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J. Biol. Chem., Vol. 280, Issue 30, 28133-28141, July 29, 2005

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Induction of p53 by Urokinase in Lung Epithelial Cells^*

Sreerama Shetty, Margaret R. Gyetko¶, and Andrew P. Mazar||

From the Department of Specialty Care Services, the University of Texas Health Center, Tyler, Texas 75708, ^¶Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, and ^||Attenuon, LLC, San Diego, California 92121

Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. The plasminogen/plasmin system includes the uPA, its receptor, and its inhibitor (plasminogen activator inhibitor-1). Interactions between these molecules regulate cellular proteolysis as well as adhesion, cellular proliferation, and migration, processes germane to the pathogenesis of lung injury and neoplasia. In previous studies, we found that uPA regulates cell surface fibrinolysis by regulating its own expression as well as that of the uPA receptor and plasminogen activator inhibitor-1. In this study, we found that uPA alters expression of the tumor suppressor protein p53 in Beas2B airway epithelial cells in both a time- and concentration-dependent manner. These effects do not require uPA catalytic activity because the amino-terminal fragment of uPA lacking catalytic activity was as potent as two chain active uPA. Single chain uPA also enhanced p53 expression to the same extent as intact two chain active uPA and the amino-terminal fragment. Pretreatment of cells with anti-1 integrin antibody blocked uPA-induced p53 expression. uPA-induced p53 expression occurs without increased p53 mRNA expression. However, uPA induced oncoprotein MDM2 in a concentration-dependent manner. uPA-induced p53 expression does not require activation of tyrosine kinases. Inactivation of protein-tyrosine phosphatase SHP-2 inhibits both basal and uPA-induced p53 expression. Plasmin did not alter uPA-mediated p53 expression. The induction of p53 expression by exposure of lung epithelial cells to uPA is a newly recognized pathway by which urokinase may influence the proliferation of lung epithelial cells. This pathway could regulate pathophysiologic alterations of p53 expression in the setting of lung inflammation or neoplasia.

Received for publication, November 22, 2004 , and in revised form, April 29, 2005.

^* This work was supported by NHLBI Grants R01-HL-62453 and HL071147 from the National Institutes of Health. 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.

To whom correspondence should be addressed: Dept. of Specialty Care Services, the University of Texas Health Center, 11937 U. S. Highway 271, Tyler, TX 75708-3154. Tel.: 903-877-7668; Fax: 903-877-7927; E-mail: sreerama.shetty{at}uthct.edu.

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				S. Shetty, P. Shetty, S. Idell, T. Velusamy, Y. P. Bhandary, and R. S. Shetty Regulation of Plasminogen Activator Inhibitor-1 Expression by Tumor Suppressor Protein p53 J. Biol. Chem., July 11, 2008; 283(28): 19570 - 19580. [Abstract] [Full Text] [PDF]

				V. Stepanova, T. Lebedeva, A. Kuo, S. Yarovoi, S. Tkachuk, S. Zaitsev, K. Bdeir, I. Dumler, M. S. Marks, Y. Parfyonova, et al. Nuclear translocation of urokinase-type plasminogen activator Blood, July 1, 2008; 112(1): 100 - 110. [Abstract] [Full Text] [PDF]

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