Département de biochimie
In our lab we have two main research interests
 Apoptosis is a form of programmed cell death that can be triggered by extracellular or intracellular signals. Apoptosis plays critical roles in a wide variety of physiological processes during embryogenesis and in the integrity and homeostasis of adult tissues. However, deregulation of apoptosis can be damaging to the organism and cause numerous human diseases including cancer.
Protein folding is a cellular process essential for life. Defects in protein folding constitute the molecular basis of numerous pathologies including cystic fibrosis, juvenile emphysema, certain types of haemophilia, Alzheimer’s disease and Parkinson’s disease. The folding of membrane and secreted proteins is a tightly regulated process that takes place at the level of the endoplasmic reticulum (ER). Protein folding in the ER is assisted by a battery of molecular chaperones and foldases that increase the efficiency and the rate of the folding process.
The ER is highly sensitive to cellular stresses that perturb cellular energy levels, changes in the redox state or Ca2+ concentration. Such stresses reduce the protein folding capacity of the ER resulting in the accumulation and aggregation of unfolded proteins, a condition referred to as ER stress. ER stresses compromise the cell’s viability. To counteract the deleterious effects of ER stress, the unfolded protein response (UPR) signal transduction pathway is activated, a mechanism that is conserved from yeast to mammalian cells. The UPR halts general protein synthesis and upregulates the transcription of genes encoding ER resident chaperones and other regulatory components of the secretory pathway, giving the cell a chance to correct the environment within the ER. However, if the damage is too strong and homeostasis cannot be restored, the UPR ultimately initiates apoptosis. A major current question regarding the cell’s response to ER stress is how the switch from pro-survival to pro-death is mechanistically decided.
Calnexin is a molecular chaperone having crucial roles in the ER, including the folding of newly synthesized proteins, quality control, and calcium homeostasis. Recently, calnexin has been implicated in apoptosis induced by ER stress in mammalian cells.
Our laboratory has demonstrated that calnexin is involved in apoptosis triggered by ER stress in the yeast Schizosaccharomyces pombe, a powerful genetic model whose genes and cellular pathways are very similar to those of human cells. Our studies provided the first direct evidence of the importance of the trans-membrane domain of calnexin and its anchoring to the ER membrane in apoptosis caused by ER stress. The current objectives of our research are: 1) Identify the molecular determinants of calnexin that are involved in apoptosis triggered by ER stress. 2) Determine the role of calnexin in apoptosis triggered by different inducing signals. 3) Identify the molecules that interact with calnexin in diverse apoptotic processes.
In our studies, we utilize the powerful approaches of yeast genetics combined with state of the art post-genomic methods as well as biochemistry and molecular biology methods. Given the similarities of S. pombe and mammalian cells in terms of the protein-folding machineries and diverse cellular processes, our research will further the current understanding of the signaling pathways regulating apoptosis due to ER stress. As such, our research will contribute to development of pharmacological strategies for the treatment of human pathologies involving ER stress.
 Cellular aging is generally defined as the progressive decline of cellular functions eventually leading to death. There are two types of cellular aging: 1) Replicative aging, which is measured as the number of divisions a cell undergoes before death. 2) Chronological aging, which is measured as the mean and maximal survival time of a non-dividing cell population.
Much remains to be elucidated about the mechanisms of aging. However, genetic studies with Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans, and mouse models revealed the conservation of regulatory mechanisms that regulate longevity. However, so far the picture is a fragmented array of individual genes. Therefore, many more studies are required to organize them into molecular signaling pathways and develop and integrated depiction of the mechanisms of cellular aging.
Our laboratory was the first to validate the fission yeast Schizosaccharomyces pombe as a model for the study of cellular aging. We demonstrated that the Sck2p kinase of S. pombe is the functional homologue of Sch9 of S. cerevisiae. Moreover, we showed the link between apoptosis and cellular aging. Our genetic model allows us to explore the pathways involved in cellular aging. Our first objective is to identify novel genes regulating chronological aging. Our second objective is to identify the interactions of the genes discovered with their cellular partners, and tol depict the cellular pathways involved. As apoptosis is involved in chronological aging, it is of great interest to assess the potential role of calnexin in this specific apoptotic pathway.
The advantage of S. pombe, our model organism, is that it possesses numerous similarities with mammalian cells in terms of basic cellular processes. Thus, our research will further the current knowledge of the basic mechanisms of the aging in mammals. Ultimately, our studies will contribute to a better understanding of the human pathologies related to cellular aging.
- Guérin R, Arsenault G, Dumont S, and Rokeach LA (2008). Calnexin is involved in apoptosis induced by ER stress in the fission yeast. Mol.Biol.Cell., sous presse.
- Hajar F, Beauregard PB, Rokeach, LA The 160 N-terminal residues of calnexin define a novel region supporting viability in Schizosaccharomyces pombe. Yeast. 24(2):89-103 (2007).
- Turcotte C., Roux A., Beauregard P.B., Guérin R., Sénéchal P., Hajjar F., Rokeach LA. The calnexin-independent state do not compensate for all calnexin functions in Schizosaccharomyces pombe. FEMS Yeast Res. (7)2: 196-208 (2007).
- Roux AE, Quissac A, Chartrand P, Ferbeyre G, Rokeach LA. Regulation of chronological aging in Schizosaccharomyces pombe by the protein kinases Pka1 and Sck2. Aging Cell. 5(4): 345-57 (2006).
- Collin P, Beauregard PB, Elagöz A, Rokeach LA. A non-chromosomal factor allows viability of S. pombe lacking the essential chaperone calnexin. J. Cell Sci. 117: 907-918 (2004).
- Maréchal A, Tanguay P-L, Callejo M, Guérin R, Rokeach, LA. Cell viability and secretion of active proteins in Schizosaccharomyces pombe do not require the chaperone function of calnexin. Biochemical. J. 380: 441-448 (2004).
- Elagoz A, Callejo M, Armstrong J, Rokeach LA. Although calnexin is essential in S. pombe, its highly conserved central domain is dispensable for viability. J Cell Sci; 112:4449-60 (1999).