Title:
Post-transcriptional control of metabolism and cancer by the mTORC1 signaling pathway

 

Speaker:
Masahiro Morita
Assistant Professor, University of Texas Health Science Center at San Antonio, Texas, USA
Research Associate, Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

 

Abstract:
Cancer cells rely on metabolic reprogramming (e.g., Warburg effect) to generate sufficient energy and fuel protein, nucleotide and lipid synthesis, ultimately to drive neoplastic growth1. Post-transcriptional regulation of gene expression, including mRNA translation and degradation, directly modulate protein synthesis, and are dysregulated in a variety of diseases including cancer. However, the mechanisms that underpin the role of post-transcriptional regulation in controlling cancer energetics remain largely unknown.
Our genome-wide translational analysis reveals that oncogenic mTORC1 signaling stimulates not only global protein synthesis, but also translation of a subset of mRNAs that encode pivotal regulators of mitochondrial function2-5. Protein synthesis is considered to be the most energy consuming process in the cell. We demonstrate that mTORC1 coordinates energy consumption by translation machinery, and energy production by bolstering mitochondrial functions and dynamics via activation of eIF4E cap-binding protein. Furthermore, we show that the CCR4-NOT poly(A) nuclease (deadenylase) controls susceptibility to metabolic disorders, which is a cancer-predisposing state, by selectively regulating turnover of mRNAs encoding hormone-like proteins6-7. Taken together, our findings highlight the pathways that relate the post-transcriptional regulation to metabolic perturbations in cancer, which in long term may provide novel therapeutic avenues to target cancer energetics.

 

Reference:
1. Morita, M. et al. mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle (Review) 14, 473-480, (2015).
2. Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab 18, 698-711, (2013).
3. *Larsson, O., *Morita, M. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci USA 109, 8977-8982, (2012). *Co-First authors
4. *Alain, T., *Morita, M. et al. eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Research 72, 6468-6476, (2012). *Co-First authors
5. Morita, M. et al. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol Cell Biol 32, 3585-3593, (2012).
6. Watanabe, C., Morita, M. et al. Stability of mRNA influences osteoporotic bone mass via CNOT3. Proc Natl Acad Sci USA 111, 2692-2697, (2014).
7. Morita, M. et al. Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/- mice. EMBO J 30, 4678-4691, (2011).