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J. Biol. Chem., Vol. 283, Issue 28, 19570-19580, July 11, 2008

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Regulation of Plasminogen Activator Inhibitor-1 Expression by Tumor Suppressor Protein p53^*

From the Texas Lung Injury Institute, University of Texas Health Center, Tyler, Texas 75708

H1299 lung carcinoma cells lacking p53 (p53^-/-) express minimal amounts of plasminogen activator inhibitor-1 (PAI-1) protein as well as mRNA. p53^-/- cells express highly unstable PAI-1 mRNA. Transfection of p53 in p53^-/- cells enhanced PAI-1 expression and stabilized PAI-1 mRNA. On the contrary, inhibition of p53 expression by RNA silencing in non-malignant human lung epithelial (Beas2B) cells decreased basal as well as urokinase-type plasminogen activator-induced PAI-1 expression because of accelerated degradation of PAI-1 mRNA. Purified p53 protein specifically binds to the PAI-1 mRNA 3'-un-translated region (UTR), and endogenous PAI-1 mRNA forms an immune complex with p53. Treatment of purified p53 protein with anti-p53 antibody abolished p53 binding to the 3'-UTR of PAI-1 mRNA. The p53 binding region maps to a 70-nucleotide PAI-1 mRNA 3'-UTR sequence, and insertion of the p53-binding sequence into β-globin mRNA destabilized the chimeric transcript. Deletion experiments indicate that the carboxyl-terminal region (amino acid residues 296–393) of p53 protein interacts with PAI-1 mRNA. These observations demonstrate a novel role for p53 as an mRNA-binding protein that regulates increased PAI-1 expression and stabilization of PAI-1 mRNA in human lung epithelial and carcinoma cells.

Received for publication, December 18, 2007 , and in revised form, May 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-HL071147 and P01HL-62453 from the NHLBI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Texas Lung Injury Institute, Dept. of Specialty Care Services, University of Texas Health Center, 11937 U. S. Highway 271, Lab C-6, Tyler, TX 75708. Tel.: 903-877-7668; Fax: 903-877-5627; E-mail: sreerama.shetty{at}uthct.edu.

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