Description of Research Expertise

Research Interests: Molecular mechanisms of the hypoxic response.

Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human high altitude 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, erythropoietin, endothelin, and vascular endothelial growth factor. HIF is regulated by a distinctive mechanism. Under normoxic conditions, the enzyme PHD2 prolyl hydroxylates the alpha subunit of HIF (HIF-α), 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 PHD2 is regulated, and in understanding the physiologic relevance of the pathway. 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 red cell mass in humans. We are also interested in understanding how this pathway is genetically altered in human populations that have adapted to the chronic hypoxia of high altitude. Tibetans possess PHD2 mutations. We have found that this results in differential effects on the interactions of PHD2 with two proteins, p23 and NACA. This could account for why Tibetans have augmented hypoxic ventilatory responses but are not predisposed to erythrocytosis. Andeans possess a HIF-2α mutation. We have found that this impairs heterodimerization with ARNT and results in a partial loss of function. These studies have provided insights into how the HIF pathway is altered in humans. We employ biochemical, molecular biologic, and mouse model approaches.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior Research Investigator)
Manuela Palacio (Undergraduate)
Daisy Lockshire (Undergraduate)
Jake Brewington (Undergraduate)
Dawn Williams (Administrative Assistant)

Selected Publications

Lee, F.S.: Hypoxia Inducible Factor pathway proteins in high-altitude mammals Trends Biochem. Sci. 49 : 79-92,2024.

Jorgensen, K.#, Song, D.#, Weinstein, J., Garcia, O.A., Pearson, L.N., Inclan, M., Rivera-Chira, M., Leon-Velarde, F., Kiyamu, M., Brutsaert, T.D., Bigham, A.W.*, and Lee, F.S.*: High-Altitude Andean H194R HIF2A Allele is a Hypomorphic Allele. Mol. Biol. Evol. 40 : msad162,2023.

Song D., Peng K., Palmer B.E., & Lee F.S.: The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α EMBO J 41 : e112059,2022.

Song, D., Bigham, A.W., & Lee, F.S.: High-altitude deer mouse Hypoxia inducible factor-2α shows defective interaction with CREB-binding protein. J. Biol. Chem. 296 : 100461,2021.

Song, D., Navalsky, B.E., Guan, W., Ingersoll, C., Wang, T., Loro, E., Eeles, L., Matchett, K.B., Percy, M.J., Medina, R.J., Khurana, T.S., Bigham, A.W., Lappin, T.R., & Lee, F.S.: Tibetan PHD2, an allele with loss of function properties Proc. Natl. Acad. Sci. USA 117 : 12230-12238,2020.

Bigham, A.W., & Lee, F.S.: Human high-altitude adaptation: forward genetics meets the HIF pathway Genes & Dev 28 (20): 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 (21): 14656–14665,2014.

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 (2): 162-168,2008.

Percy M.J., Zhao Q., Flores A., Harrison C., Lappin T.R., Maxwell P.H., McMullin M.F.*, & Lee F.S.*: A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 103 (3): 654-659,2006.

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 (17): 9630-9635,2001.

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Academic Contact Information

Department of Pathology and Laboratory Medicine
Perelman School of Medicine
University of Pennsylvania
509 Stellar Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104
Phone: 215-898-4701