Published online 26 August 2005
Article |
Involvement of KSRP in the post-transcriptional regulation of human iNOS expression–complex interplay of KSRP with TTP and HuR
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. Jalonen, E.-L. Paukkeri, and E. Moilanen Compounds That Increase or Mimic Cyclic Adenosine Monophosphate Enhance Tristetraprolin Degradation in Lipopolysaccharide-Treated Murine J774 Macrophages J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 514 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. R. Moulton, V. C. Kyttaris, Y.-T. Juang, B. Chowdhury, and G. C. Tsokos The RNA-stabilizing Protein HuR Regulates the Expression of {zeta} Chain of the Human T Cell Receptor-associated CD3 Complex J. Biol. Chem., July 18, 2008; 283(29): 20037 - 20044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Emmons, W.H. D. Townley-Tilson, K. M. Deleault, S. J. Skinner, R. H. Gross, M. L. Whitfield, and S. A. Brooks Identification of TTP mRNA targets in human dendritic cells reveals TTP as a critical regulator of dendritic cell maturation RNA, May 1, 2008; 14(5): 888 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Suswam, Y. Li, X. Zhang, G. Y. Gillespie, X. Li, J. J. Shacka, L. Lu, L. Zheng, and P. H. King Tristetraprolin Down-regulates Interleukin-8 and Vascular Endothelial Growth Factor in Malignant Glioma Cells Cancer Res., February 1, 2008; 68(3): 674 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Winzen, B. K. Thakur, O. Dittrich-Breiholz, M. Shah, N. Redich, S. Dhamija, M. Kracht, and H. Holtmann Functional Analysis of KSRP Interaction with the AU-Rich Element of Interleukin-8 and Identification of Inflammatory mRNA Targets Mol. Cell. Biol., December 1, 2007; 27(23): 8388 - 8400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. David, R. Tanveer, and J. D. Port FRET-detectable interactions between the ARE binding proteins, HuR and p37AUF1 RNA, September 1, 2007; 13(9): 1453 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Frasca, A. M. Landin, J. P. Alvarez, P. J. Blackshear, R. L. Riley, and B. B. Blomberg Tristetraprolin, a Negative Regulator of mRNA Stability, Is Increased in Old B Cells and Is Involved in the Degradation of E47 mRNA J. Immunol., July 15, 2007; 179(2): 918 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ziesche, M. Bachmann, H. Kleinert, J. Pfeilschifter, and H. Muhl The Interleukin-22/STAT3 Pathway Potentiates Expression of Inducible Nitric-oxide Synthase in Human Colon Carcinoma Cells J. Biol. Chem., June 1, 2007; 282(22): 16006 - 16015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Korhonen, K. Linker, A. Pautz, U. Forstermann, E. Moilanen, and H. Kleinert Post-Transcriptional Regulation of Human Inducible Nitric-Oxide Synthase Expression by the Jun N-terminal Kinase Mol. Pharmacol., May 1, 2007; 71(5): 1427 - 1434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pautz, K. Linker, T. Hubrich, R. Korhonen, S. Altenhofer, and H. Kleinert The Polypyrimidine Tract-binding Protein (PTB) Is Involved in the Post-transcriptional Regulation of Human Inducible Nitric Oxide Synthase Expression J. Biol. Chem., October 27, 2006; 281(43): 32294 - 32302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Fritz, S. Jiang, J. Xu, and M. B. Rogers A Polymorphism in a Conserved Posttranscriptional Regulatory Motif Alters Bone Morphogenetic Protein 2 (BMP2) RNA:Protein Interactions Mol. Endocrinol., July 1, 2006; 20(7): 1574 - 1586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-F. Chou, A. Mulky, S. Maitra, W.-J. Lin, R. Gherzi, J. Kappes, and C.-Y. Chen Tethering KSRP, a Decay-Promoting AU-Rich Element-Binding Protein, to mRNAs Elicits mRNA Decay Mol. Cell. Biol., May 15, 2006; 26(10): 3695 - 3706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. H. CHMIEL, D. C. RIO, and J. A. DOUDNA Distinct contributions of KH domains to substrate binding affinity of Drosophila P-element somatic inhibitor protein RNA, February 1, 2006; 12(2): 283 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Barreau, L. Paillard, and H. B. Osborne AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res., January 3, 2006; 33(22): 7138 - 7150. [Abstract] [Full Text] [PDF]
|
|