PEOPLE

Frank S. Lee, MD, PhD

Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact InformationDepartment of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine
605 Stellar Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104
Office: (215) 898-4701
Fax: (215) 573-2272

Email: franklee@pennmedicine.upenn.edu

Specialty Division

Immunobiology and Experimental Pathology

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.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior research investigator)
Patrick Arsenault (Research Associate)
Kai Peng (Postdoctoral Researcher)
Bradleigh Navalsky (Research Specialist)
Andrew Ravaschiere (Undergraduate)





Clinical Expertise

Medical (autopsy) pathology

CVI Expertise

CVI Program Unit(s):
Lipid / Atherosclerosis / CAD / ACS / Prevention

CVI Research Description:
We are interested in the Hypoxia Inducible Factor (HIF) pathway, and whether manipulation of this pathway may offer benefit in models of ischemic heart disease.

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.

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.

Itmat Expertise

Molecular mechanisms of the hypoxic response.

Graduate Groups

Cell and Molecular Biology

Education

B.A. (Biochemistry), Harvard College , 1983
M.D. (Medicine), Harvard Medical School, 1991
Ph.D. (Biological Chemistry), Harvard University, 1991

Specialty Certification

American Board of Pathology (Anatomic Pathology), 1994

Postgraduate Training

Resident in Pathology, Brigham & Women’s Hospital, Boston, 1991-1993
Chief Resident in Pathology, Brigham &Women’s Hospital, Boston, 1993-1993
Fellow in Renal Pathology, Brigham & Women’s Hospital, Boston, 1993-1994
Postdoctoral Research Fellow, Harvard University, Cambridge, MA, 1994-1998

Awards and Honors

Detur Prize, Harvard College, 1980
Phi Beta Kappa, Harvard College, 1982
Carrington Prize in Molecular Mechanisms of Disease, Stanford University School of Medicine, 2000
Tranformative R01 (T-R01) Award, NIH, 2009-2014
F1000 Faculty Member (Hematology), 2016-Present

Memberships and Professional Organizations

American Association for the Advancement of Science, 1998 - Present
NIH General Medicine B Study Section, 2001 - 2001
Ad hoc grant reviewer for the following Review Committees: Wellcome Trust International Research Fellowship (U.K.), 2002; French National Cancer Institute, 2007; Telethon Foundation (Italy), 2007; Wellcome Trust Research Training Fellowship (U.K.), 2009; Wellcome Trust Project Grant (U.K.), 2011; Wellcome Trust Senior Investigator Award (U.K.), 2014, 2002 - 2014
American Society for Biochemistry and Molecular Biology, 2004 - Present
Jeffress Memorial Trust (Virginia), 2005 - 2005
American Federation for Aging Research National Scientific Advisory Council, 2006 - Present
University of Texas Southwestern Medical Center Promotion Committee, 2008 - 2008
Queen's University Belfast Promotion Committee, 2009 - 2009
NIH Challenge Grants Special Emphasis Panel ZRG VH D (58), 2009 - 2009
NIH Drug Discovery Special Emphasis Panel, ZRG1 MDCN-B (91), 2009 - 2009
NIH Cellular Signaling and Regulatory Systems Study Section, 2010 - 2010
NIH Stem Cell and Developmental Biology Special Emphasis Panel, ZRG1 BDA-P (90) S, 2010 - 2010
American Heart Association, 2012 - Present
University of Colorado School of Dental Medicine Promotion Committee, 2013 - 2013
American Society of Hematology, 2014 - Present
American Heart Association Peer Review Committee, 2016 - Present

Web Links


Selected Publications

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 is Essential for Efficient Hydroxylation of Hypoxia Inducible Factor-alpha

Arsenault, P.R., Song, D., Chung, Y.J, Khurana, T.S., & Lee, F.S., Mol. Cell. Biol. 36(): 2328-2343, 2016

Identification of Small Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor

Arsenault, P.S., Song, D., Bergkamp, M., Ravaschiere, A.M., Navalsky, B.E., Lieberman, P.M., & Lee, F.S., ChemBioChem 17(): 2316-2323, 2016, PMID:27770548

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Human high-altitude adaptation: forward genetics meets the HIF pathway (review)

Bigham, A.W., & Lee, F.S., Genes & Dev 28(): 2189-2204, 2014

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Song, D., Li, L.-S., Arsenault, P.R., Tan, Q., Bigham, A.W., Heaton-Johnson, K.J., Master, S.R., & Lee, F.S., J. Biol. Chem. 289(): 14656–14665, 2014

A Knockin Mouse Model of Human PHD2-Gene Associated Erythrocytosis Establishes a Haploinsufficiency Mechanism.

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., J. Biol. Chem. 288(): 33571-33584, 2013

Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain-of-function mutation

Tan, Q., Kerestes, H., Percy, M.J., Pietrofesa, R., Chen, L., Khurana, T.S., Christofidou-Solomidou, M., Lappin, T.R.J., & Lee, F.S., J. Biol. Chem. 288(): 17134–17144, 2013

Prolyl Hydroxylase Domain Protein 2 (PHD2) Binds a Pro-Xaa-Leu-Glu Motif, Linking it to the Heat Shock Protein 90 Pathway.

Song, D., Li, L.-S., Heaton-Johnson, K.J., Arsenault, P.R., Master, S.R., & Lee, F.S., J. Biol. Chem. 288(): 9662-74, 2013

A gain of function mutation in the HIF2A gene in familial erythrocytosis.

Percy, M.J., Furlow, P.W., Lucas, G.W., Li, X., Lappin, T.R.J., McMullin, M.F., & Lee, F.S., N Engl J Med 358(): 162-168, 2008

A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.

Percy M.J., Zhao Q., Flores A., Harrison C., Lappin T.R., Maxwell P.H., McMullin M.F.*, & Lee F.S.* *Equal senior coauthors, Proc Natl Acad Sci U S A 103(): 654-659, 2006

HIF-1α Binding to VHL is Regulated by Stimulus-Sensitive Proline Hydroxylation

Yu, F., White, S.B., Zhao, Q., & Lee, F.S., Proc. Natl. Acad. Sci. USA 98(): 9630-9635, 2001

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