Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability.
Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability.
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数学建模将细胞凋亡的抑制剂鉴定为阳性反馈和双重性的介体。
DOI：
10.1371/journal.pcbi.0020120
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发表时间：
2006-09-15
影响因子：
4.3
通讯作者：
Herzel H
中科院分区：
文献类型：
--
作者：
Legewie S;Blüthgen N;Herzel H
半胱天冬酶激活的内在或线粒体途径对于包括细胞毒性应激在内的各种刺激诱导细胞凋亡至关重要。这取决于细胞环境，从线粒体释放的细胞色素c是否诱导半胱天冬酶的激活逐渐或以全或无的方式，以及半胱天冬酶的激活是否不可逆地使细胞凋亡。通过分析定量动力学模型，我们表明，抑制凋亡抑制剂（IAP）的caspase-3（Casp 3）和Casp 9的结果在一个隐含的正反馈，因为切割的Casp 3增强其自身的激活隔离IAP远离Casp 9。我们证明了这种正反馈带来了双稳态（即，全或无行为），并且其与Casp 3介导的Casp 9反馈切割合作以在胱天蛋白酶活化中产生不可逆性。我们的计算还揭示了细胞特异性蛋白质表达如何导致所观察到的半胱天冬酶激活的定性差异（渐进与全或无，可逆与不可逆）。最后，已知的调节途径被证明可以有效地改变凋亡阈值刺激，这表明caspase级联反应将多个输入计算为全或无caspase输出。作为细胞抑制蛋白（例如，IAP）经常抑制细胞信号级联中的连续中间体（例如，Casp 3和Casp 9），本文中描述的反馈机制可能是细胞如何实现超灵敏度，双稳态和不可逆性的普遍原理。多细胞生物通过程序性细胞死亡（也称为细胞凋亡）消除受损或多余的细胞。通过模拟参与细胞凋亡启动的信号通路，作者提供了细胞如何防止自发凋亡，但一旦促凋亡信号超过阈值，仍有效地进入细胞死亡的见解。模拟还解释了细胞如何准确地将一组复杂的促凋亡和抗凋亡信号转化为生死决定。一旦细胞凋亡被启动，即使最初的触发因素被去除，细胞死亡也必须不可逆地进行，因为部分细胞解体可能导致组织炎症或细胞失调。作者解释了这种不可逆转的承诺是如何在细胞凋亡的起始途径中产生的，并提供了实验可检验的预测。最后，模拟揭示了蛋白质的凋亡抑制剂家族的意想不到的作用，因为这些蛋白质被预测参与死亡信号的放大，而不仅仅是在它们的抑制。
The intrinsic, or mitochondrial, pathway of caspase activation is essential for apoptosis induction by various stimuli including cytotoxic stress. It depends on the cellular context, whether cytochrome c released from mitochondria induces caspase activation gradually or in an all-or-none fashion, and whether caspase activation irreversibly commits cells to apoptosis. By analyzing a quantitative kinetic model, we show that inhibition of caspase-3 (Casp3) and Casp9 by inhibitors of apoptosis (IAPs) results in an implicit positive feedback, since cleaved Casp3 augments its own activation by sequestering IAPs away from Casp9. We demonstrate that this positive feedback brings about bistability (i.e., all-or-none behaviour), and that it cooperates with Casp3-mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation. Our calculations also unravel how cell-specific protein expression brings about the observed qualitative differences in caspase activation (gradual versus all-or-none and reversible versus irreversible). Finally, known regulators of the pathway are shown to efficiently shift the apoptotic threshold stimulus, suggesting that the bistable caspase cascade computes multiple inputs into an all-or-none caspase output. As cellular inhibitory proteins (e.g., IAPs) frequently inhibit consecutive intermediates in cellular signaling cascades (e.g., Casp3 and Casp9), the feedback mechanism described in this paper is likely to be a widespread principle on how cells achieve ultrasensitivity, bistability, and irreversibility. Multicellular organisms eliminate damaged or excess cells by programmed cell death, also known as apoptosis. By modelling the signaling pathways involved in the initiation of apoptosis, the authors provide insight into how cells prevent spontaneous apoptosis, but yet efficiently enter cell death, once proapoptotic signals exceed a threshold. The simulations also explain how cells accurately translate a complex set of pro- and anti-apoptotic signals into a life-or-death decision. Once apoptosis has been initiated, cellular demise must irreversibly proceed even if the initial trigger is removed, as partial cellular disintegration might lead to tissue inflammation or cellular deregulation. The authors explain how such irreversible commitment arises in the initiation pathways of apoptosis and provide experimentally testable predictions. Finally, the simulations reveal an unanticipated role for the inhibitor of apoptosis family of proteins, as these proteins are predicted to be involved in the amplification of death signals and not only in their suppression.
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