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Frank S. Lee, MD, PhD
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Professor of Pathology and Laboratory Medicine
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Department: Pathology and Laboratory Medicine
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Graduate Group Affiliations
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Contact information
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Department of Pathology and Laboratory Medicine
23 Perelman School of Medicine
23 University of Pennsylvania
1f 509 Stellar Chance Labs
36 422 Curie Boulevard
Philadelphia, PA 19104
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23 Perelman School of Medicine
23 University of Pennsylvania
1f 509 Stellar Chance Labs
36 422 Curie Boulevard
Philadelphia, PA 19104
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Office: (215) 898-4701
34 Fax: (215) 573-2272
34 Lab: (215) 898-4700
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34 Fax: (215) 573-2272
34 Lab: (215) 898-4700
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Publications
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Education:
21 9 B.A. 19 (Biochemistry) c
29 Harvard College , 1983.
21 a Ph.D. 21 (Biological Chemistry) c
2b Harvard University, 1991.
21 9 M.D. 15 (Medicine) c
2f Harvard Medical School, 1991.
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21 9 B.A. 19 (Biochemistry) c
29 Harvard College , 1983.
21 a Ph.D. 21 (Biological Chemistry) c
2b Harvard University, 1991.
21 9 M.D. 15 (Medicine) c
2f Harvard Medical School, 1991.
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Links
123 Search PubMed for articles
a5 Cell and Molecular Biology graduate group faculty webpage.
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Permanent link123 Search PubMed for articles
a5 Cell and Molecular Biology graduate group faculty webpage.
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6c Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human high-altitude adaptation
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84a 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 collaborated with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University Belfast to examine 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. More recently, we have been 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. The current interest of my laboratory is in determining whether high altitude HIF pathway mutations may offer protection against complications of pregnancy, including intrauterine growth restriction and preeclampsia. Our studies have provided insights into how the HIF pathway is altered in humans. We employ biochemical, molecular biologic, and mouse model approaches.
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17 Lab Personnel:
2a Frank Lee (Principal investigator)
34 Daisheng Song (Senior Research Investigator)
27 Manuela Palacio (Undergraduate)
27 Daisy Lockshire (Undergraduate)
27 Jake Brewington (Undergraduate)
2f Dawn Williams (Administrative Assistant)
65
1a 29
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Description of Research Expertise
53 Research Interests: Molecular mechanisms of the hypoxic response.8
6c Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human high-altitude adaptation
8
84a 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 collaborated with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University Belfast to examine 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. More recently, we have been 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. The current interest of my laboratory is in determining whether high altitude HIF pathway mutations may offer protection against complications of pregnancy, including intrauterine growth restriction and preeclampsia. Our studies have provided insights into how the HIF pathway is altered in humans. We employ biochemical, molecular biologic, and mouse model approaches.
8
17 Lab Personnel:
2a Frank Lee (Principal investigator)
34 Daisheng Song (Senior Research Investigator)
27 Manuela Palacio (Undergraduate)
27 Daisy Lockshire (Undergraduate)
27 Jake Brewington (Undergraduate)
2f Dawn Williams (Administrative Assistant)
65
Description of Clinical Expertise
21 Medical pathology1a 29
23
1e0 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, July 2023 Notes: #These authors contributed equally to this work. *These authors jointly supervised the work, corresponding authors.
ab Song D., Peng K., Palmer B.E., & Lee F.S.: The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α 3b EMBO J 41: e112059, November 2022.
100 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, Feb 2021.
16f 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, June 2020.
e5 Bigham, A.W., & Lee, F.S.: Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes & Dev 28(20): 2189-2204, Oct 2014 Notes: doi: 10.1101/gad.250167.114. 14
fe 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 7e J. Biol. Chem. 289(21): 14656–14665, May 2014 Notes: doi: 10.1074/jbc.M113.541227. Epub 2014 Apr 7.
173 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, Jan 2008 Notes: Cited as “Exceptional” by Faculty of 1000 Medicine. doi: 10.1056/NEJMoa073123.
1a0 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, Jan 2006 Notes: Comment in J. Am. Soc. Nephrol. *Equal senior coauthors. Epub 2006 Jan 9.
fd 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, Aug 2001.
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Selected Publications
c1 Lee, F.S.: Hypoxia Inducible Factor pathway proteins in high-altitude mammals. Trends Biochem. Sci. 49: 79-92, Jan 2024.1e0 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, July 2023 Notes: #These authors contributed equally to this work. *These authors jointly supervised the work, corresponding authors.
ab Song D., Peng K., Palmer B.E., & Lee F.S.: The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α 3b EMBO J 41: e112059, November 2022.
100 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, Feb 2021.
16f 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, June 2020.
e5 Bigham, A.W., & Lee, F.S.: Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes & Dev 28(20): 2189-2204, Oct 2014 Notes: doi: 10.1101/gad.250167.114. 14
fe 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 7e J. Biol. Chem. 289(21): 14656–14665, May 2014 Notes: doi: 10.1074/jbc.M113.541227. Epub 2014 Apr 7.
173 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, Jan 2008 Notes: Cited as “Exceptional” by Faculty of 1000 Medicine. doi: 10.1056/NEJMoa073123.
1a0 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, Jan 2006 Notes: Comment in J. Am. Soc. Nephrol. *Equal senior coauthors. Epub 2006 Jan 9.
fd 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, Aug 2001.
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