NFAT and NFkappaB activation in T lymphocytes: a model of differential activation of gene expression.
NFAT and NFkappaB activation in T lymphocytes: a model of differential activation of gene expression.
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DOI：
10.1007/s10439-006-9179-4
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发表时间：
2006-11
影响因子：
3.8
通讯作者：
Jafri, M. Saleet
中科院分区：
文献类型：
--
作者：
Fisher, Wayne G.;Yang, Pei-Chi;Medikonduri, Ram K.;Jafri, M. Saleet
已经开发出调节 Ca2+ 依赖性转录因子 NFAT 和 NFκB 的数学模型，这些转录因子参与 T 淋巴细胞中免疫和炎症反应的激活。这些途径是药物的重要靶点，药物通过抑制 T 细胞中 NFAT 和 NFκB 的激活而发挥强大的免疫抑制剂作用。该模型使用单步和周期性逐步增加来模拟 Ca2+、二酰基甘油 (DAG) 和 PKCθ 生理浓度的激活和失活。该模型表明：（1）NFAT 的激活不会以低频率发生，因为 NFAT 需要由 Ca2+ 激活的钙调神经磷酸酶才能保持去磷酸化并位于细胞核中； (2) NFκB 在比 NFAT 更低的 Ca2+ 振荡频率下被激活，因为 IκB 响应 Ca2+ 升高而降解，从而允许游离 NFκB 易位到细胞核中； (3) IκB 的降解对于 NFκB 有效转位至细胞核至关重要。通过敏感性分析，该模型还表明，NFAT激活的最大控制因素是NFAT：钙调磷酸酶复合物的解离/重结合速率以及复合物进入细胞核的易位速率，而对于NFκB来说，最大的控制因素是IκB的降解/再合成速率和IκB进入细胞核的导入速率。
Mathematical models for the regulation of the Ca2+-dependent transcription factors NFAT and NFκB that are involved in the activation of the immune and inflammatory responses in T lymphocytes have been developed. These pathways are important targets for drugs, which act as powerful immunosuppressants by suppressing activation of NFAT and NFκB in T cells. The models simulate activation and deactivation over physiological concentrations of Ca2+, diacyl glycerol (DAG), and PKCθ using single and periodic step increases. The model suggests the following: (1) the activation NFAT does not occur at low frequencies as NFAT requires calcineurin activated by Ca2+ to remain dephosphorylated and in the nucleus; (2) NFκB is activated at lower Ca2+ oscillation frequencies than NFAT as IκB is degraded in response to elevations in Ca2+ allowing free NFκB to translocate into the nucleus; and (3) the degradation of IκB is essential for efficient translocation of NFκB to the nucleus. Through sensitivity analysis, the model also suggests that the largest controlling factor for NFAT activation is the dissociation/reassociation rate of the NFAT:calcineurin complex and the translocation rate of the complex into the nucleus and for NFκB is the degradation/resynthesis rate of IκB and the import rate of IκB into the nucleus.
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影响因子：
16
作者：
Aramburu, J;Garcia-Cozar, F;Hogan, PG
通讯作者：
Hogan, PG
DOI：
10.1073/pnas.142298399
发表时间：
2002-07-09
影响因子：
11.1
作者：
Huang, JY;Lo, PF;Grey, HM
通讯作者：
Grey, HM
影响因子：
10.5
作者：
Beals, CR;Clipstone, NA;Crabtree, GR
通讯作者：
Crabtree, GR
影响因子：
10.5
作者：
FIERING, S;NORTHROP, JP;HERZENBERG, LA
通讯作者：
HERZENBERG, LA
影响因子：
56.9
作者：
Hoffmann, A;Levchenko, A;Baltimore, D
通讯作者：
Baltimore, D