The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability.
The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.
Shetty
Sreerama
S
Lab C-6, Biomedical Research Bldg., The Univ. of Texas Health Science Center at Tyler, 11937 U.S. Hwy. 271, Tyler, TX 75708, USA. sreerama.shetty@uthct.edu
Padijnayayveetil
Joseph
J
Tucker
Torry
T
Stankowska
Dorota
D
Idell
Steven
S
D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011658:Pulmonary Fibrosis / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014568:Urokinase-Type Plasminogen Activator