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It takes two to regulate

NF-B levels settle to steady-state unless IB is missing (bottom).

Two isoforms of the IB inhibitor of NF-B are required to turn oscillation into steady regulation during chronic stimulation, according to Kearns et al. (page 659). The use of two out-of-phase regulators may be a common means to control signaling pathways.

NF-B activation triggers expression of IB, which leads to down-regulation of the signaling pathway and a decrease in IB transcription. However, under chronic stimulation the NF-B signaling pathway becomes reactivated as soon as the amount of IB drops below a certain level. Thus, in cells engineered so that IB is the only IB isoform present, NF-B activity oscillates over many cycles. In unmodified cells, however, NF-B activity is steady, and computational modeling suggested the existence of an active damping mechanism that limits fluctuation.

Kearns et al. found that IB expression was also induced by NF-B. There was, though, a significant delay in its expression relative to IB. Mathematical modeling and cell experiments showed that, with the two regulators out of phase due to IB's lag, NF-B expression was dampened to a steady half-maximal level in chronically stimulated cells after an initial peak.

A recent report showed that two signals that trigger NF-B activity also induce oscillation individually but lead to an even activity level when combined (Covert et al. 2005 Science. 309:1854-7). Thus, Kearns et al. speculate that this sort of regulatory mechanism may be a way for cells to modulate the level of activity of a signaling pathway, rather than being limited to simple on/off switches.

Rabiya S. Tuma

rabiya{at}nasw.org

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This Article Full Text (PDF, 939K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tuma, R. S. Search for Related Content PubMed Articles by Tuma, R. S. Related Collections Related Article Social Bookmarking                            What's this?