The long-term objectives of this project are to understand how stress signals are transduced to control cellular metabolism, and how dysregulation of specific stress response pathways contributes to human disease. The checkpoint kinase mTOR is an essential regulator of cellular metabolism in all human cells. Dysregulated activity of the mTOR protein complex I (mTORC1) has been associated with a wide variety of human diseases, including diabetes, autoimmune disease, and many types of cancer. One critical upstream regulator of mTORC1 activity is another protein complex composed of the human tuberous sclerosis tumor suppressors TSC1 and TSC2. The importance of TSC-dependent regulation of mTORC1 activity is evidenced by the high frequency of neoplasms observed in patients with inherited germline mutation of either TSC1 or TSC2. We have identified the stress response gene REDD1 as an essential regulator of mTORC1 activity in response to hypoxia and energy stress. Genetic studies in Drosophila and our own work in mammalian cells demonstrate that REDD1 functions as an inhibitor of TORC1 activity through the TSC1/2 complex. We provide evidence for a mechanism of REDD1 function that has broad implications for understanding upstream signal integration by the TSC1/2 complex. These findings imply a potentially important contribution of REDD1-mediated signaling to disease states characterized by mTORC1 dysregulation. In particular, our data suggest that the REDD1-TSC pathway may function as a tumor suppressor mechanism in human cells. This proposal aims to uncover the biochemistry of REDD1 regulation and signaling within the TSC-mTORC1 pathway. In addition, we will directly investigate the contribution of REDD1 to regulation of protein translation under hypoxic conditions and will identify specific genes and proteins exhibiting REDD1-dependent regulation. Finally, we will investigate the mechanisms by which loss of REDD1 may cooperate with other relevant genetic events during tumorigenesis. By characterizing this novel and essential pathway for TSC1/2 and mTORC1 regulation through the REDD1 protein, these studies have the potential to provide new targets for diagnosis and treatment of tuberous sclerosis and a wide variety of other human diseases.
| Gordon, Bradley S; Steiner, Jennifer L; Rossetti, Michael L et al. (2017) REDD1 induction regulates the skeletal muscle gene expression signature following acute aerobic exercise. Am J Physiol Endocrinol Metab 313:E737-E747 |
| Qiao, Shuxi; Dennis, Michael; Song, Xiufeng et al. (2015) A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nat Commun 6:7014 |
| Vadysirisack, Douangsone D; Ellisen, Leif W (2012) mTOR activity under hypoxia. Methods Mol Biol 821:45-58 |
| Vadysirisack, Douangsone D; Baenke, Franziska; Ory, Benjamin et al. (2011) Feedback control of p53 translation by REDD1 and mTORC1 limits the p53-dependent DNA damage response. Mol Cell Biol 31:4356-65 |
| Horak, Peter; Crawford, Andrew R; Vadysirisack, Douangsone D et al. (2010) Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci U S A 107:4675-80 |
| Zhong, Lei; D'Urso, Agustina; Toiber, Debra et al. (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280-93 |
| Ellisen, Leif W (2010) Smoking and emphysema: the stress connection. Nat Med 16:754-5 |
| DeYoung, Maurice Phillip; Horak, Peter; Sofer, Avi et al. (2008) Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 22:239-51 |
| Harvey, Kieran F; Mattila, Jaakko; Sofer, Avi et al. (2008) FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J Cell Biol 180:691-6 |
