The environments in which cells grow often change rapidly. Consequently, cells have evolved mechanisms for regulating their biochemistry in response to signals that indicate environmental change. For example, many fundamental biological processes such as transcription and translation are repressed during exposure to environmental stress to conserve energy. My interest in cellular adaptation to environmental cues and stresses began during my undergraduate studies at Concordia University, which led to a Ph.D. under the supervision of Dr. William Zerges. There, we used the unicellular alga Chlamydomonas reinhardtii as a model system to study the spatial organization of mRNAs and proteins during conditions of cellular stress. During this time, we identified novel mechanisms of organelle biogenesis, mRNA localization, and regulation of mRNA translation. These findings inspired me to join the laboratory of Dr. Stephen Lee at the University of Ottawa as a Terry Fox Postdoctoral Fellow to investigate the control of mRNA translation in human disease with a focus on hypoxia and cancer. The discovery that the cap-dependent protein synthesis machinery adapts to hypoxia, and that this mechanism is exploited by cancer cells exposed to low oxygen was covered by national media including the National Post and CBC. My laboratory will continue to investigate how the protein synthesis machinery adapts to environmental stresses such as hypoxia, and how cancer cells exploit the hypoxic protein synthesis machinery for tumorigenesis.
- B.Sc. Concordia University
- Ph.D. Concordia University
- PDF. University of Ottawa
Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis consists of the eukaryotic translation initiation factor 4E (eIF4E) binding to the 5’ cap of mRNAs. However, many cellular stresses repress cap-dependent translation to conserve energy by sequestering eIF4E. This raises a fundamental question in biology as to how proteins are synthesized during periods of cellular stress and eIF4E inhibition. Research in our laboratory will build upon the discovery that cells switch to an alternative cap-binding protein, eIF4E2, to synthesize the bulk of their proteins during periods of oxygen scarcity (hypoxia). One of our main focuses will be on cancer because as human tumors display considerable diversity in their genetic makeup, they share common physiological attributes such as a hypoxic microenvironment that contribute to the malignant phenotype. As oxygen only diffuses through a few layers of cells, the vast majority of cancer cells that populate a tumor are thought to be exposed to hypoxic conditions. Therefore, understanding how eIF4E2-dependent translation, a mechanism scarcely used by normal oxygenated cells, functions and contributes to the expression of the tumor cell phenotype will provide unique opportunities for cancer therapy.
Current areas of research include:
- Investigating how various cancers exploit eIF4E2-directed translation for tumorigenesis.
- Characterizing the eIF4E2 complex and understanding the mechanism of hypoxic cap-dependent translation initiation.
- Examining how the cap-dependent protein synthesis machinery adapts to diverse environmental cues.
We currently have positions open for those who are interested in studying the fundamental biological process of protein synthesis, how it adapts to stress, and how it is exploited by cancer. Our lab will provide you with the opportunity to present your work at international meetings and to gain expertise in many traditional and modern techniques in molecular biology and biochemistry including in vitro and in vivo tumor models. Interested candidates are invited to contact us.
- Kelly, N.J., Varga, J.F.A., Specker, E.J., Romeo, C.M., Coomber, B.L., Uniacke, J. (2017). Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion, and adhesion. Oncogene. (In press).
- Brasher, M.I., Martynowicz, D.M., Grafinger, O.R., Hucik, A., Shanks-Skinner, E., Uniacke, J., Coppolino, M.G. (2017). Interaction of Munc18c and Syntaxin4 facilitates invadopodium formation and extracellular matrix invasion of tumour cells. J Biol Chem. Aug 10. doi: 10.1074/jbc.M117.807438.
- *Timpano, S., *Melanson, G., Evagelou, S. L., Guild, B. D., Specker, E. J., and Uniacke, J. (2016). Analysis of cap-binding proteins in human cells exposed to physiological oxygen conditions. J. Vis. Exp. (118), e55112, doi:10.3791/55112 (2016). (*joint first author)
- Timpano, S. and Uniacke, J. (2016). Human cells cultured under physiological oxygen utilize two cap-binding proteins to recruit distinct mRNAs for translation. J. Biol. Chem. 291(20): 10772-82
- Ho, J.J.D., Wang, M., Audas, T.E., Kwon, D., Carlsson, S.K., Timpano, S., Evagelou, S.L., Brothers, S., Gonzalgo, M.L., Krieger, J.R., Chen, S., *Uniacke, J., *Lee, S. (2016). Systemic reprograming of translation efficiencies on oxygen stimulus. Cell Reports. 14(6):1293-300. (*joint senior author)
- Zhan, Y., Dhaliwal, J., Adjibade, P., Uniacke, J., Mazroui, R., and Zerges, W. (2015). Localized control of oxidized RNA. J Cell Science. 128(22): 4210-9
- Uniacke, J. (2014). Cellular adaptation to low oxygen availability by a switch in the protein synthesis machinery. Can. Y. Sci. J.2014 (3): 53-58.
- Lachance, G., Uniacke, J., Audas, TE., Holterman, CE., Franovic, A., Payette, J., and Lee, S. (2014). DNMT3a Epigenetic Program Regulates the HIF-2a Oxygen-Sensing Pathway and the Cellular Response to Hypoxia. Proc Natl Acad Sci U S A. 111(21): 7783-7788.
- Uniacke, J., Perera, JK., Lachance, G., Francisco, CB., and Lee, S. (2014). Cancer cells exploit eIF4E2-directed synthesis of hypoxia response proteins to drive tumor progression. Cancer Res. 74:1379-89.
- Jacob, MD., Audas, TE., Uniacke, J., Trinkle-Mulcahy, L., and Lee, S. (2013). Environmental cues induce a long noncoding RNA-dependent remodeling of the nucleolus. Mol Biol Cell. 24: 2943-53.
- Uniacke, J., Holterman, CE., Lachance, G., Franovic, A., Jacob, MD., Fabian, MR., Holcik, M., Pause, A., and Lee, S. (2012). An oxygen-regulated switch in the protein synthesis machinery. Nature. 486: 126-9.
- Uniacke, J., Colon-Ramos, D., and Zerges, W. (2011). FISH and immunofluorescence staining in Chlamydomonas. Methods Mol Biol. 714: 15-29.
- Uniacke, J. and Zerges, W. (2009). Chloroplast protein targeting involves; localized translation in Chlamydomonas. Proc Natl Acad Sci USA. 106: 1439-44.
- Uniacke, J. and Zerges, W. (2008). Stress induces the assembly of RNA granules in the chloroplast of Chlamydomonas reinhardtii. J Cell Biol. 182: 641-6.
- Uniacke, J. and Zerges, W. (2007). Photosystem II assembly and repair are differentially localized in Chlamydomonas. Plant Cell. 19: 3640-54.
- Sara Timpano (Ph.D.)
- Gaelan Melanson (Ph.D.)
- Andrea Brumwell (Ph.D.)
- Sonia Evagelou (M.Sc.)
- Sydney Pascetta (M.Sc.)
- Thomas Corazzola (Undergraduate Research Project)
- Lindsay Obress (Undergraduate Research Project)
- MCB*6310 - Advanced Topics in Molecular and Cellular Biology
- MBG*2040 – Foundations in Molecular Biology and Genetics
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