Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover.
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 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.
Shetty
Praveenkumar
P
The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas 75708, USA.
Velusamy
Thirunavukkarasu
T
Bhandary
Yashodhar P
YP
Shetty
Rashmi S
RS
Liu
Ming-Cheh
MC
Shetty
Sreerama
S
D020413:3' Untranslated Regions; D001483:Base Sequence; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D004591:Electrophoresis, Polyacrylamide Gel; D020868:Gene Silencing; D005914:Globins / Q000235:genetics; D006801:Humans; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D020413:3' Untranslated Regions; D018076:DNA, Complementary; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005914:Globins; D014568:Urokinase-Type Plasminogen Activator