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Molecular and Cellular Biology, July 2003, p. 4901-4916, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4901-4916.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nitric Oxide Increases the Decay of Matrix Metalloproteinase 9 mRNA by Inhibiting the Expression of mRNA-Stabilizing Factor HuR

El-Sayed Akool,1,2 Hartmut Kleinert,3 Farid M. A. Hamada,2 Mohamed H. Abdelwahab,2 Ulrich Förstermann,3 Josef Pfeilschifter,1 and Wolfgang Eberhardt1*

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main,1 Institut für Pharmakologie, Johannes Gutenberg-Universität Mainz, Mainz, Germany,3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt2

Received 26 March 2003/ Accepted 25 April 2003

Dysregulation of extracellular matrix turnover is an important feature of many inflammatory processes. Rat renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin-1 beta. We demonstrate that NO does strongly destabilize MMP-9 mRNA, since different luciferase reporter gene constructs containing the MMP-9 3' untranslated region (UTR) displayed significant reduced luciferase activity in response to the presence of NO. Moreover, by use of an in vitro degradation assay we found that the cytoplasmic fractions of NO-treated cells contained a higher capacity to degrade MMP-9 transcripts than those obtained from control cells. An RNA electrophoretic mobility shift assay demonstrated that three of four putative AU-rich elements present in the 3' UTR of MMP-9 were constitutively occupied by the mRNA-stabilizing factor HuR and that the RNA binding was strongly attenuated by the presence of NO. The addition of recombinant glutathione transferase-HuR prevented the rapid decay of MMP-9 mRNA, whereas the addition of a neutralizing anti-HuR antibody caused an acceleration of MMP-9 mRNA degradation. Furthermore, the expression of HuR mRNA and protein was significantly reduced by exogenously and endogenously produced NO. These inhibitory effects were mimicked by the cGMP analog 8-bromo-cGMP and reversed by LY-83583, an inhibitor of soluble guanylyl cyclase. These results demonstrate that NO acts in a cGMP-dependent mechanism to inhibit the expression level of HuR, thereby reducing the stability of MMP-9 mRNA.

* Corresponding author. Mailing address: Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany. Phone: 49 69 6301 6953. Fax: 49 696301 7942. E-mail: w.eberhardt{at}em.uni-frankfurt.de.

Molecular and Cellular Biology, July 2003, p. 4901-4916, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4901-4916.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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