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J. Biol. Chem., Vol. 280, Issue 30, 27728-27741, July 29, 2005

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Simultaneous Blockade of NFB, JNK, and p38 MAPK by a Kinase-inactive Mutant of the Protein Kinase TAK1 Sensitizes Cells to Apoptosis and Affects a Distinct Spectrum of Tumor Necrosis Target Genes^*

Axel Thiefes, Sabine Wolter, J. Frederic Mushinski¶, Elke Hoffmann, Oliver Dittrich-Breiholz, Nadine Graue, Anneke Dörrie, Heike Schneider, Dagmar Wirth||, Bruno Luckow**, Klaus Resch, and Michael Kracht

From the Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany, ^¶Molecular Genetics Section, Laboratory of Genetics, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4258, ^||Department of Gene Regulation and Differentiation, GBF-National Research Institute for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany, and ^**Clinical Biochemistry, Ludwig-Maximilians-University, Schillerstrasse 42, D-80336 Munich, Germany

The inflammatory response is characterized by the induction (or repression) of hundreds of genes. The activity of many of these genes is controlled by MAPKs and the IB kinase-NFB pathway. To reveal the effects of blocking these pathways simultaneously, fibroblasts were infected with retroviruses encoding TAK1K63W, an inactive mutant of the protein kinase TAK1. Expression of this protein inhibited tumor necrosis factor (TNF)-induced activation of NFB, JNK, and p38 MAPK and sensitized the cells to TNF-induced apoptosis. 23 different microarray experiments were used to analyze the expression of >7000 genes in these cells. We identified 518 genes that were regulated by TNF in both TAK1K63W-expressing cells and control cells, 37 genes induced by TNF only when TAK1K63W was present, and 48 TNF-induced genes that were suppressed by TAK1K63W. The TNF-inducible genes that were most strongly suppressed by TAK1K63W, ccl2, ccl7, ccl5, cxcl1, cxcl5, cxcl10, saa3, and slpi also had much lower basal levels of expression, indicating that TAK1 also played a role in their normal expression. Chromatin immunoprecipitation studies on four of these genes suggested that inactivation of TAK1 activity led to direct suppression of expression at the transcriptional level because of impaired recruitment of RNA polymerase II to their promoters. ccl2 induction by TNF or interleukin-1 was also suppressed in cells that expressed TAK1 antisense RNA or that were genetically deficient in JNK1/2 or p65 NFB. These data suggest that regulation of the expression of a selected group of inflammation-related genes is funneled through TAK1, making it a potentially useful target for more specific anti-inflammatory drug development.

Received for publication, October 13, 2004 , and in revised form, March 24, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants KR-1143/2-4, KR-1143/5-1, and SFB566/B06/Z02 (to M. K.). 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 Figs. 1–3 and Tables I and II.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Institute of Pharmacology, Medical School Hannover Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Tel.: 49-511-5322800; Fax: 49-511-532-4081; E-mail: Kracht.Michael{at}MH-Hannover.de.

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