The Bcl-2-associated death promoter (BAD) lowers the threshold at which the Bcl-2-interacting domain death agonist (BID) triggers mitochondria disintegration
The Bcl-2-associated death promoter (BAD) lowers the threshold at which the Bcl-2-interacting domain death agonist (BID) triggers mitochondria disintegration
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DOI：
10.1016/j.jtbi.2010.11.040
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发表时间：
2011-02-21
影响因子：
2
通讯作者：
Finkielstein, Carla V.
中科院分区：
文献类型：
--
作者：
Howells, Christopher C.;Baumann, William T.;Finkielstein, Carla V.
Bcl-2相关死亡启动子（BAD）蛋白，像许多其他BH 3-唯一的蛋白质，已知通过内在线粒体途径促进细胞凋亡。与BH 3相互作用结构域死亡激动剂（BID）蛋白不同，BAD不能直接触发细胞凋亡，而是降低诱导细胞凋亡的阈值。在许多细胞凋亡的数学模型中，BAD被忽略或抽象。本文介绍的工作考虑了BAD及其各种修饰在巴克（Bcl-2同源拮抗剂杀伤）的tBID诱导或BAX（Bcl-2相关X蛋白）的tBID诱导模型中的掺入。稳态方程用于开发描述保证触发细胞凋亡的tBID的总浓度水平的显式公式，其为总BAD浓度水平和总抗细胞凋亡蛋白浓度水平（通常为Bcl-2或Bcl-x（L））的双线性函数。特别地，该公式解释了促凋亡蛋白BAD如何降低tBID诱导巴克/BAX激活的阈值-降低可用于抑制线粒体中tBID信号传导的总Bcl-2/Bcl-x（L）的水平。然后将注意力转向围绕BAD磷酸化的实验数据，该过程已知抑制BAD的促凋亡作用。为了解决该数据，磷酸化过程按照两个单独的动力学建模，其中游离的未结合的BAD是假定的底物或Bcl-x（L）/Bcl-2结合的BAD是假定的底物。分叉分析和双线性方程的进一步分析验证了实验，这些实验表明BAD磷酸化阻止了不可逆的巴克/BAX介导的细胞凋亡，即使当磷酸化诱导的Bcl-x（L）/Bcl-2结合的BAD的解离被阻断时。它还表明，一个合作，甚至协同，线粒体BAD的去除被认为是当两种类型的磷酸化是可能的。然而，目前的工作表明，BAD磷酸化和去磷酸化之间的平衡调节了BAD影响从tBID到巴克/BAX的信号传导的程度。我们的模型表明，磷酸化模式和BAD去磷酸化速率成为决定BAD是否影响巴克/BAX信号激活的重要因素。BAD的促凋亡作用中的这种潜在变化被用来解释围绕BAD磷酸化的一些不一致的实验数据。尽管如此，我们的模型用于评估BAD及其对巴克/BAX的tBID诱导的敏化作用，从而有助于预测BAD在凋亡信号传导模型中的掺入何时重要，何时不重要。(C)2010爱思唯尔有限公司保留所有权利。
The Bcl-2-associated death promoter (BAD) protein, like many other BH3-only proteins, is known to promote apoptosis through the intrinsic mitochondrial pathway. Unlike the BH3-interacting domain death agonist (BID) protein, BAD cannot directly trigger apoptosis but, instead, lowers the threshold at which apoptosis is induced. In many mathematical models of apoptosis, BAD is neglected or abstracted. The work presented here considers the incorporation of BAD and its various modifications in a model of the tBID-induction of BAK (Bcl-2 homologous antagonist killer) or the tBID-induction of BAX (Bcl-2-associated X protein). Steady state equations are used to develop an explicit formula describing the total concentration level of tBID, guaranteed to trigger apoptosis, as a bilinear function of the total BAD concentration level and the total anti-apoptotic protein concentration level (usually Bcl-2 or Bcl-x(L)). In particular, the formula explains how the pro-apoptotic protein BAD lowers the threshold at which tBID induces BAK/BAX activation-reducing the level of total Bcl-2/Bcl-x(L), available to inhibit tBID signaling in the mitochondria. Attention is then turned to the experimental data surrounding BAD phosphorylation, a process known to inhibit the pro-apoptotic effects of BAD. To address this data, the phosphorylation process is modeled following two separate kinetics in which either free unbound BAD is the assumed substrate or Bcl-x(L)/Bcl-2-bound BAD is the assumed substrate. Bifurcation analysis and further analysis of the bilinear equation validate experiments, which suggest that BAD phosphorylation prevents irreversible BAK/BAX-mediated apoptosis, even when phosphorylation-induced dissociation of Bcl-x(L)/Bcl-2-bound BAD is blocked. It is also shown that a cooperative, even synergistic, removal of mitochondrial BAD is seen when both types of phosphorylation are assumed possible. The presented work, however, reveals that the balance between BAD phosphorylation and dephosphorylation modulates the degree to which BAD influences the signaling from tBID to BAK/BAX. Our model shows that both the mode(s) of phosphorylation and the BAD dephosphorylation rate become important factors in determining whether BAD influences the activation of the BAK/BAX signal or not. Such potential variations in the pro-apoptotic effects of BAD are used to explain some of the inconsistent experimental data surrounding BAD phosphorylation. Nonetheless, our model serves to evaluate BAD and its sensitizing effects on the tBID-induction of BAK/BAX and thus aid in predicting when the incorporation of BAD in an apoptosis signaling model is important and when it is not. (C) 2010 Elsevier Ltd. All rights reserved.