Faculty

		Thomas D. Gelehrter, M.D. Professor, Human Genetics Department Professor, Internal Medicine Department tdgum@umich.edu 734/764-5491
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Research Interests

The plasimongen 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 (PAl-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 PAl-1 gene.

Transforming growth factor-beta (TGFβ), a major regulator of extracellular matrix biosynthesis, is a potent inducer of PAl-1 gene expression. Glucocorticoids, dramatically repress the transcriptional activation of PAl-1 by TGFβ , 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 PAl-1 mRNA. We have defined a region of the PAl-1 mRNA that confers cyclic nucleotide regulation of mRNA stability, and have isolated and cloned a novel, conserved PAl-1 mRNA-binding protein (PAl-RBP1) that specifically binds this region. Surprisingly, recent experiments suggest that PAl-RBP1 may also play an important role in the cellular response to DNA damage.

Education

1963 Harvard Medical School, M.D.

1959 University of Oxford, M.A.

1957 Oberlin College, B.A.

Editorial Boards

1995-00 Journal of Biological Chemistry

2002 - NIH Recombinant DNA Advisory Committee

Honors and Awards

2005 Kaiser-Permanente Award for Excellence in Pre-clinical Teaching

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

Representative Publications

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-ß 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 PAl-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- β action. J Biol Chem 2003; 278: 41779-88

Li, G., Heaton, J.H., Gelehrter, T.D. Role of steroid receptor co-activators in glucocorticoid and TGFβ regulation of PAl-1 gene expression. Mol. Endocrinol. 2006;20:1025-1034.

updated 4/06