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Nucleic Acids Research 2005 33(15):4813-4827; doi:10.1093/nar/gki797
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Published online 26 August 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Involvement of KSRP in the post-transcriptional regulation of human iNOS expression–complex interplay of KSRP with TTP and HuR

Katrin Linker, Andrea Pautz, Marcel Fechir, Thomas Hubrich, Jobst Greeve1 and Hartmut Kleinert*

Department of Pharmacology, Johannes Gutenberg University Obere Zahlbacher Strasse 67, D-55101 Mainz, Germany 1Department of General Internal Medicine, Inselspital-University Hospital Bern CH-3010 Bern, Switzerland

*To whom correspondence should be addressed. Tel: +49 6131 393 3245; Fax: +49 6131 393 6611; Email: kleinert{at}mail.uni-mainz.de

Received June 16, 2005. Revised August 11, 2005. Accepted August 11, 2005.

We purified the KH-type splicing regulatory protein (KSRP) as a protein interacting with the 3'-untranslated region (3'-UTR) of the human inducible nitric oxide (iNOS) mRNA. Immunodepletion of KSRP enhanced iNOS 3'-UTR RNA stability in in vitro-degradation assays. In DLD-1 cells overexpressing KSRP cytokine-induced iNOS expression was markedly reduced. In accordance, downregulation of KSRP expression increases iNOS expression by stabilizing iNOS mRNA. Co-immunoprecipitations showed interaction of KSRP with the exosome and tristetraprolin (TTP). To analyze the role of KSRP binding to the 3'-UTR we studied iNOS expression in DLD-1 cells overexpressing a non-binding mutant of KSRP. In these cells, iNOS expression was increased. Mapping of the binding site revealed KSRP interacting with the most 3'-located AU-rich element (ARE) of the human iNOS mRNA. This sequence is also the target for HuR, an iNOS mRNA stabilizing protein. We were able to demonstrate that KSRP and HuR compete for this binding site, and that intracellular binding to the iNOS mRNA was reduced for KSRP and enhanced for HuR after cytokine treatment. Finally, a complex interplay of KSRP with TTP and HuR seems to be essential for iNOS mRNA stabilization after cytokine stimulation.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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