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Papers In Press, published online ahead of print February 4, 2005
Biochemistry and Cell Biology, SUNY @ Stony Brook, Stony Brook, NY 11794-5215
Corresponding Author: kmarcu{at}ms.cc.sunysb.edu
Cellular responses to stress-like stimuli require the IKK signalsome (IKKa, IKKß and NEMO/IKK_ to activate NF-B dependent genes. IKKß and NEMO/IKK are required to release NF-B p65/p50 heterodimers from IBa, resulting in their nuclear migration and sequence specific DNA binding; but IKKa was found to be dispensable for this initial phase of canonical NF-B activation. Nevertheless, IKKa(-/-) MEFs fail to express NF-B targets in response to pro-inflammatory stimuli, uncovering a nuclear role for IKKa in NF-B activation. However, it remains unknown if the global defect in NF-B dependent gene expression of IKKa(-/-) cells is caused by the absence of IKKa kinase activity. We show by gene expression profiling that rescue of near physiological levels of Wt. IKKa in IKKa(-/-) MEFs globally restores expression of their canonical NF-B target genes. To prove that IKKa’s kinase activity was required on a genomic scale, the same physiological rescue was performed with a kinase dead, ATP binding domain IKKa mutant [IKKa(K44M)]. Remarkably, the IKKa(K44M) protein rescued ~28% of these genes, albeit in a largely stimulus independent manner with the notable exception of several genes that also acquired TNFa responsiveness. Thus the IKKa containing signalsome unexpectedly functions in the presence and absence of extracellar signals in both kinase dependent and independent modes to differentially modulate the expression of specific NF-B target genes thereby revealing the existence of five distinct classes of IKKa dependent genes in the canonical NF-B pathway.
J. Biol. Chem, 10.1074/jbc.M414401200
Submitted on December 22, 2004
Revised on February 4, 2005
Accepted on February 4, 2005
Gene expression profiling in conjunction with physiological rescues of IKKa null cells with Wt. or mutant IKKa reveals distinct classes of IKKa/NF-kB dependent genes
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