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J. Biol. Chem., Vol. 283, Issue 17, 11689-11699, April 25, 2008

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Genome-wide Analysis Identifies Interleukin-10 mRNA as Target of Tristetraprolin^*

Georg Stoecklin¹, Scott A. Tenenbaum^¶, Thomas Mayo, Sridar V. Chittur^¶, Ajish D. George^¶, Timothy E. Baroni^¶, Perry J. Blackshear^||, and Paul Anderson

From the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, the German Cancer Research Center, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, the ^¶Department of Biomedical Sciences, Gen^*NY^*Sis Center for Excellence in Cancer Genomics and the Center for Functional Genomics, School of Public Health, University at Albany-SUNY, Rensselaer, New York 12144, and ^|| NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Tristetraprolin (TTP) is an RNA-binding protein required for the rapid degradation of mRNAs containing AU-rich elements. Targets regulated by TTP include the mRNAs encoding tumor necrosis factor-, granulocyte-macrophage colony-stimulating factor, interleukin-2 (IL-2), and immediate early response 3. To identify novel target mRNAs of TTP in macrophages, we used a genome-wide approach that combines RNA immunoprecipitation and microarray analysis. A list was compiled of 137 mRNAs that are associated with TTP with an estimated accuracy on the order of 90%. Sequence analysis revealed a highly significant enrichment of AU-rich element motifs, with AUUUA pentamers present in 96% and UUAUUUAUU nonamers present in 44% of TTP-associated mRNAs. We further show that IL-10 is a novel target regulated by TTP. IL-10 mRNA levels were found to be elevated because of a reduced decay rate in primary macrophages from TTP^-/- mice. Our study demonstrates the importance of experimental approaches for identifying targets of RNA-binding proteins.

Received for publication, November 27, 2007 , and in revised form, February 4, 2008.

^* This work was supported by National Institutes of Health Grants AI-33600 and AI-50167 (to P. A.), National Human Genome Research Institute, National Institutes of Health Grants U01HG004571 and R21HG003679 (to S. A. T.), and a Young Investigators Grant from the Helmholtz Association of German Research Centres (to G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S4 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: German Cancer Research Center, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Tel.: 49-6221-546887; Fax: 49-6221-545891; E-mail: g.stoecklin{at}dkfz.de.

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