Stephen Lee, Ph.D.
Professor
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Degrees
Ph.D. McGill University, Montreal, Quebec - 1994
Post-doctoral Fellow: National Cancer Institute, National Institutes of Health, Bethesda MD - 1998
Contact info:
RGN, 451 Smyth Road, Rm. 3157, Ottawa ON K1H 8M5 Phone: 562-5800 x8385 Email: slee@uottawa.ca
Scientific Environment
Our laboratory provides a vibrant bilingual environment for highly motivated students and post-doctoral Fellows. Members of my laboratory are part of a multi-discipline team trained in protein biochemistry, cell biology and molecular biology techniques to answer fundamental questions in modern molecular oncology. Successful trainees regularly publish in premier scientific journals, present their work at international forums and receive local as well as National honors and awards. The laboratory is very-well funded and equipped providing an excellent setting for creativity and productivity.
Les étudiants francophones qui sont à la recherche d’un environnement scientifique bilingue sont les bienvenus dans mon laboratoire
Research Projects
Functional Characterization of the von Hippel-Lindau Tumor Suppressor Gene Product
The von Hippel-Lindau (VHL) tumor suppressor gene was isolated in 1993 as the gene that causes the inherited VHL cancer syndrome. Individuals afflicted with VHL disease are at high risk of developing multiple, highly vascularized, tumors of the kidney, brain and eye. VHL patients inherit at conception a mutated, inactivated allele of the VHL tumor suppressor gene. Tumors arise in susceptible cells when the remaining wild-type copy of VHL acquires a somatic mutation, in keeping with Knudson's "two-hit" hypothesis of tumor suppressor genes (Fig. 1A). Biallelic inactivating mutations of the VHL gene are also found in sporadic clear cell renal cell carcinoma (RCC), the most common and deadliest form of kidney cancer in human (Fig. 1B). Approximately 12,000 Canadians suffer from RCC, another 4,000/year will be diagnosed with RCC and 1,100 will die this year alone of this disease. RCC is in dire need of fresh therapeutical approaches since patients are ultimately refractory to traditional chemical- and radiological-based therapies and generally have a bleak prognostic.
Our laboratory is divided in two main research themes.
The first theme consists of examining the subcellular trafficking properties of VHL in relationship to its tumor suppressor function. We showed that an increase in the extracellular [H+], which occurs as a consequence of anaerobic metabolism, triggers nucleolar sequestration of VHL. Nucleolar sequestration of proteins is emerging as a novel mechanism of regulation of gene expression. We reported that the nucleolar architecture is able to converts VHL from a dynamic to a static state in response to regulatory cues, such as acidosis. The data provided the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching participating proteins between a mobile and static state. We are presently investigating the role of a newly identified motif, referred to as a ‘Nucleolar Detention Sequence regulated by H+” (NoDSH+) in nucleolar detention of VHL and a wide array of different proteins including cIAP2 and DNA Polymerase.
The second theme consists of examining the mechanisms involved in tumorigenesis followed VHL loss. Work from our laboratory as revealed that HIF-2a activates a TGF-a/EGFR autocrine loop that is required for tumorigenesis following VHL-loss. Interestingly, the tumor microenvironment can also activate the same HIF-2a oncogenic pathway in many human cancers including breast, lung and ovarian. We are investigating whether HIF-2a acts as a common denominator of malignancies and if inhibition of HIF2a can prevent human cancer.
Awards
Our laboratory has been successful in securing several University and National Awards. Below is a chronological list of some of these Awards
2010- Dr. James Uniacke; Recipient of a Post-Doctoral Scholarship from the National Cancer Institute of Canada
2009- Dr. Aleksandra Franovic; Recipient of the Harold E. Johns Award from the Canadian Cancer Society for 1st Place in the National Doctoral Award Competition.
2008- Dr. Karim Mekhail; Recipient of NSERC Best Ph.D. Thesis of the Year in Canada Award
2007- Dr. Karim Mekhail; Recipient of the Governor General Gold Medal Award for Best Ph.D. Thesis at the University of Ottawa in the Natural Sciences.
2007- Ms. Aleksandra Franovic; Recipient of the Excellence in Research Award of the Faculty of Medicine of the University of Ottawa.
2007- Dr. Karim Mekhail; Represented the University of Ottawa for the National CAGS/UMI Distinguished Dissertation Award
2007- Mr. Luis Rivero; Nominated for Best M.Sc. Thesis at the University of Ottawa.
2005- Ms. Aleksandra Franovic; Recipient of the Best Poster Award in CMM .
2005- Dr. Karim Mekhail; Recipient of the Canada Award from NSERC.
2003- Ms. Natalie de Paulson; Recipient of the Best M.Sc. Thesis at the University of Ottawa.
2001- Ms. Marie-Eve Bonicalzi; Recipient of the Best M.Sc. Thesis at the University of Ottawa.
Boss
Stephen Lee, Ph.D.
Professor
- Received his Ph.D. from McGill University in 1994.
- Trained as a post-doctoral fellow in the laboratory of Dr. Richard Klausner at the National Cancer Institute, Bethesda MD.
- Joined the Department of Cellular and Molecular Medicine in 1998.
- Recipient of the Harold E. Johns Award from the National Cancer Institute of Canada
- Funded by three grants from the CIHR
Research Assistant
Josianne Payette - Laboratory Manager
Biography:
- Joined the Laboratory in 2004
- Graduated with a College Degree in Biotechnology from La Cite Collégiale in 2004
- Published published several high profile manuscripts
- Attended multiple international scientific conference
- Established a productive, responsible and convivial training environment
Trainees
Dr. Timothy Audas - Post Doctoral Fellow
Biography
2007: Ph.D Molecular and Cellular Biology, University of Guelph
2005: NSERC Postgraduate Student Scholarship
2002: B.Sc. (Hons) Molecular Biology and Genetics, University of Guelph
Dr. James Uniacke - Post Doctoral Fellow
Biography
- 2011: Best talk prize, fourth place. International Hypoxia Symposia. Lake Louise, Alberta
- 2010: Best poster prize, first place. Riboclub annual meeting. Mount-Orford, Qc
- 2009: The Terry Fox Foundation Postdoctoral Fellowship. Canadian Cancer Society, 3 years
- 2009: Ph.D. Biology, Concordia University. Supervisor: Dr. William Zerges
- 2009: Represented Concordia University as the NSERC Doctoral Prize nominee
- 2008: Best paper of the year. The Canadian Society of Plant Physiologists.
- 2008: Best seminar of the year. Riboclub monthly RNA meetings. University of Sherbrooke, Sherbrooke, Qc.
Camille Francisco - Graduate Student
Biography
- 2010: Recipient of Ontario Graduate Scholarship
- 2009-2011: University of Ottawa Excellence Scholarship
- 2009: Graduated from Carleton University: Bachelor of Science Honours Major in Integrated Science: Concentration in Forensic
- Science and a Minor Psychology (Summa Cum Laude)
Gabriel Lachance - Graduate Student
Biography:
- Present: Ph.D. in Cellular and Molecular Medicine, University of Ottawa.
- Title of Thesis: Mechanism of EPAS1 activation in human cancers.
- 2008: M.Sc. in Cellular and Molecular Biology, Sherbrooke University.
- 2005:B.Sc in Biochemistry, Université Laval
Mathieu Jacob - Graduate Student
Biography
- 2009: Present: PhD Cellular and Molecular Medicine, University of Ottawa
- 2008: Hon.B.Sc. in Genetics and Biotechnology, University of Toronto
- 2008: Manufacturing Technology intern, Sanofi Pasteur Ltd
- 2007-2008: Honours Student, Dept. of Molecular Genetics
- 2007: Research Assistant, Dept. of Chemistry
Tahmina Omar - Graduate Student
Biography
- 2009: Canadian Institute of Health Research Studentship Scholarship
- 2009: Bachelor of Science, Honours in Biopharmaceutical Sciences from the University of Ottawa.
Joseph Kishan Perera - Graduate Student
Biography
- 2011: Bsc. Honours in Biomedical Science (Magna Cum Laude)
- 2011: Ontario Graduate Scholarship
- 2011: University of Ottawa Excellence Scholarship
- 2010: endMS Studentship
- 2007-2011: University of Ottawa Admission Scholarship
- 2007-2011: Dean's Honour list
Alumni
Dr. Aleksandra Franovic
Biography
- 2004: B.Sc. Honors Biochemistry (Summa Cum Laude)
- 2004: B.A.Sc. Chemical Engineering, Biotechnology (Magna Cum Laude)
- 2005: NSERC Postgraduate Student Scholarship
- 2005: University of Ottawa Excellence Scholarship
- 2007: Research Excellence Award, Faculty of Medicine
- 2009: Recipient of the Harold E. Johns Award from the Canadian Cancer Society for 1st Place in the National Doctoral Award Competition.
- 2009: Ph.D. in Cellular and Molecular Medicine, University of Ottawa.
- 2010: Post-doctoral Fellow, UCSD
- Published several high profile scientific manuscript as first author
Mireille Khacho, Ph.D. Student
Biography
- 2000: Honors Biochemistry, University of Ottawa.
- 2003: M. Sc. in Cellular and Molecular Medicine, University of Ottawa.
- 2008: Ph.D. in Cellular and Molecular Medicine, University of Ottawa.
- 2010: Post-doctoral Fellow, University of Ottawa
- Published several high profile scientific manuscript as first author
Dr. Lakshman Gunaratnam, M.D., M.Sc.
Biography
- 2009: Assistant Professor, Western University
- 2007: Instructor, Harvard Medical School
- 2005: Canadian Institutes of Health Research Fellowship
- 2005: Royal college of Physicians and Surgeons of Canada-Canadian Research Award for Specialty Residents (Single National Award)
- 2005: Fellowship in Nephrology, Harvard Medical School/Brigham and Women’s Hospital-Massachusetts General Hospital Joint Program
- 2002: Doctorate in Medicine, University of Ottawa
- Selected Publications:
Franovic A, Gunaratnam L(equal first authorhip), Smith K, Robert I, Patten D, and Lee S. (2007) Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci. 104:13092-13097.
Mekhail K, Gunaratnam L, Bonicalzi ME, Lee S. (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nature Cell Biol. 6:642-647.
Gunaratnam L, Morley M, Franovic A, De Paulsen N, Mekhail K, Parolin DA, Nakamura E, Lorimer IA, and Lee S. (2003) HIF activates the TGF-alpha /EGF-R growth stimulatory pathway in VHL-/- renal cell carcinoma cells. J Biol Chem. 278:44966-44974.
Dr. Karim Mekhail, Ph.D.
Biography
- 2009: Assistant Professor, University of Toronto
- 2008: NSERC, Best Ph.D. Thesis in Canada
- 2007: Canadian Governor General’s Gold Medal in the Sciences (2007)
- 2006: Post-doctoral Fellow, Harvard University
- 2006: CIHR Post-doctoral Fellowship
- 2005: NSERC Canada Graduate Scholarship-Doctoral
- 2006: Ph.D. in Cellular and Molecular Medicine, University of Ottawa.
- Selected Publications:
Mekhail , K., Gunaratnam, L., Bonicalzi, M. E., and Lee, S. (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nature Cell Biol.6:642-647.
Mekhail , K., Khacho, M., Carrigan, A., Hache, R. J., Gunaratnam, L., and Lee, S. (2005) Regulation of ubiquitin ligase dynamics by the nucleolus. J. Cell Biol. 170:733-744.
Mekhail , K., Rivero-Lopez, L., Al-Masri, A., Brandon, C., Khacho, M., and Lee, S. (2007) Identification of a common subnuclear localization signal. Mol. Biol. Cell 18:3966-3977.
Recent Relevant Publications
(Trainees in my laboratory are underlined).
- Audas, T., Jacob, M., and Lee, S. (2011) Immobilization of proteins by non-coding RNA. Mol. Cell 45:147-157
- Franovic, A., Holterman, C., and Lee, S. (2009) Human cancers converge at the HIF-2a oncogenic axis. Proc. Natl. Acad. Sci USA (track II)106:21306-21311
- Citation in Faculty of 1000 for exceptional conceptual advance in the field - Khacho, M., Mekhail, K., Pilon-Larose, K., Payette, J., and Lee, S. (2008) Cancer-causing mutations in the novel transcription-dependent nuclear export motif of VHL abrogates oxygen-dependent degradation of HIF. Mol. Cell. Biol. 28:302-314.
- Franovic, A., Gunaratnam, L., Smith, K., Robert, I., Patten, D., and Lee, S. (2007) Translation upregulation of EGFR by hypoxia provides a non-mutational explanation for its overexpression in human cancer. Proc. Natl. Acad. Sci USA (track II) 104:13092-13097.
- Mekhail, K., Khacho, M., Carrigan, A, Hache, R. J., Gunaratnam, L., and Lee, S. (2005) Regulation of ubiquitin ligase dynamics by the nucleolus. J. Cell. Biol. 170:733-744.
- Citation in Faculty of 1000 for exceptional conceptual advance in the field
- See “Bound and Gagged” Nature 437:298.
- See “Hiding Proteins in the Nucleolus: J. Cell. Biol. 170:696. - Mekhail, K., Gunaratnam, L., Bonicalzi, M. E. and Lee, S. (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nature Cell. Biol. 6: 642-647.
- Four (4) citations in Faculty of 1000.
- Nature Paper of the Month in Stress Signaling.
See "Policing Cells Under Stress: Noncoding RNAs Capture Proteins in Nucleolus Detention Centers". Mol. Cell 45:141-142
Citation in Faculty of 1000 for exceptional conceptual advance in the field
Last update: 06/14/2011