Description of Research Expertise:
Research Interests: Molecular mechanisms of the hypoxic response.
Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation
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 characterizing novel regulators of the HIF pathway, determining whether prolyl hydroxylation plays a more general role in the hypoxic response, 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 examining the molecular basis of idiopathic erythrocytosis, and this has identified critical roles for HIF-2α and the HIF prolyl hydroxylase, PHD2, 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.
Lab Rotation Projects:
1. Examine mechanisms by which HIF-α is regulated.
2. Determine whether proline hydroxylation plays a more general role in hypoxia.
3. Develop mouse models for examining the HIF pathway.
Frank Lee (Principal investigator)
Daisheng Song (Senior research investigator)
Patrick Arsenault (Research Associate)
Kai Peng (Postdoctoral Researcher)
Bradleigh Navalsky (Research Specialist)
Andrew Ravaschiere (Undergraduate)
Arsenault, P.R., Song, D., Chung, Y.J, Khurana, T.S., & Lee: 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: Identification of Small Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor ChemBioChem 17 : 2316-2323,2016.
Bigham, A.W., & Lee: 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: 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: 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: 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: 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: A gain of function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358 : 162-168,2008.
Percy M.J., Zhao Q., Flores A., Harrison C., Lappin T.R., Maxwell P.H., McMullin M.F.*: 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.
Yu, F., White, S.B., Zhao, Q., & Lee: 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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