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Urokinase Expression by Tumor Suppressor Protein p53

A Novel Role in mRNA Turnover

¹ Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas; and ² Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, Ohio

Correspondence and requests for reprints should be addressed to Sreerama Shetty, Ph.D., Professor of Medicine, The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U.S. Highway 271, Lab C-6, Tyler, TX 75708. E-mail: sreerama.shetty{at}uthct.edu

Lung carcinoma (H1299) cells deficient in p53 (p53^–/–) express large amounts of urokinase-type plasminogen activator (uPA) protein and uPA mRNA, and exhibit slower degradation of uPA mRNA than that of p53-expressing nonmalignant Beas2B human airway epithelial cells. Expression of p53 protein in H1299 cells, upon transfection with p53 cDNA, suppressed basal as well as uPA-induced expression of uPA protein in both conditioned media and cell lysates, and decreased the level of steady-state uPA mRNA primarily due to increased uPA mRNA turnover. Inhibition of p53 expression by RNA silencing (SiRNA) in Beas2B cells enhanced basal and uPA-mediated uPA protein and mRNA expression with stabilization of uPA mRNA. Purified p53 binds to the uPA mRNA 3' untranslated region (UTR) in a sequence-specific manner and endogenous uPA mRNA associates with p53 protein isolated from Beas2B cytosolic extracts. p53 binds to a 35-nucleotide uPA 3'UTR sequence and insertion of this sequence into β-globin mRNA accelerates degradation of otherwise stable β-globin mRNA. 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.

Key Words: post-transcriptional regulation • urokinase-type plasminogen activator • p53 • mRNA stability • RNA binding protein

CLINICAL RELEVANCE The current study describes the underlying mechanism involved in lung epithelial cell death during injury such as acute respiratory distress syndrome or acute lung injury.