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Currently seeking Ph.D. students.
Sam & Ann Barshop Institute for Longevity and Aging
Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells change their metabolic programs to efficiently utilize the limited nutrients, ultimately driving macromolecule synthesis (e.g., protein, lipid and nucleotide synthesis) and cell growth and proliferation. Protein, the most abundant macromolecule in the cell, is aberrantly synthesized in malignant cells. Post-transcriptional regulation of gene expression, including mRNA translation and degradation, directly modulate protein synthesis and are dysregulated in a variety of metabolic diseases including cancer. However, the mechanisms that underpin the role of post-transcriptional regulation in controlling cancer and metabolism remain largely unknown. The focus on our research is to determine how mutually dependent changes in protein synthesis and cellular metabolism contribute to the development of cancer and metabolic diseases. To this end, we will investigate the role of one of the central energy-sensing signaling pathways known to regulate both cellular energetics and protein synthesis: the mammalian/mechanistic target of rapamycin (mTOR) pathway in cancer and metabolic diseases.
The mTOR complex 1 (mTORC1) pathway is one of the major oncogenic signaling pathways that stimulate anabolism (e.g., protein synthesis) and suppresses catabolism (e.g., autophagy) in response to nutrient availability through multiple downstream effectors (in the Figure below). Prominent ones include translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). 4E-BPs are translation initiation repressors, which bind to the mRNA 5’cap-binding protein eIF4E and prevent the assembly of the eIF4F complex, consisting of eIF4E, that facilitates ribosome recruitment to the mRNA. Phosphorylation of 4E-BPs by mTORC1 results in their dissociation from eIF4E, thus allowing assembly of the eIF4F complex and promoting protein synthesis and cell proliferation. The oncogenic activity of the mTORC1 pathway is mediated through 4E-BP-dependent translational activation of mRNAs encoding tumor-promoting proteins, such as cell cycle regulators and metabolic enzymes.
Our laboratory focuses on mTORC1-dependent control of mRNA translation and degradation in cancer and metabolic diseases. We have developed a genome-wide analysis of mRNA translation and degradation to find the target mRNAs. Our genome-wide analysis reveals that the oncogenic mTORC1 signaling pathway stimulates not only global protein synthesis but also translation of a subset of mRNAs that encode pivotal regulators of mitochondrial dynamics. Our group demonstrates that mTORC1 coordinates energy consumption by translation machinery, and energy production by bolstering mitochondrial functions and dynamics via regulation of 4E-BPs. 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 the turnover of mRNAs encoding hormone-like proteins. Dissecting the mechanistic underpinnings of these translational and metabolic signatures should provide a molecular basis to improve the efficacy of existing drugs and devise more effective therapies to treat poor outcome cancer patients. Taken together, our laboratory is currently highlighting the pathways that relate the post-transcriptional regulation to metabolic perturbations in cancer, which in long term will provide novel therapeutic avenues to target cancer energetics.
Jafarnejad, S. M.
Gelbart, I. A.
Hesketh, G. G.
Kim, S. H.
Gingras, A. C.
Duchaine, T. F.
Sonenberg, N. Translational control of ERK signaling through miRNA/4EHP-directed silencing Elife 2018 Feb;. M. Morita, J. Prudent, K. Basu, V. Goyon, S. Katsumura, L. Hulea, D. Pearl, N. Siddiqui, S. Strack, S. McGuirk, J. St-Pierre, O. Larsson, I. Topisirovic, H. Vali, H.M. McBride, J.J. Bergeron, N. Sonenberg. mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1 Molecular Cell 2017 Sep;67(6):922-935. K. Araki, M. Morita, A.G. Bederman, B.T. Konieczny, H.T. Kissick, N. Sonenberg, R. Ahmed. Translation is actively regulated during the differentiation of CD8 effector T cells Nature Immunology 2017 Sep;18(9):1046-1057. Li, X.
Yamamoto, T. Adipocyte-specific disruption of mouse Cnot3 causes lipodystrophy FEBS Lett 2017 Jan;. M. Bhat, A. Yanagiya, T. Graber, N. Razumilava, S. Bronk, D. Zammit, Y. Zhao, C. Zakaria, P. Metrakos, M. Pollak, N. Sonenberg, G. Gores, M. Jaramillo, M. Morita, T. Alain. Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells Oncotarget 2016 Jul;8(31):50542-50556. Gandin, V.
Gravel, S. P.
Porco, J. A., Jr.
Topisirovic, I. nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs Genome Res 2016 May;. V. Gandin, L. Masvidal, M. Cargnello, L. Gyenis, S. McLaughlan, Y. Cai, C. Tenkerian, M. Morita, P. Balanathan, O. Jean-Jean, V. Stambolic, M. Trost, L. Furic, L. Larose, A.E. Koromilas, K. Asano, D. Litchfield, O. Larsson, I. Topisirovic. mTORC1 and CK2 coordinate ternary and eIF4F complex assembly Nature Communications 2016 Apr;:11127-11127. A. Takahashi, S. Adachi, M. Morita, M. Tokumasu, T. Natsume, T. Suzuki, T. Yamamoto. Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity Cell Rep 2015 Dec;13(12):2756-2767. Inoue T, Morita M, Hijikata A,Fukuda-Yuzawa Y, Adachi S, Isono K, Ikawa T, Kawamoto H, Koseki H, Natsume T, Fukao T, Ohara O, Yamamoto T, Kurosaki T. CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability J Exp Med 2015 Aug;212(9):1465-1479. Fonseca, B. D.
Jia, J. J.
Graber, T. E.
Hoang, H. D.
Jensen, J. M.
Diao, I. T.
Smith, E. M.
Gonzalez, J. L.
Damgaard, C. K. La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1) J Biol Chem 2015 Jun;. El-Assaad, W.
Mohammad, A. H.
Tremblay, M. L.
Kelliher, M. A.
Teodoro, J. G. Deletion of the gene encoding G0/G 1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice Diabetologia 2015 Jan;. Rouya, C.
Duchaine, T. F.
Fabian, M. R.
Sonenberg, N. Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1 RNA 2014 Sep;. Gandin, V.
Topisirovic, I. Polysome fractionation and analysis of mammalian translatomes on a genome-wide scale J Vis Exp 2014 May;.
M. Morita, S.P. Gravel, L. Hulea, O. Larsson, M. Pollak, J. St-Pierre, I. Topisirovic. mTOR coordinates protein synthesis, mitochondrial activity and proliferation Cell Cycle 2015 Feb;14(4):473-480. Shirai, Y. T.
Yamamoto, T. Multifunctional roles of the mammalian CCR4-NOT complex in physiological phenomena Front Genet 2014 Sep;.