As a biochemist, I am interested in the molecular events that control cellular responses to external stimuli – the field of research is ‘signal transduction’, and it has applications in virtually any disease. The overall aim of our studies is to identify key enzymes and molecules that play functional roles in cell regulation, with the hope that these could be targeted therapeutically in disease states. Our studies can contribute to a better understanding of cellular growth and survival, with relevance to cancer, cardiovascular and many other diseases. Our model systems range from macrophages that respond to oxidized LDL to cytokine-dependent cells of the blood, and fibroblasts from tendon tissue.
signal transduction; programmed cell death (apoptosis); protein kinases; phosphorylation networks; oxidized LDL and macrophages in atherosclerosis; gene regulation
Our body is made up of millions of cells that together form our organs and tissues. While every cell has a full complement of all the genes that make us humans, there are many differences among the cells; for example, a blood cell has very different activities compared to a muscle cell or a brain cell. Each of the cell types develops and then functions as it does as a result of the sub-set of genes that are active in that cell. Each of the genes makes a protein that has its own specific function. Our studies are elucidating how many of the signals that are received by cells, whether from hormones or growth factors, or from other factors in the cell’s surroundings, contribute to the cells’ overall survival and growth potential. In many cases, enzyme action transmits signals into cells in a complex network of responses based on many interactions among the proteins. It is the sum total of this network of interacting molecules that our research aims to understand. Each of the key signalling molecules may serve as a potential target for therapies that may correct mistakes that serve as the underlying cause of a disease.
1. Vilimek, D. and Duronio, V. Cytokine-stimulated phosphorylation of GSK-3 is primarily dependent upon PKC’s rather than PKB. Biochem. Cell Biol., 84, 20-29 (2006).
2. Marotta, A., Parhar, K., Hundal, R., DuronioV. and Salh, B. Differential Targeting of Protein Kinase B in Cell Death Induced by Sulindac And Its Metabolite Sulindac Sulfide. Intl. J. Oncology, 28:1471-1479 (2006).
3. Demirjian, L., Abboud, R.T., Li, H. and Duronio, V. Acute effect of cigarette smoke on TNF-alpha release by macrophages mediated through the erk1/2 pathway. Biochem. Biophys. Acta 1762: 592-597 (2006).
4. Lian, O., Scott, A., Duronio, V., Khan, K. and Bahr, R. Excessive apoptosis in patellar tendinopathy in athletes. Am. J. Sports Medicine. 35: 605-11 (2007).
5. Behzad, H., Jamil, S., Denny, T.A., and Duronio, V. Cytokine-mediated FOXO3a phosphorylation suppresses FasL expression in hemopoietic cell lines. Investigation of the role of Fas in apoptosis due to cytokine starvation. Cytokine 38: 74-83 (2007).
6. Wang, S.W., Parhar, K., Chiu, K.J., Tran, A., Gangoiti, P., Kong, J., Gonzalez, M., Salh, B., Duronio, V., Steinbrecher, U.P., Gomez-Munoz, A. Pertussis toxin promotes macrophage survival through inhibition of acid sphingomyelinase and activation of the phosphoinositide 3-kinase/protein kinase B pathway. Cellular Signalling. 19: 1772-83 (2007).
7. Ong, C.J., Ming-Lum, A., Nodwell, M., Ghanipour, A., Yang, L., Williams, D.E., Kim, J., Demirjian, L., Qasimi, P., Ruschmann, J., Cao, L.P., Ma, K., Chung, S.W., Duronio, V., Andersen, R.J., Krystal, G., Mui, A.L. Small molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood. 110:1942-9 (2007).
8. Scott, A., Cook, J.L., Hart, D.A., Walker, D.C., Duronio, V., Khan, K.M. Tenocyte responses to mechanical loading in vivo: a role for local insulin-like growth factor 1 signaling in early tendinosis in rats. Arthritis Rheum. 56:871-81 (2007).
9. Germain, M. and Duronio, V. The amino terminus of the anti-apoptotic BCL-2 homologue MCL-1 regulates its localization and function. J. Biol. Chem. 282: 32233-32242 (2007).
10. Mojtahedi, A., Salehi, R., Navabakbar, F., Tamizifar, H., Tavakkoli, H. and Duronio, V. Evaluation of apoptosis induction using PARP cleavage on gastric adenocarcinoma and fibroblast cell lines by different strains of Helicobacter pylori. Pak. J. Biol. Sci. 10(22): 4097-4102 (2007).
11. Forouzandeh, F., Jalili, R.B., Germain, M., Duronio, V. and Ghahary, A. Differential immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO) on primary human CD4(+) and CD8 (+) T cells. Mol. Cell. Biochem. 309: 1-7 (2008)
12. Scott, A., Lian, O., Roberts, C.R., Cook, J.L., Handley, C.J., Bahr, R., Samiric, T., Ilic, M.Z., Parkinson, J., Hart, D.A., Duronio, V. and Khan, K.M. Increased versican content is associated with tendinosis pathology in the patellar tendon of athletes with jumper’s knee. Scand J Med Sci Sports. 18:427-35 (2007).
13. Germain, M., Milburn, J. and Duronio, V. MCL-1 inhibits BAX in the absence of MCL-1/BAX interaction. J. Biol. Chem. 283(10): 6384-6392 (2008).
14. Ma, K., Cheung, S.M., Marshall, A.J. and Duronio, V. PI(3,4,5)P3 and PI(3,4)P2 levels correlate with PKB/akt phosphorylation at Thr308 and Ser473, respectively; PI(3,4)P2 levels determine PKB activity. Cellular Signalling, 20: 684-694 (2008).
15. Forouzandeh, F., Jalili, R.B., Germain, M., Duronio, V. and Ghahary, A. Skin cells, but not T cells, are resistant to Indoleamine 2,3-Dioxygenase (IDO) Expressed by Allogeneic Fibroblasts. Wound Repair and Regeneration16: 379-387 (2008).
16. Scott, A., Lian, Ø., Bahr, R., Hart, D.A. and Duronio, V. VEGF Expression in Patellar Tendinopathy: A Preliminary Study. Clinical Orthopaedics and Related Research, 466(7):1598-1604 (2008).
17. Jamil S, Mojtabavi S, Hojabrpour P, Cheah S, Duronio V. An Essential Role for MCL-1 in ATR-mediated CHK1 Phosphorylation. Mol. Biol. Cell. 19(8):3212-20 (2008).
18. Chen JH, Riazy M, Smith EM, Proud CG, Steinbrecher UP, Duronio, V. Oxidized LDL-mediated macrophage survival involves elongation factor 2-kinase. Art. Thromb. Vasc. Biol. 29(1): 92-98 (2009).
19. Schaeffer DF, Riazy M, Parkar KS, Chen JH, Duronio V, Sawamura T, Steinbrecher UP. LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma. J. Lipid Res. 50: 1676-1684 (2009).
20. Astanehe A, Finkbeiner MR, Hojabrpour P, To K, Fotovati A, Shadeo A, Stratford AL, Lam WL, Berquin IM, Duronio V, Dunn SE. The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1. Oncogene 28: 2406-18 (2009).
21. Higo T, Duronio V, Tudan C, Burt HM, Jackson JK. Calcium pyrophosphate dihydrate crystal-induced inhibition of neutrophil apoptosis: involvement of Bcl-2 family members. Inflamm. Res. 59: 71-81 (2010).
22. Chen, J.H. Riazy, M., Wang, S.W., Dai, J.M., Duronio, V. and Steinbrecher, U.P. Sphingosine kinase regulates oxidized low density lipoprotein mediated calcium oscillations and macrophage survival. J. Lipid Res. 51: 991-998 (2010).
23. Prevention of cytokine withdrawal-induced apoptosis by MCL-1 requires synergistic interaction between Mcl-1 and Bim. Jamil, S., Wang, S., Bondy, L., Mojtabavi, S. and Duronio, V. Biochem. Cell Biol. 88: 809-18 (2010).
24. MCL-1 localizes to sites of DNA damage and regulates DNA damage response. Jamil, S., Hackett, T-L., Stoica, AC. and Duronio, V. Cell Cycle 9:2843-55 (2010).
25. OxLDL-mediated survival of macrophages does not require LDL internalization or signalling by majorpattern recognition receptorsRiazy, M., Chen, J.H., Yamamato, Y., Yamamato, H., Duronio, V. and Steinbrecher, U.P. Biochem. Cell Biol. 89, 387-395 (2011).
BC Lung Association/Medical Research Council Scientist, 1993-98
BC Lung Association/Medical Research Council (CIHR) Senior Scientist, 1998-2003
MIchael Smith Foundation for Health Research Senior Scholar