The objective of this project is a biochemical and molecular analysis of hormonal regulation of tPA and its major physiological inhibitor, PAI-1, in rat hepatoma cells and hepatocytes in tissue culture. The first and major aim is an analysis of the molecular basis of posttranscriptional down- regulation of PAI-1 gene expression in HTC cells by cyclic nucleotides.
The second aim i s to examine mechanisms of transcriptional silencing important for the down-regulation of PAI-1 gene expression in HTC cells.
The third aim will define the molecular basis for the synergistic induction of tPA gene transcription by glucocorticoids and cyclic nucleotides in HTC cells, and will also investigate the antagonistic actions of these hormones in primary cultures of normal rat hepatocytes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022729-23
Application #
6137379
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1978-01-01
Project End
2000-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
23
Fiscal Year
2000
Total Cost
$421,365
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
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
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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