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Molecular and Cellular Biology, August 2007, p. 5607-5618, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00080-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of Urokinase Receptor Expression by p53: Novel Role in Stabilization of uPAR mRNA{triangledown}

Sreerama Shetty,1* Thirunavukkarasu Velusamy,1 Steven Idell,1 Praveenkumar Shetty,1 Andrew P. Mazar,2 Yashodhar P. Bhandary,1 and Rashmi S. Shetty1

Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U.S. Highway 271, Tyler, Texas 75708,1 Attenuon LLC, 11535 Sorrento Valley Rd., San Diego, California 921212

Received 15 January 2007/ Returned for modification 13 February 2007/ Accepted 10 April 2007

We found that p53-deficient (p53–/–) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53–/– cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA. Purified p53 protein specifically binds to the uPAR mRNA 3' untranslated region (3'UTR), and endogenous uPAR mRNA associates with p53. The p53 binding region involves a 37-nucleotide uPAR 3'UTR sequence, and insertion of the p53 binding sequence into ß-globin mRNA destabilized ß-globin mRNA. Inhibition of p53 expression in these cells reverses decay of chimeric ß-globin-uPAR mRNA. These observations demonstrate a novel regulatory role for p53 as a uPAR mRNA binding protein that down-regulates uPAR expression, destabilizes uPAR mRNA, and thereby contributes to the viability of human airway epithelial or lung carcinoma cells.

* Corresponding author. Mailing address: 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. Phone: (903) 877-7668. Fax: (903) 877-5627. E-mail: sreerama.shetty{at}uthct.edu

{triangledown} Published ahead of print on 4 June 2007.

Molecular and Cellular Biology, August 2007, p. 5607-5618, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00080-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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