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. Activation of mTORC1 orchestrates cell growth and cellular proliferation in large part by promoting protein translation and by inhibiting a process of self-catabolism known as macro-autophagy. The complex interplay of signaling pathways to mTORC1 and the resulting physiologic outputs remain poorly understood. Studies in the previous funding cycle identified the stress response gene REDD1 as an essential inhibitor of mTORC1 activity in response to hypoxia and energy stress. We elucidated the mechanism whereby hypoxia inhibits mTORC1 activity, in which REDD1 functions to activate the tuberous sclerosis (TSC1/2) tumor suppressor complex. We demonstrated how mTORC1 via REDD1 regulates translation of key proteins including p53 to control the DNA damage response in vivo. In the absence of p53, genetic loss of REDD1 is potent driver of tumorigenesis, in keeping with the silencing or loss of REDD1 observed in several human tumors. REDD1-dependent tumorigenesis is associated with glycolytic reprogramming and suppression of oxidative metabolism in cells and tissues of REDD1-deficient mice. Preliminary data suggest these effects are attributable to a critical role for REDD1 in promoting both autophagy and mitochondrial activity, functioning through distinct mechanisms upstream and downstream of mTORC1. These findings position REDD1 as a critical control point for metabolic homeostasis and tumor suppression. Here we propose a systematic approach to pursuing the biochemical and physiological role of REDD1 in controlling mTORC1, autophagy, and mitochondrial function in human cancer. We will first determine the molecular mechanism of REDD1-mediated regulation of autophagy and oxidative metabolism independent of mTORC1. Second, we have established a novel primary cell/in vivo orthotopic model, which we will use to functionally dissect the contribution of these individual REDD1-controlled pathways to cellular signaling, metabolism, and tumorigenesis in vivo. Finally, we will uncover specific tumor genetic contexts in which REDD1 silencing activates autophagy and the glycolytic switch to drive tumorigenesis, through genetic crosses and through analysis of our established repository of thousands of genotyped human tumors. These studies will provide new insights into tumor metabolism and its relationship to specific oncogenic driver events. Our findings will thus contribute directly to the knowledge base required to therapeutically target de-regulated metabolism and cellular signaling in human cancer.
Metabolic activity within individual cells must be carefully controlled, as abnormalities of metabolism have been linked to diabetes, cancer, and other common diseases. We have identified and studied key regulators of cellular metabolism, and have begun to uncover exactly how their malfunction can promote human cancer. By discovering precisely how these regulators and normal metabolism become re-wired and subverted in disease states, we seek to find new and more effective ways to diagnose and treat many common diseases.
|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|
|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|