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Emeritus Professor of Human Genetics Professor of Internal Medicine |
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| 5718A Med Sci II 1241 E. Catherine St. SPC 5618 Ann Arbor, MI 48109 -5618 |
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The plasminogen activator (PA)-plasmin cascade plays a central role in processes involving limited protein breakdown, including dissolving blood clots, tissue remodeling, and tumor cell invasion. Type-1 PA-inhibitor (PAI-1) is the major physiologic regulator of plasminogen activation and its expression is tightly regulated. Our laboratory is investigating the molecular mechanisms by which hormones and growth factors regulate expression of the PAI-1 gene.
Transforming growth factor-beta , a major regulator of extracellular matrix biosynthesis, is a potent inducer of PAI-1 gene expression. Glucocorticoids, dramatically repress the transcriptional activation of PAI-1 by TGF beta, in human hepatoma cells, by direct interaction of the glucocorticoid receptor (GR) with Smad3. Over-expression of steroid receptor co- activators enhances this repression. Because glucocorticoids are commonly used in treating chronic inflammatory diseases with fibrosis, understanding the mechanisms of this regulation will have significant clinical implications.
Cyclic nucleotides enhance PA activity in rat hepatoma cells, primarily by accelerating the rate of degradation of PAI-1 mRNA. We have defined a region of the PAI-1 mRNA that confers cyclic nucleotide regulation of mRNA stability, and have isolated and cloned a novel, conserved PAI-1 mRNA-binding protein (PAI-RBP1) that specifically binds this region. Surprisingly, recent experiments suggest that PAI-RBP1 may also play an important role in the cellular response to DNA damage.
2005 Kaiser Permanente Award for Excellence in Teaching in Pre-clinical Sciences
1997 Distinguished Faculty Achievement Award
1995 Keeley Visiting Fellowship, Wadham College, University of Oxford
1988-95 MERIT Award, National Cancer Institute
1986- Who's Who in America
1979-80 Josiah Macy, Jr. Foundation Faculty Scholar Award
1975-79 Faculty Research Award, American Cancer Society
1963 Harvard Medical School, M.D.
1959 University of Oxford, M.A.
1957 Oberlin College, B.A.
Gelehrter TD, Collins FS, Ginsburg D: Principles of Medical Genetics, 2nd ed. Baltimore, Lippincott Williams and Wilkins, 1998. (3rd edition in progress)
Song C-Z, Tian X, Gelehrter TD. Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Proc Natl Acad Sci USA 1999; 96:11776-11781 .
Heaton JH, Dlakic W, Dlakic M, Gelehrter TD: Identification and cDNA cloning of a novel RNA-binding protein that interacts with the cyclic nucleotide-responsive sequence in the type-1 plasminogen activator inhibitor. J Biol Chem 2001; 276:3341-3347.
Heaton JH, Dlakic WM, Gelehrter TD: Posttranscriptional regulation of PAI-1 gene expression. Thromb Haemost 2003; 89: 949-66.
Li G, Wang S, Gelehrter TD: Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor- beta action. J Biol Chem 2003; 278: 41779-88.
Li G, Heaton JH, Gelehrter TD: Role of steroid receptor co-activators in glucocorticoid and TGF-beta regulation of PAI-1 gene expression. Mol Endocrinol 2006; 20:1025-34.
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