笔谤辞蹿别蝉蝉辞谤听
Department of Biochemistry听
Regulation of mRNA Translation and Metabolism
McIntyre Medical Sciences Building听
Office and Lab: Room 805听
3655 promenade Sir William Osler听
Montreal, Quebec H3G 1Y6听
Tel: (514)3985928听
ivan.topisirovic [at] mcgill.ca听">ivan.topisirovic [at] mcgill.ca听
M.D. (2000), Ph.D. (20003) University of Belgrade, Yugoslavia听
Research Interests听
- We combine standard molecular and cellular biology and biochemical assays with newly developed systems biology approaches to study the role of energy metabolism and mRNA translation in adaptation to stress and their dysregulation in human pathologies including cancer. To this end, we have broad interests in studying signaling, metabolism, and gene expression. Our present research focus can be summarized in the following research themes:听
I. Deciphering the role of signaling pathways in modulating mRNA translation in homeostasis and disease听
- We focus on studying the molecular mechanisms underlying the role of mRNA translation in coordination of pivotal cellular processes. To this end, we uncovered a mechanism whereby mTORC1 and CK2 coordinate the eIF4F complex assembly and ternary complex recycling, which are two rate limiting steps in translation initiation, and demonstrated that eIF2b plays a critical role in mediating the effects of mTORC1 and CK2 on proliferation [1]. Furthermore, we uncovered the 5鈥橴TR features that render mRNA translation mTOR-sensitive and dissected molecular mechanisms that explain cytostatic effects of mTOR inhibitors vs. cytotoxic effects of eIF4A inhibitors [2]. Finally, we have demonstrated a role for mTORC1/S6K/PDCD4/eIF4A axis in translational control during mitosis [3]. Collectively, these findings provided hitherto unappreciated molecular insights into the mechanisms that link protein synthesis, proliferation and neoplastic growth.听
1.听 Gandin, V., et al., mTORC1 and CK2 coordinate ternary and eIF4F complex assembly. Nat Commun, 2016. 7: p. 11127.;
2. Gandin, V., et al., nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Res, 2016. 26(5): p. 636-48.;
3. Moustafa-Kamal, M., et al., The mTORC1/S6K/PDCD4/eIF4A axis determines outcome of mitosis, Cell Reports, 2020, 33(1):108230.听
II. Coordination of translational and metabolic programs.听
- Notwithstanding that translation is one of the most energy consuming processes in the cell, how translational and metabolic programs are coordinated in mammals remained largely unknown. We uncovered a feed-forward mechanism whereby mTORC1 stimulates translation of nuclear-encoded mitochondria-related mRNAs thereby bolstering mitochondrial ATP production to fuel protein synthesis [4]. Therefore, mTORC1 maintains cellular energy balance by coordinating protein synthesis, which is the most energy consuming process in the cells and mitochondrial energy production [5]. Providing molecular basis for targeting translational machinery and metabolic vulnerabilities in cancer is one of the major focuses of our research program. To this end, we have demonstrated that the mTORC1/4E-BP/eIF4E axis plays a major role in metabolic plasticity of cancer cells which predicts therapeutic responses to kinase inhibitors and their combination with biguanides across a number of cancers [6]. We have also demonstrated that transcriptional regulator PRDM15 plays a major role in metabolic reprogramming in B-cell lymphomas [7]. Finally, we uncovered a cytoplasmic hydride ion equivalent transfer complex formed by PC, MDH1 and ME1 that regenerates NAD+ and supplies NADPH, ameliorates senescence-induced mitochondrial dysfunction and drives neoplastic growth [8].听
4. Morita, M., et al., mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation. Cell Metab, 2013. 18(5): p. 698-711.;
5. .Morita, M., et al., mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle, 2015. 14(4): p. 473-80;
6. Hulea, L., et al., Translational and HIF-1alpha-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. Cell Metab, 2018. 28(6):817-832.
7. Mzoughi, S., et al., PRDM15 is a key regulator of metabolism critical to sustain B-cell; lymphomagenesis. Nature Comm, 2020. 11(1):3701.8. Igelmann, S., et al., A Hydride transfer complex reprograms NAD metabolism preventing senescence. Mol Cell. 2021; 81(18):3848-3865.e19.听听
III. Uncovering the mechanisms of translational regulation under stress and co-translational protein quality control.
- Another major focus of our lab is to understand how protein homeostasis is maintained under stress, with a particular focus on co-translational regulation of degradation of newly synthesized polypeptides. To this end, we demonstrated that that ribosome-associated RACK1/JNK/eEF1A2 complexes regulate stability of newly synthesized polypeptides under stress [9]. We have also delineated mechanism of translational adaptation to prolonged ER-stress [10]. Moreover, we have developed methods to analyze changes in translation on a transcriptome-wide scale [11] and reported on a mechanism of translational offsetting, whereby translation acts to prevent changes in the protein levels under conditions where mRNA levels are altered [12]. We also deciphered the mechanisms of rewiring of the translational machinery during adaptation to osmotic stress) [13]. Finally, we demonstrated previously unappreciated plasticity of mammalian integrated stress response [14].听
9. Gandin, V., et al., Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex. Mol Cell Biol, 2013. 33(13): p. 2510-26.;
10. Guan, B.J., et al., A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell, 2017. 68(5): p. 885-900 e6.;
11. Oertlin, C., et al., Generally applicable transcriptome-wide analysis of translation using anota2seq. Nucleic Acids Res, 2019. 47(12): p. e70.;
12. Lorent, J., et al., Translational offsetting as a mode of estrogen receptor alpha-dependent regulation of gene expression. EMBO J, 2019. 38(23): p. e101323.;
13. Krokowski D et al., Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR. Cell Rep 40(3):111092. doi: 10.1016/j.celrep.2022.111092;
14. Chen et al, Plasticity of the Mammalian Integrated Stress Response 2025 Nature in press.听