The nuclear translocation and accumulation of IκBα represents an important mechanism regulating transcription of NFκB-dependent pro-inflammatory and anti-apoptotic genes. The nuclear accumulation of IκBα can be induced by post-induction repression in stimulated cells, inhibition of the CRM1-dependent nuclear IκBα export by leptomycin B, and by the inhibition of the 26S proteasome. In addition, IκBα is constitutively localized in the nucleus of human neutrophils, likely contributing to the high rate of spontaneous apoptosis in these cells. In the nucleus, IκBα suppresses transcription of NFκB-dependent pro-inflammatory and anti-apoptotic genes, representing an attractive therapeutic target. However, the inhibition of NFκB-dependent genes by nuclear IκBα is promoter specific, and depends on the subunit composition of NFκB dimers and post-translational modifications of the recruited NFκB proteins. In addition, several recent studies have demonstrated an NFκB-independent role of the nuclear IκBα. In this review, we discuss the mechanisms leading to the nuclear accumulation of IκBα and its nuclear functions as potential targets for anti-inflammatory and anti-cancer therapies.
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