Frank S. Lee

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Associate Professor of Pathology and Laboratory Medicine
Staff Pathologist, Medical Pathology Section, Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennnsylvania
Department: Pathology and Laboratory Medicine

Contact information
Department of Pathology and Laboratory Medicine
Perelman School of Medicine
University of Pennsylvania
605 Stellar Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104
Office: (215) 898-4701
Fax: (215) 573-2272
Lab: (215) 898-4700
Graduate Group Affiliations
Education:
B.A. (Biochemistry)
Harvard College , 1983.
Ph.D. (Biological Chemistry)
Harvard University, 1991.
M.D. (Medicine)
Harvard Medical School, 1991.
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Description of Research Expertise

Research Interests: Molecular mechanisms of the hypoxic response.

Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human adaptation

Research Details: An important cellular response to hypoxia is the activation of the transcription Hypoxia Inducible Factor (HIF). HIF is a master regulator of the hypoxic response and upregulates many genes involved in hypoxic adaptation, including those encoding for enzymes of glycolysis, glucose transporters, erythropoietin, and vascular enthothelial growth factor. We are interested in the regulation and physiologic importance of this pathway. We and others have shown that HIF is regulated by a distinctive mechanism. Under normoxic conditions, the alpha subunit of HIF (HIF-α) is site-specifically hydroxylated on proline, which in turn constitutively targets HIF-α for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, this modification is inhibited, thereby allowing HIF-α to escape degradation and activate transcription. We are interested in understanding mechanisms by which the HIF prolyl hydroxylase PHD2 is regulated, and in understanding the physiologic relevance of the pathway. With regard to the latter, we have an ongoing collaboration with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University Belfast examining the molecular basis of idiopathic erythrocytosis, and this has identified critical roles for PHD2 and HIF-2α in the control of erythropoietin in humans. We are also interested in understanding the molecular basis for Tibetan adaptation to the chronic hypoxia of high altitude. We employ biochemical, molecular biologic, and mouse model approaches.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior Research Investigator)
Kai Peng (Postdoctoral Researcher)
Bradleigh Navalsky (Research Specialist)
Wei Guan (Visiting Scholar)
Andrew Ravaschiere (Undergraduate)
Dawn Williams (Administrative Assistant)

Description of Itmat Expertise

Molecular mechanisms of the hypoxic response.

Selected Publications

Arsenault, P.R., Song, D., Chung, Y.J, Khurana, T.S., & Lee, F.S. : The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 is Essential for Efficient Hydroxylation of Hypoxia Inducible Factor-alpha. Mol. Cell. Biol. 36: 2328-2343, 2016.

Arsenault, P.R., Song, D., Bergkamp, M., Ravaschiere, A.M., Navalsky, B.E., Lieberman, P.M., & Lee, F.S. : Identification of Small Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor. ChemBioChem 17: 2316-2323, 2016.

Bigham, A.W., & Lee, F.S.: Human high-altitude adaptation: forward genetics meets the HIF pathway (review). Genes & Dev 28: 2189-2204, 2014.

Song, D., Li, L.-S., Arsenault, P.R., Tan, Q., Bigham, A.W., Heaton-Johnson, K.J., Master, S.R., & Lee, F.S. : Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing J. Biol. Chem. 289: 14656–14665, 2014.

Arsenault, P.R., Pei, F., Kerestes, H., Percy, M.J., Keith, B., Simon, M.C., Lappin, T.R., Khurana, T.S., and Lee, F.S. : A Knockin Mouse Model of Human PHD2-Gene Associated Erythrocytosis Establishes a Haploinsufficiency Mechanism. J. Biol. Chem. 288: 33571-33584, 2013.

Tan, Q., Kerestes, H., Percy, M.J., Pietrofesa, R., Chen, L., Khurana, T.S., Christofidou-Solomidou, M., Lappin, T.R.J., & Lee, F.S. : Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain-of-function mutation. J. Biol. Chem. 288: 17134–17144, 2013.

Song, D., Li, L.-S., Heaton-Johnson, K.J., Arsenault, P.R., Master, S.R., & Lee, F.S. : Prolyl Hydroxylase Domain Protein 2 (PHD2) Binds a Pro-Xaa-Leu-Glu Motif, Linking it to the Heat Shock Protein 90 Pathway. J. Biol. Chem. 288: 9662-74, 2013.

Percy, M.J., Furlow, P.W., Lucas, G.W., Li, X., Lappin, T.R.J., McMullin, M.F., & Lee, F.S. : A gain of function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358: 162-168, 2008 Notes: Cited as “Exceptional” by Faculty of 1000 Medicine.

Percy M.J., Zhao Q., Flores A., Harrison C., Lappin T.R., Maxwell P.H., McMullin M.F.*, & Lee F.S.* *Equal senior coauthors: A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 103: 654-659, 2006 Notes: Comment in J. Am. Soc. Nephrol.

Yu, F., White, S.B., Zhao, Q., & Lee, F.S.: HIF-1α Binding to VHL is Regulated by Stimulus-Sensitive Proline Hydroxylation. Proc. Natl. Acad. Sci. USA 98: 9630-9635, 2001.

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Last updated: 12/01/2017
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