This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Doller, A.
Right arrow Articles by Eberhardt, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Doller, A.
Right arrow Articles by Eberhardt, W.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2008, p. 2608-2625, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01530-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Posttranslational Modification of the AU-Rich Element Binding Protein HuR by Protein Kinase C{delta} Elicits Angiotensin II-Induced Stabilization and Nuclear Export of Cyclooxygenase 2 mRNA{triangledown}

Anke Doller, El-Sayed Akool, Andrea Huwiler,{dagger} Roswitha Müller, Heinfried H. Radeke, Josef Pfeilschifter, and Wolfgang Eberhardt*

pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Received 22 August 2007/ Returned for modification 20 September 2007/ Accepted 6 February 2008

The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate that in human mesangial cells (hMC) the amplification of cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase of mRNA stability. Using COX-2 promoter constructs with different portions of the 3' untranslated region of COX-2, we found that the increase in COX-2 mRNA stability is attributable to a distal class III type of AU-rich element (ARE). Likewise, the RNA immunoprecipitation assay showed AngII-induced binding of HuR to this ARE. Using the RNA pulldown assay, we demonstrate that the AngII-caused HuR assembly with COX-2 mRNA is found in free and cytoskeleton-bound polysomes indicative of an active RNP complex. Mechanistically, the increased HuR binding to COX-2-ARE by AngII is accompanied by increased nucleocytoplasmic HuR shuttling and depends on protein kinase C{delta} (PKC{delta}), which physically interacts with nuclear HuR, thereby promoting its phosphorylation. Mapping of phosphorylation sites identified serines 221 and 318 as critical target sites for PKC{delta}-triggered HuR phosphorylation and AngII-induced HuR export to the cytoplasm. Posttranslational modification of HuR by PKC{delta} represents an important novel mode of HuR activation implied in renal COX-2 regulation.

* Corresponding author. Mailing address: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Phone: 49 696301 6953. Fax: 49 696301 79 42. E-mail: w.eberhardt{at}em.uni-frankfurt.de

{triangledown} Published ahead of print on 19 February 2008.

{dagger} Present address: Institut für Pharmakologie, Universität Bern, CH-3010 Bern, Switzerland.

Molecular and Cellular Biology, April 2008, p. 2608-2625, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01530-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lopez de Silanes, I., Gorospe, M., Taniguchi, H., Abdelmohsen, K., Srikantan, S., Alaminos, M., Berdasco, M., Urdinguio, R. G., Fraga, M. F., Jacinto, F. V., Esteller, M. (2009). The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA. Nucleic Acids Res 37: 2658-2671 [Abstract] [Full Text]  
  • Doller, A., Gauer, S., Sobkowiak, E., Geiger, H., Pfeilschifter, J., Eberhardt, W. (2009). Angiotensin II Induces Renal Plasminogen Activator Inhibitor-1 and Cyclooxygenase-2 Expression Post-Transcriptionally via Activation of the mRNA-Stabilizing Factor Human-Antigen R. Am. J. Pathol. 174: 1252-1263 [Abstract] [Full Text]  
  • Abdelmohsen, K., Srikantan, S., Kuwano, Y., Gorospe, M. (2008). miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc. Natl. Acad. Sci. USA 105: 20297-20302 [Abstract] [Full Text]  
  • Baglole, C. J., Maggirwar, S. B., Gasiewicz, T. A., Thatcher, T. H., Phipps, R. P., Sime, P. J. (2008). The Aryl Hydrocarbon Receptor Attenuates Tobacco Smoke-induced Cyclooxygenase-2 and Prostaglandin Production in Lung Fibroblasts through Regulation of the NF-{kappa}B Family Member RelB. J. Biol. Chem. 283: 28944-28957 [Abstract] [Full Text]  
  • Ohama, T., Okada, M., Murata, T., Brautigan, D. L., Hori, M., Ozaki, H. (2008). Sphingosine-1-phosphate enhances IL-1{beta}-induced COX-2 expression in mouse intestinal subepithelial myofibroblasts. Am. J. Physiol. Gastrointest. Liver Physiol. 295: G766-G775 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»