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.
Frank Lee (Principal investigator)
Daisheng Song (Senior Research Investigator)
Bradleigh Navalsky (Research Specialist)
Wei Guan (Visiting Scholar)
Andrew Ravaschiere (Undergraduate)
Cassandra Ingersoll (Undergraduate)
Dawn Williams (Administrative Assistant)
Sinnema, M., Song, D., Guan, W., Janssen, J.W.H., van Wijk, R., Navalsky, B.E., Peng, K., Donker, A.E., Stegmann, A.P.A., & Lee, F.S.: Loss-of-function zinc finger mutation in the EGLN1 gene associated with erythrocytosis
Blood 132 : 1455-1458,2018.
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 (18): 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 (24): 2316-2323,2016.
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.
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 (24): 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 (14): 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 (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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