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Molecular and Cellular Biology, December 2007, p. 8388-8400, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.01493-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Functional Analysis of KSRP Interaction with the AU-Rich Element of Interleukin-8 and Identification of Inflammatory mRNA Targets{triangledown} ,{dagger}

Reinhard Winzen,1,{ddagger} Basant Kumar Thakur,1,{ddagger} Oliver Dittrich-Breiholz,2 Meera Shah,1 Natalie Redich,1 Sonam Dhamija,1 Michael Kracht,2 and Helmut Holtmann1*

Institute of Biochemistry,1 Institute of Pharmacology, Medical School Hannover, D-30623 Hannover, Germany2

Received 17 August 2007/ Returned for modification 13 September 2007/ Accepted 19 September 2007

mRNA stability is a major determinant of inflammatory gene expression. Rapid degradation of interleukin-8 (IL-8) mRNA is imposed by a bipartite AU-rich element (ARE) in the 3' untranslated region (R. Winzen et al., Mol. Cell. Biol. 24:4835-4847, 2004). Small interfering RNA-mediated knockdown of the ARE-binding protein KSRP resulted in stabilization of IL-8 mRNA or of a ß-globin reporter mRNA containing the IL-8 ARE. Rapid deadenylation was impaired, indicating a crucial role for KSRP in this step of mRNA degradation. The two IL-8 ARE domains both contribute to interaction with KSRP, corresponding to the importance of both domains for rapid degradation. Exposure to the inflammatory cytokine IL-1 has been shown to stabilize IL-8 mRNA through p38 mitogen-activated protein (MAP) kinase and MK2. IL-1 treatment impaired the interaction of KSRP with the IL-8 ARE in a manner dependent on p38 MAP kinase but apparently independent of MK2. Instead, evidence that TTP, a target of MK2, can also destabilize the IL-8 ARE reporter mRNA is presented. In a comprehensive approach to identify mRNAs controlled by KSRP, two criteria were evaluated by microarray analysis of (i) association of mRNAs with KSRP in pulldown assays and (ii) increased amounts in KSRP knockdown cells. According to both criteria, a group of 100 mRNAs is controlled by KSRP, many of which are unstable and encode proteins involved in inflammation. These results indicate that KSRP functions as a limiting factor in inflammatory gene expression.

* Corresponding author. Mailing address: Institute of Biochemistry, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Phone: (49) 511-5323384. Fax: (49) 511-5322827. E-mail: holtmann.helmut{at}mh-hannover.de

{triangledown} Published ahead of print on 1 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} R.W. and B.K.T. contributed equally to this work.

Molecular and Cellular Biology, December 2007, p. 8388-8400, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.01493-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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