SREBP: A Key Effector of mTORC1 Signaling in Metabolism and Cancer
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CitationYecies, Jessica. 2012. SREBP: A Key Effector of mTORC1 Signaling in Metabolism and Cancer. Doctoral dissertation, Harvard University.
AbstractThe mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth and proliferation, is aberrantly activated in cancer, genetic tumor syndromes and obesity. Much progress has been made to understand the upstream pathways that regulate mTORC1, most of which converge upon its negative regulator, the Tuberous Sclerosis Complex (TSC) 1-TSC2 complex. However, the cell intrinsic consequences of aberrant mTORC1 activation remain poorly characterized. Using systems in which mTORC1 is constitutively activated by genetic loss of TSC1 or TSC2 and pharmacologically inhibited by treatment with an mTORC1-specific inhibitor rapamycin, we have identified that mTORC1 controls specific aspects of cellular metabolism, including glycolysis, the pentose phosphate pathway, and de novo lipogenesis. Induction of the pentose phosphate pathway and de novo lipogenesis is achieved by activation of a transcriptional program affecting metabolic gene targets of sterol regulatory element-binding protein (SREBP). We have demonstrated that mTORC1 stimulates the accumulation of processed, active SREBP, although details of the molecular mechanism remain to be elucidated. To understand the physiological and pathological relevance of mTORC1-dependent activation of SREBPs and lipogenesis, we explored these findings in the liver and in cancer. While we find that the induction of hepatic SREBP1c and lipogenesis by insulin requires mTORC1, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We demonstrate that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. In cancer, our initial findings demonstrate that mTORC1 plays a role downstream of TSC-deficiency and oncogenic PIK3CA and K-Ras to activate lipogenic SREBP targets and de novo lipogenesis. Further studies of the connection between mTORC1 and SREBPs in disease may offer insights into novel therapeutic approaches.
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