Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-Amyloid Precursor Protein

mediators and modulators of immune activation, cell is temporally linked to selective recruitment of a Tip60 death, and inflammatory processes that have been coactivator complex. Surprisingly, KAI1 is also directly shown to be involved in neurodegenerative conditions activated by a ternary complex, dependent on the ace-including Alzheimer's disease (reviewed in Mrak and tyltransferase activity of Tip60, consisting of the pre-Griffin, 2000), and inappropriate regulation of NF-␬B is senilin-dependent C-terminal cleavage product of the directly involved in neurodegenerative disease (re-amyloid ␤ precursor protein (APP), Fe65, and Tip60, viewed in Mattson and Camandola, 2001). When stimu-identifying a specific in vivo gene target of an APP-lated by IL-1␤, IL-1 receptor-associated kinase (IRAK) dependent transcription complex in the brain.The ability to integrate multiple signaling pathways to minal kinase (JNK) activation. Activation of NF-␬B oc-achieve unique responses is a critical requirement for curs following upregulation of the expression of proin-development and homeostasis in all metazoans. One flammatory genes in the nucleus (reviewed in Baldwin, level at which this type of regulation occurs is in the 1996). NF-␬B p65 functions as a transcriptional activator nucleus, based on regulation of the multiple coactivator for p50-p65 heterodimers; conversely, p50 homodimers, and corepressor complexes that modulate gene tran-which lack an activation region, are detected in the nu-scription (reviewed in Glass and Rosenfeld, 2000). For cleus and appear to function as repressors (reviewed example, an interrelationship between distinct signaling in Silverman and Maniatis, 2001). pathways has been defined for nuclear receptors and ␤-amyloid precursor protein (APP) is a ubiquitously nuclear factor-␬B (NF-␬B), based on transrepression of expressed cell surface protein from which the activities NF-␬B by nuclear receptors and the linkage of inflamma-of ␤-and ␥-secretase generate the amyloid ␤-peptide tory responses to nuclear receptor repression (reviewed (A␤). A␤ is deposited in amyloid plaques in brains of in McKay and Cidlowski, 1999). These interrelationships Alzheimer's disease individuals (reviewed in Steiner and raise questions regarding the molecular mechanisms by Haass, 2001), as a component of a progressive neurode-which control of specific coregulatory complexes affect generative disease. ␥-secretase cleavage not only leads the transcriptional responses to intra-and extracellular to the generation of A␤ but also results in the liberation signals. of an intracellular domain of APP (AICD), which has been Active repression of gene expression by unliganded suggested to potentially function in nuclear signaling.