It takes two to regulate
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联合生物学 2006年第6期
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.
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.