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 stimulates 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-depenedent control of mRNA translation and degradation in cancer and metabolic diseases. We have developed a genome-wide analyses 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 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.
*,#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, 67 (2017) 922-935. *First and #Co-Corresponding authors.
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, Nat Immunol, 18 (2017) 1046-1057.
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, 8 (2017) 50542-50556. *Co-Corresponding authors.
X. Li, M. Morita, C. Kikuguchi, A. Takahashi, T. Suzuki, T. Yamamoto, Adipocyte-specific disruption of mouse Cnot3 causes lipodystrophy, FEBS letters, 591 (2017) 358-368.
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, Nat Commun, 7 (2016) 11127.
T. Inoue, M. Morita, A. Hijikata, Y. Fukuda-Yuzawa, S. Adachi, K. Isono, T. Ikawa, H. Kawamoto, H. Koseki, T. Natsume, T. Fukao, O. Ohara, T. Yamamoto, T. Kurosaki, CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability, J Exp Med, 212 (2015) 1465-1479.
*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 (review), 14 (2015) 473-480. *Co-First authors.
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, 13 (2015) 2756-2767.
C. Watanabe, M. Morita, T. Hayata, T. Nakamoto, C. Kikuguchi, X. Li, Y. Kobayashi, N. Takahashi, T. Notomi, K. Moriyama, T. Yamamoto, Y. Ezura, M. Noda, Stability of mRNA influences osteoporotic bone mass via CNOT3, Proc Natl Acad Sci USA, 111 (2014) 2692-2697.
C. Rouya, N. Siddiqui, M. Morita, T.F. Duchaine, M.R. Fabian, N. Sonenberg, Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1, RNA, 20 (2014) 1398-1409.
M. Morita, S.P. Gravel, V. Chenard, K. Sikstrom, L. Zheng, T. Alain, V. Gandin, D. Avizonis, M. Arguello, C. Zakaria, S. McLaughlan, Y. Nouet, A. Pause, M. Pollak, E. Gottlieb, O. Larsson, J. St-Pierre, I. Topisirovic, N. Sonenberg, mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation, Cell metabolism, 18 (2013) 698-711.
Selected in “Cell Metabolism Best of 2013” and Recommended by “Faculty of 1000 in Cell Biology”
*O. Larsson, *M. Morita, *I. Topisirovic, T. Alain, M.J. Blouin, M. Pollak, N. Sonenberg, Distinct perturbation of the translatome by the antidiabetic drug metformin, Proc Natl Acad Sci USA Proceedings of the National Academy of Sciences of the United States of America, 109 (2012) 8977-8982. *Co-First authors.
M. Morita, L.W. Ler, M.R. Fabian, N. Siddiqui, M. Mullin, V.C. Henderson, T. Alain, B.D. Fonseca, G. Karashchuk, C.F. Bennett, T. Kabuta, S. Higashi, O. Larsson, I. Topisirovic, R.J. Smith, A.C. Gingras, N. Sonenberg, A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development, Molecular and cellular biology, 32 (2012) 3585-3593.
A. Takahashi, M. Morita, K. Yokoyama, T. Suzuki, T. Yamamoto, Tob2 inhibits peroxisome proliferator-activated receptor gamma2 expression by sequestering Smads and C/EBPalpha during adipocyte differentiation, Molecular and cellular biology, 32 (2012) 5067-5077.
*T. Alain, *M. Morita, B.D. Fonseca, A. Yanagiya, N. Siddiqui, M. Bhat, D. Zammit, V. Marcus, P. Metrakos, L.A. Voyer, V. Gandin, Y. Liu, I. Topisirovic, N. Sonenberg, eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies, Cancer research, 72 (2012) 6468-6476. *Co-First authors.
M. Morita, Y. Oike, T. Nagashima, T. Kadomatsu, M. Tabata, T. Suzuki, T. Nakamura, N. Yoshida, M. Okada, T. Yamamoto, Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/- mice, The EMBO journal, 30 (2011) 4678-4691.
M.R. Fabian, M.K. Cieplak, F. Frank, M. Morita, J. Green, T. Srikumar, B. Nagar, T. Yamamoto, B. Raught, T.F. Duchaine, N. Sonenberg, miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4-NOT, Nature structural & molecular biology, 18 (2011) 1211-1217.
H. Wang, M. Morita, X. Yang, T. Suzuki, W. Yang, J. Wang, K. Ito, Q. Wang, C. Zhao, M. Bartlam, T. Yamamoto, Z. Rao, Crystal structure of the human CNOT6L nuclease domain reveals strict poly(A) substrate specificity, The EMBO journal, 29 (2010) 2566-2576.
X. Yang, M. Morita, H. Wang, T. Suzuki, W. Yang, Y. Luo, C. Zhao, Y. Yu, M. Bartlam, T. Yamamoto, Z. Rao, Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity, Nucleic acids research, 36 (2008) 6872-6881.
*T. Miyasaka, *M. Morita, K. Ito, T. Suzuki, H. Fukuda, S. Takeda, J. Inoue, K. Semba, T. Yamamoto, Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex, Cancer science, 99 (2008) 755-761. *Co-First authors.
M. Morita, T. Suzuki, T. Nakamura, K. Yokoyama, T. Miyasaka, T. Yamamoto, Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth, Molecular and cellular biology, 27 (2007) 4980-4990.