Department of Chemistry, Bioscience, and Environmental Engineering, University of Stavanger, Stavanger, Norway.
Division of Mathematical and Physical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
PLoS One. 2020 May 20;15(5):e0227786. doi: 10.1371/journal.pone.0227786. eCollection 2020.
Homeostasis is an essential concept to understand the stability of organisms and their adaptive behaviors when coping with external and internal assaults. Many hormones that take part in homeostatic control come in antagonistic pairs, such as glucagon and insulin reflecting the inflow and outflow compensatory mechanisms to control a certain internal variable, such as blood sugar levels. By including negative feedback loops homeostatic controllers can exhibit oscillations with characteristic frequencies. In this paper we demonstrate the associated frequency changes in homeostatic systems when individual controllers -in a set of interlocked feedback loops- gain control in response to environmental changes. Taking p53 as an example, we show how Per2, ATM and Mdm2 feedback loops -interlocked with p53- gain individual control in dependence to the level of DNA damage, and how each of these controllers provide certain functionalities in their regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 level to allow its rapid up-regulation in case of DNA damage. When DNA damage occurs the ATM controller increases the level of p53 and defends it towards uncontrolled degradation, which despite DNA damage, would drive p53 to lower values and p53 dysfunction. Mdm2 on its side keeps p53 at a high but sub-apoptotic level to avoid premature apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by HSP90 and other p53 stabilizers leading finally to apoptosis. An emergent aspect of p53 upregulation during cell stress is the coordinated inhibition of ubiquitin-independent and ubiquitin-dependent degradation reactions. Whether oscillations serve a function or are merely a by-product of the controllers are discussed in view of the finding that homeostatic control of p53, as indicated above, does in principle not require oscillatory homeostats.
稳态是理解生物体稳定性及其应对外部和内部攻击时的适应行为的一个基本概念。许多参与稳态控制的激素形成拮抗对，例如胰高血糖素和胰岛素，反映了流入和流出补偿机制，以控制血糖等特定内部变量。通过包括负反馈回路，稳态控制器可以表现出具有特征频率的振荡。在本文中，我们展示了当个体控制器（在一组互锁反馈回路中）响应环境变化获得控制时，稳态系统相关的频率变化。以 p53 为例，我们展示了 Per2、ATM 和 Mdm2 反馈回路 - 与 p53 互锁 - 如何根据 DNA 损伤水平获得个体控制，以及这些控制器中的每一个如何在其对 p53 的调节中提供特定功能。在未受压力的细胞中，生物钟调节剂 Per2 确保了基本的 p53 水平，以允许其在 DNA 损伤时快速上调。当发生 DNA 损伤时，ATM 控制器会增加 p53 的水平并防止其失控降解，尽管存在 DNA 损伤，但这会导致 p53 降低并导致 p53 功能障碍。另一方面，Mdm2 将 p53 保持在高但亚凋亡水平，以避免过早凋亡。然而，随着持续的 DNA 损伤，Mdm2 的设定点会被 HSP90 和其他 p53 稳定剂增加，最终导致细胞凋亡。细胞应激过程中 p53 上调的一个新出现方面是协调抑制泛素非依赖性和泛素依赖性降解反应。鉴于上述关于 p53 的稳态控制原则上不需要振荡稳态的发现，正在讨论振荡是否具有功能还是仅仅是控制器的副产品。
