Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 39, Issue 3, Pages 364-372Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2007-0406OC
Keywords
post-transcriptional regulation; urokinase-type plasminogen activator; p53; mRNA stability; RNA binding protein
Funding
- National Heart, Lung, and Blood Institute [R01 HL071147]
- [P01 HL62453]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL062453, R01HL071147] Funding Source: NIH RePORTER
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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 p-globin mRNA accelerates degradation of otherwise stable P-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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