CONTROL OF FIBRINOLYTIC PATHWAYS IN LUNG DISEASE

Summary

Principal Investigator: Sreerama Shetty
Abstract: 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.
Funding Period: 1999-09-06 - 2005-08-31
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

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

Detail Information

Publications12

  1. 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...
  2. 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)...
  3. 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...
  4. 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...
  5. 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...
  6. 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
    ....
  7. 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
    ....
  8. 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
    ....
  9. 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...
  10. 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...
  11. 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...
  12. 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...