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Molecular and Cellular Biology, March 2006, p. 2399-2407, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2399-2407.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Regulates Tumor Necrosis Factor mRNA Stability and Translation Mainly by Altering Tristetraprolin Expression, Stability, and Binding to Adenine/Uridine-Rich Element

Edward Hitti,1 Tatiana Iakovleva,1 Matthew Brook,2 Stefanie Deppenmeier,3 Achim D. Gruber,3 Danuta Radzioch,4 Andrew R. Clark,2 Perry J. Blackshear,5 Alexey Kotlyarov,1 and Matthias Gaestel1*

Medical School Hannover, Institute of Biochemistry, Hannover, Germany,1 Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, United Kingdom,2 Montreal General Hospital Research Institute, Montreal, Quebec, Canada,3 Free University Berlin, Department of Veterinary-Pathology, Berlin, Germany,4 Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina5

Received 26 August 2005/ Returned for modification 5 October 2005/ Accepted 22 December 2005

The mitogen-activated protein kinase (MAPK) p38/MAPK-activated protein kinase 2 (MK2) signaling pathway plays an important role in the posttranscriptional regulation of tumor necrosis factor (TNF), which is dependent on the adenine/uridine-rich element (ARE) in the 3' untranslated region of TNF mRNA. After lipopolysaccharide (LPS) stimulation, MK2-deficient macrophages show a 90% reduction in TNF production compared to the wild type. Tristetraprolin (TTP), a protein induced by LPS, binds ARE and destabilizes TNF mRNA. Accordingly, macrophages lacking TTP produce large amounts of TNF. Here, we generated MK2/TTP double knockout mice and show that, after LPS stimulation, bone marrow-derived macrophages produce TNF mRNA and protein levels comparable to those of TTP knockout cells, indicating that in the regulation of TNF biosynthesis TTP is genetically downstream of MK2. In addition, we show that MK2 is essential for the stabilization of TTP mRNA, and phosphorylation by MK2 leads to increased TTP protein stability but reduced ARE affinity. These data suggest that MK2 inhibits the mRNA destabilizing activity of TTP and, in parallel, codegradation of TTP together, with the target mRNA resulting in increased cellular levels of TTP.

* Corresponding author. Mailing address: Medical School Hannover, Institute of Biochemistry, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Phone: 49-511-532-2825. Fax: 49-511-532-2827. E-mail: gaestel.matthias{at}mh-hannover.de.

Molecular and Cellular Biology, March 2006, p. 2399-2407, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2399-2407.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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