Alan L. Schwartz, Ph.D., M.D. [ contact information ]
Harriet B. Spoehrer Professor of Pediatrics;
Physician-in-Chief, St. Louis Children's Hospital;
Physician-in-Chief Saint Louis Children's Hospital;
Chairman Department of Pediatrics
Dr. Schwartz's laboratory is focused
on the cell and molecular biology of intracellular protein targeting
and degradation. Specifically, his laboratory has defined two areas
of concentration, which are closely integrated.
The first area of
focus is understanding the role of protein processing and
degradation within the endosomal/lysosomal pathway and in the
cytoplasm. The lysosomal pathway is responsible for degradation of
extracellular proteins. Within the cytoplasm the major (and best
understood) proteolytic system is the ubiquitin-proteasome system.
This pathway involves dozens of distinct components and is involved
in the degradation of short lived and abnormal proteins. Using
eukaryotic mutants of the pathway and specific antibodies to
components of the pathway, the Schwartz laboratory identified a
linkage between these two systems. Furthermore, using in vitro
reconstituted systems they have begun to dissect the structural
elements of substrates (including oncoproteins) which signal their
processing and degradation. Our recent focus is on the role of the
ubiquitin-proteasome in transcription factor (e.g., MyoD, E2A)
degradation in the cytoplasm and nucleus and the molecular mechanisms
involved.
The second area is the cell and
molecular biology of receptor-mediated endocytosis and its
regulation. The Schwartz research group has identified a huge,
multifunctional cell surface endocytosis receptor (LRP) which
governs the plasma clearance of several physiologically important
ligands including the plasminogen activators t-PA and u-PA, as well
as apolipoprotein E, lipoprotein lipase and most recently TFPI
(tissue factor pathway inhibitor), a regulator of blood coagulation.
Our approaches include immuno-electron microscopy as well as in
vivo gene targeting. Recent focus is directed to regulation of LRP
and ligand trafficking and turnover.
Education
- A. B., Case Western Reserve University, 1970
- Ph.D., Case Western Reserve University, 1974
- M.D., Case Western Reserve University, 1976
Training
- Research Fellow, Department of Medical Chemistry, University of Helsinki, Finland, 1972-1973
- Fellow of the Medical Research Council of New Zealand at Postgraduate School of Obstetrics and Gynaecology, National Women's Hospital, University of Auckland, New Zealand, 1975-1976
- Resident, Medicine, Children's Hospital Medical Center, Boston, 1976-1978
- Fellow in Hematology/Oncology, Children's Hospital Medical Center and the Dana-Farber Cancer Institute, Boston, 1978-1979
Licensure and Board Certification
- Missouri License, 1986
- American Board of Pediatrics, 1981
Honors
- Institute of Medicine, National Academy of Science, 1999
- Distinguished Visiting Professor, University of
Utrecht School of Medicine, Utrecht,
The Netherlands, 1993-1999
- E. Mead Johnson Award, 1993
- Gold Metal Award, Hospital Association of Greater St. Louis, 1988
- Teacher of the Year, Washington University School of Medicine, 1988
- Outstanding Clinical Teacher 1990-1991, St. Louis Children's Hospital
Selected Publications
Sun L, Trausch-Azar JS, Muglia LJ, Schwartz AL: Glucocorticoids differentially regulate degradation of MyoD and Id1 by N-terminal ubiquitination to promote muscle protein catabolism. Proc Natl Acad Sci USA 2008; 105:3339-3344 [ pubmed ] Lingbeck JM, Trausch-Azar JS, Ciechanover A, Schwartz AL: In vivo interactions of MyoD, Id1, and E2A proteins determined by acceptor photobleaching fluorescence resonance energy transfer. FASEB J 2008; Jan 15 (Epub ahead of print) [ pubmed ] Sun L, Trausch-Azar JS, Ciechanover A, Schwartz AL: E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation. Oncogene 2007; 26:441-448 [ pubmed ] Lingbeck JM, Trausch-Azar JS, Ciechanover A, Schwartz AL: E12 and E47 modulate cellular localization and proteasome-mediated degradation of MyoD and Id1. Oncogene 2005; 24:6276-6384 [ pubmed ] Sun L, Trausch-Azar JS, Ciechanover A, Schwartz AL: Ubiquitin-proteasome-mediated degradation, intracellular localization, and protein synthesis of MyoD and Id1 during muscle differentiation. J Biol Chem 2005; 280:26448-26456 [ pubmed ] McCormick LM, Urade R, Arakaki LY, Schwartz AL, Bu G: Independent and cooperative roles of N-glycans and molecular chaperones in the folding and disulfide bond formation of the low-density lipoprotein receptor-related protein. Biochemistry 2005; 44:5794-5803 [ pubmed ] Ciechanover A, Schwartz AL: The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim Biophys Acta 2004; 1695:3-17 [ pubmed ] Ben-Saadon R, Fajerman I, Ziv T, Hellman U, Schwartz AL, Ciechanover A.: The tumor suppressor protein p16(INK4a) and the human papillomavirus oncoprotein-58E7 are naturally occurring lysine-less proteins that are degraded by the ubiquitin system. Direct evidence for ubiquitination at the N-terminal residue. J Biol Chem 2004; 279:41414-41421 [ pubmed ]
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