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Sci. Signal., 8 January 2008
Vol. 1, Issue 1, p. pe1
Nuclear Ubiquitin Ligases, NF-B Degradation, and the Control of Inflammation
Gioacchino Natoli* and
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
Transcriptional control of the vast majority of genes involved in the inflammatory response requires the nuclear factor B (NF-B) family of transcription factors. Stimulation and termination of NF-B activity are subject to stringent spatiotemporal control. According to the classical model of NF-B regulation, both activation and termination mechanisms are centered on inhibitor of NF-B (IB) proteins. Whereas activation of NF-B requires degradation of the IBs, the main mechanism responsible for termination of NF-B activity is the resynthesis of a specific IB, IB, which sequesters NF-B dimers in the nucleus and translocates them to the cytoplasm in an inactive form. Studies now show that an additional mechanism that is required to prevent the uncontrolled activity of NF-B proteins is their nuclear degradation. At least two E3 ubiquitin ligases, one of which seems to be essential for control of nuclear NF-B p65 (also known as RelA) in myeloid cells, have been identified. Moreover, additional evidence indicates that individual NF-B dimers with particular activating or repressive properties may be differentially controlled by nuclear degradation, thus paving the way for the exploitation of NF-B degradation pathways for therapeutic purposes.