Holczer Marianna, Márton Margita, Kurucz Anita, Bánhegyi Gábor, Kapuy Orsolya
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
Biomed Res Int. 2015;2015:319589. doi: 10.1155/2015/319589. Epub 2015 Apr 23.
One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress. Endoplasmic reticulum (ER) has a crucial role in sensing cellular homeostasis by controlling metabolism, proteostasis, and several signaling processes. ER stressors can induce autophagy-dependent survival; however excessive level of stress results in apoptotic cell death. Although many molecular components of these networks have already been discovered, the analysis of the dynamical features of the regulatory network of life-or-death decision is still lacking. Our goal was to incorporate both theoretical and molecular biological techniques to explore the autophagy-apoptosis crosstalk under ER stress. Using various levels of different ER stressors we confirmed that the control network always generated an evidently detectable autophagy-dependent threshold for apoptosis activation. We explored the features of this threshold by introducing both autophagy activators and inhibitors, and transient treatment with excessive level of ER stressor was also performed. Our experimental data were also supported by a stochastic approach. Our analysis suggests that even if the switch-like characteristic of apoptosis activation is hardly seen on population level the double negative feedback loop between autophagy and apoptosis inducers introduces bistability in the control network.
生物体最重要的任务之一是在面对压力时维持其基因完整性。内质网（ER）通过控制新陈代谢、蛋白质稳态和多种信号传导过程，在感知细胞内稳态方面发挥着关键作用。内质网应激源可诱导自噬依赖性存活；然而，过度的应激水平会导致细胞凋亡死亡。尽管这些网络的许多分子成分已经被发现，但对生死决策调控网络动态特征的分析仍然缺乏。我们的目标是结合理论和分子生物学技术，探索内质网应激下自噬与凋亡的相互作用。使用不同水平的各种内质网应激源，我们证实了控制网络总是会产生一个明显可检测到的自噬依赖性凋亡激活阈值。我们通过引入自噬激活剂和抑制剂来探索这个阈值的特征，并且还进行了过高水平内质网应激源的短暂处理。我们的实验数据也得到了一种随机方法的支持。我们的分析表明，即使在群体水平上几乎看不到凋亡激活的开关样特征，但自噬与凋亡诱导剂之间的双负反馈回路在控制网络中引入了双稳态。
