Professor; Department of Oncology
Control of protein synthesis, environmental stress, tumor suppressor genes, oncogenes, signal transduction, protein phosphorylation, breast cancer, chemotherapeutic drugs.
Accepting graduate students
Department of Oncology
Lady Davis Institute for Medical Research
Room 508
Sir Mortimer B. Davis-Jewish General Hospital
3755 Côte-Ste-Catherine Road
Montreal, QC H3T 1E2
Tel: (514) 340-8222 x.3697 (office) 4994 (lab 1) 5653 (lab 2)
Fax: (514) 340-7576
antonis [dot] koromilas [at] mcgill [dot] ca (Email)
Biography
Dr. Koromilas was born in Larissa, Greece. He graduated from the Aristotelian University of Thessaloniki, Greece, with a B.Sc. in Chemistry in 1984 and a Ph.D. in Biochemistry in 1988. His undergraduate studies were supported by a studentship from the Hellenic State Scholarship Foundation (IKY). In 1987, he was awarded a short-term fellowship from the European Molecular Biology Organization (EMBO) for training in Cellular Immunology at Stockholm University, Sweden. After his graduation in 1988, he joined Tasuku Honjo’s group in Kyoto University, Japan, for post-doctoral studies in Molecular Biology and Immunology. During his stay in Japan, Dr. Koromilas was supported by fellowships from the Toyobo Biotechnology Foundation and Ciba-Geigy Foundation for Promotion of Science. He moved to Montreal in 1990 for his second post-doctoral training with Nahum Sonenberg in Biochemistry, McGill University. His training in the Sonenberg lab was supported by an international fellowship from the Human Frontier Science Program Organization. In July 1993, he was appointed Assistant Professor in the Department of Oncology, Faculty of Medicine, McGill University and Project Director at Lady Davis Institute-Sir Mortimer B. Davis Jewish General Hospital. He was promoted to Associate Professor with tenure in June 1999 and became full Professor in June 2006. As an independent investigator (1993-to date), Dr. Koromilas has won several awards including an international Scholarship from the American Foundation for AIDS Research (AmFAR) in 1993, a Chercheur Boursier Fonds de la Recherché en Sante du Quebec (FRSQ) in 1997, a Scientist award from the Canadian Institute for Health Research (CIHR) in 1998 and a Visiting Scientist award from the Japanese Society for the Promotion of Science (JSPS) in 2003. Since his initial appointments with McGill University and Lady Davis Institute, Dr. Koromilas’s research has been supported by national (i.e. National Cancer Institute of Canada, Health and Welfare of Canada, Canadian Institutes for Health Research, Cancer Research Society of Canada, Canadian Foundation for AIDS Research, Canadian Breast Cancer Research Alliance, Quebec Foundation of Breast Cancer) and international research grants (American Foundation for AIDS Research, Human Frontier Science Program Organization). Since 1993, his lab has published 52 peer review articles in international and high impact factor journals. Dr. Koromilas is currently a member of the Editorial Board of the Journal of Biological Chemistry published by the American Society for Biochemistry and Molecular Biology (2005-10).
Research Orientations
A brief summary of research interests
My lab investigates (i) the functions of eIF2α kinases in regulation of protein synthesis, cell proliferation and apoptosis in response to various forms of environmental stress including virus infection, genotoxic stress as well as oncogenic stress and (ii) the tumor suppressor properties of transcription factor Stat1 in response to oncogenic insults that contribute to the development of various forms of cancer with emphasis on breast cancer.
Brief outlines of my projects are as follows:
1. The function of eIF2α kinases in regulation of tumor suppressor p53 and tumor microenvironment.
The eIF2α kinases are important determinants of cell survival as well as cell death. Short-term induction of eIF2α kinase activity can lead to induction of pro-survival pathways. However, prolonged activation of eIF2α kinases is pro-apoptotic as a result of protein synthesis inhibition due to phosphorylation of eIF2α at serine 51. Our studies demonstrated the ability of eIF2α kinases to exhibit a cytoprotective function in response to distinct forms of stress that converge on the tumor suppressor p53. That is, eIF2α kinase activation is response to DNA damage conveys a cytoprotective effect by inducing p53-dependent G1 arrest and limiting p53-dependent apoptosis (Cuddihy et al., 1999b; Cuddihy et al., 1999a). On the other hand, activation of eIF2α kinases by endoplasmic reticulum (ER) stress or virus infection compromises the pro-apoptotic function of p53 (Qu et al., 2004; Qu and Koromilas, 2004; Pluquet et al., 2005). They do so by downregulating p53 protein levels independently of inhibition of protein synthesis through the activation of glycogen synthase kinase 3 beta (GSK-3β) and consequently the proteolytic degradation of p53 by Mdm2 (Baltzis et al., 2007).
Current work on this project investigates the biological significance of eIF2α kinase activation under conditions that mimic tumor microenvironment, such as hypoxia and nutrient deprivation. We use mouse and human model systems to characterize the roles of eIF2α kinases in cell survival or cell death in response to glucose deprivation or inhibition of glycolysis and examine the role of p53 in this process. We also investigate the ability of eIF2α kinases to respond to genotoxic stress in cells with inactivated p53 and the biological relevance of this process for therapies aimed at destruction of tumors with mutant p53. Also, we examine the ability of eIF2α kinases to regulate gene expression in hypoxic cells and particularly the regulation of expression and function of hypoxia inducible factor 1alpha (HIF-1α).
2. The function of eIF2α kinases downstream of PI3K-Akt-mTOR pathway.
My lab demonstrated that the pro-survival properties of eIF2α kinases are associated with a transient induction of the phosphoinositide kinase-3 (PI3K) signaling, which is eventually counteracted by eIF2α phosphorylation and inhibition of protein synthesis (Kazemi et al., 2007). Based on these findings, we investigate the mechanisms of PI3K activation by examining the ability of eIF2α kinases to regulate the function of PI3K or tumor suppressor PTEN. In addition, we examine the possible role of eIF2α kinases in mediating the anti-proliferative effects caused by the disruption of PI3K signaling as a result of PTEN activation or treatment with chemotherapeutic drugs targeting PI3K, Akt or mTOR. Finally, we examine the possible implication of eIF2α phosphorylation pathway in tumor therapies with chemotherapeutic drugs that inactivate PI3K signaling or in combination chemotherapies that inactivate the PI3K pathway and induce genotoxic stress.
3. The function of eIF2α phosphorylation pathway in development and treatment of Erb2-mediated breast tumorigenesis.
This project is based on observations that eIF2α kinase activity is elevated in human breast tumors. Given the pro-survival as well as pro-apoptotic properties of eIF2α kinases, we seek to determine whether oncogenic signaling responsible for breast tiumorigesesis, such as Erb2/Her-2 signaling, engages eIF2α kinases with implications in the development or treatment of breast cancer. To this end, we use mouse models of Erb2/Her2 tumorigenesis deficient in eIF2α kinase activity or phosphorylation of eIF2α at serine 51 to examine the oncogenic properties of Erb2/Her2. We also examine the response of eIF2α kinases to chemotherapeutic drugs targeting Erb2/Her2 and the biochemical properties that underlie the functional interplay between Erb2/Her2 and eIF2α phosphorylation. More specifically, we investigate the ability of eIF2α kinases to be regulated by tyrosine phosphorylation (Su et al., 2006; Su et al., 2008) and the implications of this property in Erb2/Her2 signaling and treatment with chemotherapeutic drugs.
4. The function of Stat1 in oncogenic signaling induced in breast tumors. The transcription factor Stat1 plays an important role in innate immunity and tumor immunosurveillance. Stat1 exhibits strong anti-viral, anti-proliferative and tumor suppressor functions. Most of these functions of Stat1 have been characterized in association with the production and action of interferons (IFNs). Interestingly, activated Stat1, as judged by its phosphorylation, has been observed in various types of human tumors including breast tumors. We have been investigating the role of Stat1 phosphorylation in oncogenic signaling induced in breast tumors. We have discovered that Stat1 phosphorylation is an important determinant in suppression of oncogenic Ras (Wang et al., 2008). That is, site specific phosphorylation can convert Stat1 from a suppressor to a promoter of Ras-mediated oncogenesis through the regulation of p27Kip1 expression (Wang et al., 2008). Current work focuses on the role of Stat1 in Erb2/Her2-mediated oncognesis using tissue culture and transgenic mouse approaches.
Selected Recent Publications
Baltzis,D., Pluquet,O., Papadakis,A.I., Kazemi,S., Qu,L.K., and Koromilas,A.E. (2007). "The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53." J. Biol. Chem. 282, 31675-31687.
Cuddihy,A.R., Li,S., Tam,N.W., Wong,A.H., Taya,Y., Abraham,N., Bell,J.C., and Koromilas,A.E. (1999a). "Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53." Mol Cell Biol 19, 2475-2484.
Cuddihy,A.R., Wong,A.H., Tam,N.W., Li,S., and Koromilas,A.E. (1999b). "The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro." Oncogene 18, 2690-2702.
Kazemi,S., Mounir,Z., Baltzis,D., Raven,J.F., Wang,S., Krishnamoorthy,J.L., Pluquet,O., Pelletier,J., and Koromilas,A.E. (2007). "A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway." Mol. Biol. Cell 18, 3635-3644.
Pluquet O, Qu LK, Baltzis D and Koromilas AE (2005) "Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and GSK-3beta." Mol. Cell. Biol. 25: 9392-9405.
Qu,L., Huang,S., Baltzis,D., Rivas-Estilla,A.M., Pluquet,O., Hatzoglou,M., Koumenis,C., Taya,Y., Yoshimura,A., and Koromilas,A.E. (2004). "Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta." Genes Dev. 18, 261-277.
Qu,L. and Koromilas,A.E. (2004). "Control of Tumor Suppressor p53 Function by Endoplasmic Reticulum Stress." Cell Cycle 3, 567-570.
Su Q, Wang S, Baltzis D, Qu LK, Wong AH, Koromilas AE (2006) "Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase." Proc Natl Acad Sci U S A 103:63-8.
Su,Q., Wang,S., Gao,H.Q., Kazemi,S., Harding,H.P., Ron,D., and Koromilas,A.E. (2008). "Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation." J. Biol. Chem. 283, 469-475.
Wang,S., Raven,J.F., Durbin,J.E., and Koromilas,A.E. (2008). "Stat1 phosphorylation determines Ras oncogenicity by regulating p27 kip1." PLoS. ONE. 3, e3476.