Regulation of Lung Epithelial Fibrinolysis by Urokinase

Summary

Principal Investigator: Sreerama Shetty
Abstract: Disordered fibrin turnover and extravascular fibrin deposition have been implicated in the pathogenesis of lung injury and repair and lung cancer. Lung epithelial cells contribute to remodeling of extravascular fibrin by elaboration of urokinase (uPA), the urokinase receptor (uPAR) and plasminogen activator inhibitor-1 (PAl-1). Abnormal expression of these molecules in lung injury and neoplasia disrupts local fibrin turnover, potentiates local inflammation, and promotes organization of transitional fibrin with eventual fibrosis. We recently found that uPA induces expression of uPAR by lung epithelial cells. We now demonstrate that exogenous uPA also induces uPA and PAI-1 expression by these cells. These studies clearly show that lung epithelial cells regulate the uPA-uPAR-PAI-1 system by novel pathways about which little is currently understood. Our preliminary data show that posttranscriptional regulation contributes to uPA-mediated autoinduction as well as that of uPAR and PAI-1. Our central hypothesis is that novel pathways by which uPA regulates its own expression as well as that of uPAR and PAI-1 by lung epithelial cells are crucial in the pathogenesis of acute lung injury, its repair and lung cancer. Our objective is to elucidate the regulatory mechanisms by which uPA induces expression of these molecules. We will accomplish the objective in four specific aims. In Aim 1, we will determine if uPA induces epithelial cell uPAR at both transcriptional or posttranscriptional levels and define the responsible mechanisms. In Aim 2, we will determine the mechanism by which a-thrombin blocks uPA-mediated uPAR induction. In Aims 3 and 4, we will determine the mechanisms by which uPA induces its own expression as well as that of PAl-1, respectively, in lung epithelial cells. We will use a wide range of molecular, immunohistochemical, protein purification, and cell culture techniques with which we are experienced to complete the proposed work. These studies will increase our understanding of novel mechanisms by which the lung epithelium regulates the uPA-uPAR-PAI-1 system. This information could hasten the development of new, mechanism-based interventions for lung disorders, including acute lung injury or lung neoplasia.
Funding Period: 2002-09-01 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. pmc Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells
    Sreerama Shetty
    Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, 75708, USA
    Am J Respir Cell Mol Biol 43:358-67. 2010
  2. ncbi Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase
    Praveenkumar Shetty
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Science Center at Tyler, 11937 US Hwy 271, Lab C 6, Tyler, TX 75708, USA
    Mol Cell Biochem 335:235-47. 2010
  3. pmc Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury
    Yashodhar P Bhandary
    The Texas Lung Injury Institute, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Am J Respir Crit Care Med 179:288-98. 2009
  4. ncbi Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C
    Thirunavukkarasu Velusamy
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U S Highway 271, Tyler, Texas 75708, USA
    Biochemistry 47:6508-17. 2008
  5. pmc Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53
    Sreerama Shetty
    Texas Lung Injury Institute, University of Texas Health Center, Tyler, Texas 75708, USA
    J Biol Chem 283:19570-80. 2008
  6. pmc Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover
    Praveenkumar Shetty
    The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas 75708, USA
    Am J Respir Cell Mol Biol 39:364-72. 2008
  7. pmc Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA
    Sreerama Shetty
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Mol Cell Biol 27:5607-18. 2007
  8. ncbi Regulation of urokinase receptor expression by protein tyrosine phosphatases
    Sreerama Shetty
    The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, TX 75708, USA
    Am J Physiol Lung Cell Mol Physiol 292:L414-21. 2007
  9. ncbi Urokinase induces activation of STAT3 in lung epithelial cells
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U S Highway 271, Tyler, TX 75708, USA
    Am J Physiol Lung Cell Mol Physiol 291:L772-80. 2006
  10. ncbi Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Mol Cell Biochem 272:107-18. 2005

Scientific Experts

  • Sreerama Shetty
  • Praveenkumar Shetty
  • Yashodhar P Bhandary
  • Thirunavukkarasu Velusamy
  • Rashmi S Shetty
  • Ming Cheh Liu
  • MING C LIU
  • Yuko Tsuruta
  • Douglas B Cines
  • Deepika Jain
  • Steven Idell
  • Edward Abraham
  • Khalil Bdeir

Detail Information

Publications13

  1. pmc Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells
    Sreerama Shetty
    Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, 75708, USA
    Am J Respir Cell Mol Biol 43:358-67. 2010
    ..This newly recognized pathway could influence expression of PAI-1 by mesothelial or mesothelioma cells at the level of mRNA stability in the context of pleural inflammation or malignancy...
  2. ncbi Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase
    Praveenkumar Shetty
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Science Center at Tyler, 11937 US Hwy 271, Lab C 6, Tyler, TX 75708, USA
    Mol Cell Biochem 335:235-47. 2010
    ..This region can effectively mimic the function of a whole PGK molecule in inhibiting tumor cell growth...
  3. pmc Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury
    Yashodhar P Bhandary
    The Texas Lung Injury Institute, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Am J Respir Crit Care Med 179:288-98. 2009
    ..uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI)...
  4. ncbi Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C
    Thirunavukkarasu Velusamy
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U S Highway 271, Tyler, Texas 75708, USA
    Biochemistry 47:6508-17. 2008
    ..Increased hnRNPC interaction with the uPAR mRNA 3'-UTR through phosphorylation of Y57 represents a novel mechanism by which uPA regulates posttranscriptional uPAR mRNA turnover and cell surface uPAR expression...
  5. pmc Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53
    Sreerama Shetty
    Texas Lung Injury Institute, University of Texas Health Center, Tyler, Texas 75708, USA
    J Biol Chem 283:19570-80. 2008
    ..These observations demonstrate a novel role for p53 as an mRNA-binding protein that regulates increased PAI-1 expression and stabilization of PAI-1 mRNA in human lung epithelial and carcinoma cells...
  6. pmc Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover
    Praveenkumar Shetty
    The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas 75708, USA
    Am J Respir Cell Mol Biol 39:364-72. 2008
    ..These observations confirm a new role for p53 as a uPA mRNA binding protein that down-regulates uPA mRNA stability and decreases cellular uPA expression...
  7. pmc Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA
    Sreerama Shetty
    Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Mol Cell Biol 27:5607-18. 2007
    ....
  8. ncbi Regulation of urokinase receptor expression by protein tyrosine phosphatases
    Sreerama Shetty
    The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, TX 75708, USA
    Am J Physiol Lung Cell Mol Physiol 292:L414-21. 2007
    ....
  9. ncbi Urokinase induces activation of STAT3 in lung epithelial cells
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U S Highway 271, Tyler, TX 75708, USA
    Am J Physiol Lung Cell Mol Physiol 291:L772-80. 2006
    ....
  10. ncbi Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
    Mol Cell Biochem 272:107-18. 2005
    ..These observations indicate a novel mechanism of uPAR gene regulation in lung epithelial cells in which cis elements within a 110 nt uPAR mRNA 3'UTR sequence interact with hnRNPC to regulate uPAR mRNA stability...
  11. ncbi Regulation of urokinase receptor expression by phosphoglycerate kinase is independent of its catalytic activity
    Sreerama Shetty
    Department of Medicine, University of Texas Health Center, Tyler, TX 75708, USA
    Am J Physiol Lung Cell Mol Physiol 289:L591-8. 2005
    ..These results demonstrate that uPAR mRNA binding activity as well as PGK-mediated regulation of uPAR mRNA are independent of PGK enzymatic activity...
  12. ncbi Induction of p53 by urokinase in lung epithelial cells
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center, Tyler, Texas 75708, USA
    J Biol Chem 280:28133-41. 2005
    ..This pathway could regulate pathophysiologic alterations of p53 expression in the setting of lung inflammation or neoplasia...
  13. ncbi Protein synthesis and urokinase mRNA metabolism
    Sreerama Shetty
    Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U S Highway 271, Tyler, TX 75708, USA
    Mol Cell Biochem 271:13-22. 2005
    ..This pathway may regulate uPA-mediated functions of the lung epithelium in the context of inflammation or neoplasia...