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Published ahead of print on April 3, 2008, doi:10.1165/rcmb.2007-0406OC

Am. J. Respir. Cell Mol. Biol., Volume 39, Number 3, September 2008, 364-372

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Submitted on November 9, 2007
Revised on April 3, 2008

Urokinase Expression by Tumor Suppressor Protein p53: A Novel Role in mRNA Turnover

Praveenkumar Shetty1, Thirunavukkarasu Velusamy1, Yashodhar P Bhandary1, Rashmi S Shetty1, Ming-cheh Liu2, and Sreerama Shetty1*

1 Department of Specialty Care Services, Texas Lung Injury Institute, The University of Texas Health Center at Tyler, Tyler, TX, USA, 2 Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH, USA

* To whom correspondence should be addressed. E-mail: sreerama.shetty{at}uthct.edu.

Lung carcinoma (H1299) cells deficient in p53 (p53-/-) express large amounts of urokinase (uPA) protein and uPA mRNA, and exhibit slower degradation of uPA mRNA than that of p53-expressing non-malignant 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'UTR in a sequence specific manner and endogenous uPA mRNA associates with p53 protein isolated from Beas2B cytosolic extracts. p53 binds to a 35 nt uPA 3'UTR sequence and insertion of this sequence into {beta}-globin mRNA accelerates degradation of otherwise stable {beta}-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.




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[Abstract] [Full Text] [PDF]


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