loss of DREF leads to reduced systemic insulin signaling, slow larval growth and smaller final size. This result phenocopies the effects of starvation and loss of TOR and is consistent with previous findings that fat-body specific activation of TOR couples nutrition to insulin release from the brain. In addition, we showed that DREF is required for expression of many ribosome biogenesis genes, suggesting that DREF may link nutrient availability and TOR activation to tissue growth by stimulating protein synthesis. We are also exploring transcriptional mechanisms that may mediate responses to nutrient starvation. We have identified several transcriptional and translational regulators whose expression, in contrast to DREF, is strongly upregulated upon starvation. We are currently exploring the role of these transcription factors in mediating homeostasis following nutrient deprivation to promote organismal survival.