The AKT/mTOR signaling pathway plays central roles in the pathology of several human diseases including cancer and diabetes. This pathway is a sensor of energy status, nutrient availability, stress and endocrine growth factors. In response to these cues the pathway modulates cell growth and proliferation. Part of this control is through regulating both protein and RNA synthesis. The pathway ensures that new proteins are translated only when conditions are favorable, while RNA synthesis is regulated by activation or inactivation of the Forkhead-box family O (FOXO) transcription factors. We have identified the direct targets of FOXO and find a connection between FOXO targets and translation initiation. Negative regulators of initiation are overrepresented in the identified set of FOXO targets suggesting a connection between the branch of the AKT/mTOR pathway that controls RNA synthesis and the branch that controls protein synthesis. Several of the newly identified FOXO targets are immune to the translational regulation imposed by the AKT/mTOR pathway. We believe this provides a mechanism for integrating the regulation of protein synthesis with transcriptional regulation of genes that are targets of this pathway. We hypothesize that: the AKT/mTOR pathway changes translational profiles through FOXO by controlling the expression of multiple translational inhibitors. To test the generality of this idea, we propose to determine the efficiency of translation of specific transcripts by profiling mRNAs being actively translated during expression of an activated FOXO. We will also define the direct FOXO targets that are responsible for this effect and functionally characterize their effects. In addition, we find that he small RNA pathway is dramatically affected by activated FOXO. Changes in small RNAs also have the potential to extensively change the translation profile of the cell, so we will define the effect of FOXO on small RNAs. The work in this proposal will illuminate an underappreciated integration of gene expression from mRNA synthesis through protein synthesis.
This project is directed at providing an integrated view of how a cell responds to energy status, nutrient availability and stress. The processes being studied are central to human pathologies such as cancer and diabetes. In addition they are a significant player in the controlling the effects of aging.
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