The urokinase (uPA)-urokinase receptor (uPAR) system is implicated in the pathogenesis of pulmonary inflammation and repair via proteolytic remodeling, regulation of cell migration and mitogenesis. Depressed uPA expression in the lungs of patients with ARDS or interstitial lung diseases potentiates fibrosing alveolitis. Work we published in the initial funding cycle of this grant shows that lung epithelial cells regulate both uPA and uPAR at the posttranscriptional level. We hypothesize that expression of uPA and uPAR by lung epithelial cells is regulated by novel posttranscriptional pathways and that these pathways influence epithelial cell responses in lung inflammation or repair. Our preliminary data support the hypothesis and show that phosphoglycerate kinase (PGK) and other newly recognized uPAR and uPA mRNA binding protein-mRNA interactions control uPAR and uPA expression by lung epithelial cells. These pathways are poorly understood at this time, representing an important gap in our understanding of the pathogenesis of lung injury and repair.
Our Specific Aims are: 1) To determine how PGK and another newly recognized uPAR mRNA coding region binding protein regulate uPAR expression in lung epithelial cells. 2) To elucidate the role of newly recognized 3'-untranslated region (3'UTR) uPAR mRNA-binding protein interactions on uPAR expression. 3) To determine the mechanism(s) by which PGK and hnRNPC, another putative regulatory protein, regulate cytokine-mediated expression of uPAR in lung epithelial cells. 4) To characterize the uPA mRNABp and determine how it regulates uPA expression in lung epithelial cells. These studies build on work accomplished in the first funding cycle of this project to extend our understanding of mechanisms by which lung epithelial cells regulate uPAR and uPA expression and will hasten development of novel therapeutics for acute lung injury or pulmonary fibrosis.
| Shetty, Praveenkumar; Velusamy, Thirunavukkarasu; Bhandary, Yashodhar P et al. (2010) Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase. Mol Cell Biochem 335:235-47 |
| Bhandary, Yashodhar P; Velusamy, Thirunavukkarasu; Shetty, Praveenkumar et al. (2009) Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury. Am J Respir Crit Care Med 179:288-98 |
| Shetty, Praveenkumar; Velusamy, Thirunavukkarasu; Bhandary, Yashodhar P et al. (2008) Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover. Am J Respir Cell Mol Biol 39:364-72 |
| Shetty, Sreerama; Shetty, Praveenkumar; Idell, Steven et al. (2008) Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53. J Biol Chem 283:19570-80 |
| Velusamy, Thirunavukkarasu; Shetty, Praveenkumar; Bhandary, Yashodhar P et al. (2008) Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry 47:6508-17 |
| Shetty, Sreerama; Velusamy, Thirunavukkarasu; Idell, Steven et al. (2007) Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. Mol Cell Biol 27:5607-18 |
| Shetty, Sreerama; Velusamy, Thirunavukkarasu; Idell, Steven et al. (2007) Regulation of urokinase receptor expression by protein tyrosine phosphatases. Am J Physiol Lung Cell Mol Physiol 292:L414-21 |
| Shetty, Sreerama; Rao, Gadiparthi N; Cines, Douglas B et al. (2006) Urokinase induces activation of STAT3 in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 291:L772-80 |
| Shetty, Sreerama (2005) Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells. Mol Cell Biochem 272:107-18 |
| Shetty, Sreerama; Gyetko, Margaret R; Mazar, Andrew P (2005) Induction of p53 by urokinase in lung epithelial cells. J Biol Chem 280:28133-41 |
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