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Frank
S. Lee, M.D., Ph.D.
Associate
Professor, Dept of Pathology and Laboratory Medicine
Genetics
and Gene Regulation Program
Address
604 Stellar-Chance
Laboratory
422 Curie Blvd.
Philadelphia, PA 19104
Office tel.: 215 898-4701
Lab tel.: 215 898-4700
Fax: 215 215-573-2272
E-mail: franklee@mail.med.upenn.edu
Education
Harvard
College, A.B. (Biochemistry), 1983
Harvard University, Ph.D. (Biological Chemistry), 1991
Harvard Medical School, M.D., 1991
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Research
Interests
- Molecular mechanisms of the hypoxic response.
Key words: hypoxia, HIF, PHD2, prolyl
hydroxylation, gene regulation
Description
of Research
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.
Selected
Publications
Yu, F., White, S.B., Zhao, Q., & Lee, F.S.
(2001). HIF-1α Binding to VHL is Regulated by Stimulus-Sensitive
Proline Hydroxylation. Proc. Natl. Acad. Sci. USA
98, 9630-9635.
Percy, M.J., Zhao, Q., Flores, A., Harrison,
C., Lappin, T.R.J., Maxwell, P.H., McMullin, M.F.*, &
Lee, F.S.* (2006). A family with erythrocytosis establishes
a role for PHD2 in oxygen homeostasis. Proc. Natl. Acad.
Sci. USA 103, 654-659. *Equal senior authorship.
Huang, J., Flores, A., Song, D., Zhao, Q., Mooney,
S.M., Shaw, L.M., & Lee, F.S. (2007). IOP1, a novel hydrogenase-like
protein that modulates Hypoxia Inducible Factor-1α activity.
Biochem J. 401, 341-352.
Song, D. & Lee, F. S. (2008). A role for
Iron-Only Hydrogenase Like Protein 1 in Mammalian Cytosolic
Iron-Sulfur Protein Biogenesis. J. Biol. Chem. 283,
9231-9238.
Percy, M.J., Furlow, P.W., Lucas, G.W., Li,
X., Lappin, T.R.J., McMullin, M.F., & Lee, F.S. (2008).
A gain of function mutation in the HIF2A gene in familial
erythrocytosis. N Engl J Med 358, 162-168.
Search PubMed for more articles
Lab
Rotation
Projects
- Examine mechanisms by which HIF-α is
regulated.
- Determine whether proline hydroxylation
plays a more general role in hypoxia.
- Develop mouse models for examining the HIF
pathway.
- Lab
personnel:
- Frank Lee (Principal investigator)
Daisheng Song (Postdoctoral researcher)
Xiping Li (Postdoctoral researcher)
Scott Sutherland (Research specialist)
Maureen Banigan (Undergraduate Vagelos Scholar)
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last updated 7/2008
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