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J. Biol. Chem., Vol. 280, Issue 14, 14057-14069, April 8, 2005

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Gene Expression Profiling in Conjunction with Physiological Rescues of IKK-null Cells with Wild Type or Mutant IKK Reveals Distinct Classes of IKK/NF-B-dependent Genes^*

Paul E. Massa¶, Xiang Li||, Adedayo Hanidu||, John Siamas, Milena Pariali¶, Jessica Pareja**, Anne G. Savitt**, Katrina M. Catron||, Jun Li||, and Kenneth B. Marcu, Senior scholar of the Institute of Advanced Studies of the University of Bologna¶**

From the Genetics Graduate Program, the Departments of Biochemistry and Cell Biology and ^**Microbiology, Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-5215, the ^||Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, and the ^¶Center for Applied Biomedical Research, San Orsola Hospital, University of Bologna, Via Massarenti 9, Bologna 40138, Italy

Cellular responses to stress-like stimuli require the IB kinase (IKK) signalsome (IKK, IKK, and NEMO/IKK) to activate NF-B-dependent genes. IKK and NEMO/IKK are required to release NF-B p65/p50 heterodimers from IB, resulting in their nuclear migration and sequence-specific DNA binding; but IKK was found to be dispensable for this initial phase of canonical NF-B activation. Nevertheless, IKK(-/-) mouse embryonic fibroblasts (MEFs) fail to express NF-B targets in response to proinflammatory stimuli, uncovering a nuclear role for IKK in NF-B activation. However, it remains unknown whether the global defect in NF-B-dependent gene expression of IKK(-/-) cells is caused by the absence of IKK kinase activity. We show by gene expression profiling that rescue of near physiological levels of wild type IKK in IKK(-/-) MEFs globally restores expression of their canonical NF-B target genes. To prove that the kinase activity of IKK was required on a genomic scale, the same physiological rescue was performed with a kinase-dead, ATP binding domain IKK mutant (IKK(K44M)). Remarkably, the IKK(K44M) protein rescued 28% of these genes, albeit in a largely stimulus-independent manner with the notable exception of several genes that also acquired tumor necrosis factor- responsiveness. Thus the IKK-containing signalsome unexpectedly functions in the presence and absence of extracellular signals in both kinase-dependent and -independent modes to differentially modulate the expression of five distinct classes of IKK/NF-B-dependent genes.

Received for publication, December 22, 2004

^* 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. This research was supported in part by a National Institutes of Health grant (to K. B. M.) and by the Fondazione Cassa di Risparmio di Bologna. 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.

To whom correspondence may be addressed: Dept. of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd., P. O. Box 368, Ridgefield, CT 06877-0368. Tel.: 203-798-5714; Fax: 203-837-5714; E-mail: jli{at}rdg.boehringer-ingelheim.com. To whom correspondence may be addressed: Dept. of Biochemistry and Cell Biology, SUNY at Stony Brook, 330 Life Sciences Bldg., Stony Brook, NY 11794-5215. Tel.: 631-632-8553; Fax: 631-632-9730; E-mail: kmarcu{at}ms.cc.sunysb.edu.

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