Anatomy of a negative feedback loop: the case of IκBα

被引:28
作者
Fagerlund, Riku [1 ]
Behar, Marcelo [1 ]
Fortmann, Karen T. [1 ]
Lin, Y. Eason [1 ,2 ,3 ]
Vargas, Jesse D. [1 ,2 ,3 ]
Hoffmann, Alexander [1 ,2 ,3 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Inst Quantitat & Computat Biosci, Los Angeles, CA 90095 USA
关键词
negative feedback; gene regulation; NF kappa B; I kappa B alpha; oscillation; NUCLEAR EXPORT SIGNAL; TEMPORAL CONTROL; GENE-EXPRESSION; ANKYRIN REPEAT; OSCILLATIONS; DYNAMICS; BETA; LOCALIZATION; PATHWAY; VARIABILITY;
D O I
10.1098/rsif.2015.0262
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an activator-induced inhibitor' regulatory motif. Within the NF kappa B signalling pathway, a key negative feedback regulator is I kappa B alpha. We show here that, contrary to current understanding, NF kappa B-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NF kappa B signalling to identify I kappa B alpha molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of I kappa B alpha and the I kappa B alpha-NF kappa B complex, as well as the free I kappa B alpha half-life, as key determinants of post-induction repression of NF kappa B and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.
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页数:8
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