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Frank S. Lee, MD, PhD

Frank S. Lee, MD, PhD Physician

Associate Professor of Pathology and Laboratory Medicine

Dr. Lee is a Penn Medicine employed physician.

Clinical Specialties


  • Pathology and Laboratory Medicine

Programs & Services:

  • Pathology and Laboratory Medicine
    • Anatomic Pathology
    • Immunobiology and Experimental Pathology

Board Certification:

  • Pathology - Anatomic Pathology, 1994

Clinical Interests

Medical (autopsy) pathology

Practice Locations and Appointments

Insurance Accepted

  • Aetna US Healthcare
  • Cigna
  • Cigna HealthSpring
  • Devon Health Services (Americare)
  • Gateway Health Plan
  • Geisinger Health Plan
  • HealthAmerica / HealthAssurance, a Coventry Plan
  • HealthPartners
  • HealthSmart
  • Highmark Blue Shield
  • Horizon Blue Cross Blue Shield of New Jersey
  • Humana / Choicecare
  • Independence Blue Cross (Keystone East)
  • Intergroup
  • Keystone First
  • Multiplan
  • NJ Medicaid
  • NJ Qualcare
  • Oxford Health Plan
  • PA Medicaid
  • PA Medicare
  • Preferred Care
  • Rail Road Medicare / Palmetto GBA
  • Tricare
  • United Healthcare
  • UnitedHealthcare Community Plan
  • US Family Health Plan

Education and Training

Medical School: Harvard Medical School
Residency: Brigham and Women's Hospital
Fellowship: Brigham and Women's Hospital


American Association for the Advancement of Science, National American Federation for Aging Research National Scientific Advisory Council, National American Society for Biochemistry and Molecular Biology, National NIH Cellular Signaling and Regulatory Systems Study Section, National NIH Challenge Grants Special Emphasis Panel ZRG VH D (58), National NIH Drug Discovery Special Emphasis Panel, ZRG1 MDCN-B (91), National NIH General Medicine B Study Section, National NIH Stem Cell and Developmental Biology Special Emphasis Panel, ZRG1 BDA-P (90) S, National


Dr. Lee is a Penn Medicine employed physician.

Hospital Privileges:

  • Hospital of the University of Pennsylvania: Has privileges to treat patients in the hospital.
  • Penn Presbyterian Medical Center: Has privileges to treat patients in the hospital.
  • Pennsylvania Hospital: Has privileges to treat patients in the hospital.


Research Interests:

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.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior research investigator)
Patrick Arsenault (NIH T32 Postdoctoral fellow)
Andrew Ravaschiere (Undergraduate)
Marla Knob (Administrative assistant)

Selected Publications:

Arsenault, P.R., Heaton-Johnson, K.J., Li, L.-S., Song, D., Ferreira, V.S., Patel, N., Master, S.R.*, & Lee, F.S.*. * Equal senior coauthors.: Identification of Prolyl Hydroxylation Modifications in Mammalian Cell Proteins. Proteomics 15 : 1259-1267,2015.

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.

Lee, F.S., & Percy, M.J.: The HIF Pathway and Erythrocytosis (review) Ann. Rev. Pathology 6 : 165-192,2011.

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.

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.

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

View all publications

Academic Contact Info

Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
605 Stellar Chance Labs
422 Curie Boulevard

Philadelphia, PA 19104
Phone: (215) 898-4701
Fax: (215) 573-2272

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