Abstract

The current project has four specific aims designed to elucidate the molecular basis for posttranscriptional regulation of tPA and PAI: 1) isolation and cloning of proteins that bind to the cyclic nucleotide responsive region of the PAI-1 mRNA; 2) analysis of the role of the mRNA binding proteins in the cyclic nucleotide regulation of PAI-1 mRNA degradation, both in intact cells and in a cell free in vitro mRNA decay system; 3) analysis of cyclic nucleotide regulation of the amount, subcellular localization, and posttranslational modification of the PAI-1 mRNA binding proteins; and 4) identification of proteins with which the mRNA binding proteins interact and analysis of their role in cyclic nucleotide regulation of PAI-1 mRNA degradation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022729-28
Application #
6854521
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Ault, Grace S
Project Start
1978-01-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
28
Fiscal Year
2005
Total Cost
$460,786
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Heaton, Joanne H; Dlakic, Wendy M; Gelehrter, Thomas D (2003) Posttranscriptional regulation of PAI-1 gene expression. Thromb Haemost 89:959-66
Heaton, J H; Dlakic, W M; Dlakic, M et al. (2001) 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 mRNA. J Biol Chem 276:3341-7
White, L A; Bruzdzinski, C; Kutz, S M et al. (2000) Growth state-dependent binding of USF-1 to a proximal promoter E box element in the rat plasminogen activator inhibitor type 1 gene. Exp Cell Res 260:127-35
Tillmann-Bogush, M; Heaton, J H; Gelehrter, T D (1999) Cyclic nucleotide regulation of PAI-1 mRNA stability. Identification of cytosolic proteins that interact with an a-rich sequence. J Biol Chem 274:1172-9
Seki, T; Healy, A M; Fletcher, D S et al. (1999) IL-1beta mediates induction of hepatic type 1 plasminogen activator inhibitor in response to local tissue injury. Am J Physiol 277:G801-9
Song, C Z; Tian, X; Gelehrter, T D (1999) Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Proc Natl Acad Sci U S A 96:11776-81
Heaton, J H; Tillmann-Bogush, M; Leff, N S et al. (1998) Cyclic nucleotide regulation of type-1 plasminogen activator-inhibitor mRNA stability in rat hepatoma cells. Identification of cis-acting sequences. J Biol Chem 273:14261-8
Song, C Z; Siok, T E; Gelehrter, T D (1998) Smad4/DPC4 and Smad3 mediate transforming growth factor-beta (TGF-beta) signaling through direct binding to a novel TGF-beta-responsive element in the human plasminogen activator inhibitor-1 promoter. J Biol Chem 273:29287-90
Seki, T; Imai, H; Uno, S et al. (1996) Production of tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in mildly cirrhotic rat liver. Thromb Haemost 75:801-7
Thornton, A J; Bruzdzinski, C J; Raper, S E et al. (1994) Plasminogen activator inhibitor-1 is an immediate early response gene in regenerating rat liver. Cancer Res 54:1337-43

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