Frequency switching between oscillatory homeostats and the regulation of p53

Abstract

1Homeostasis is an essential concept to understand the stability of organisms and their 2 adaptive behaviors when coping with external and internal assaults. Many hormones 3 that take part in homeostatic control come in antagonistic pairs, such as glucagon and 4 insulin reflecting the inflow and outflow compensatory mechanisms to control a certain 5 internal variable, such as blood sugar levels. By including negative feedback loops 6 homeostatic controllers can exhibit oscillations with characteristic frequencies. In this 7 paper we demonstrate the associated frequency changes in homeostatic systems when 8 individual controllers in a set of interlocked feedback loops gain control in response to 9 environmental changes. Taking p53 as an example, we show how the Per2, ATM and 10 Mdm2 feedback loops -interlocked with p53-gain individual control in dependence to 11 DNA damage and how each of these controllers provide certain functionalities in their 12 regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 13 level to allow its rapid up-regulation in case of DNA damage. When DNA damage 14 occurs the ATM controller increases the level of p53 and defends it towards uncontrolled 15 degradation, which despite DNA damage, would drive p53 to lower values and p53 16dysfunction. Mdm2 on its side keeps p53 at a maximum level to avoid premature 17 apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by 18 HSP90 and other p53 stabilizers leading finally to apoptosis. An essential aspect in p53 19 regulation at occurring cell stress is the coordinated inhibition of ubiquitin-independent 20 and ubiquitin-dependent degradation reactions and the increasing stabilizing 21 mechanisms of p53. Whether oscillations serve a function or are merely a by-product of 22 the controllers are discussed in view of the finding that homeostatic control of p53, as 23 indicated above, does in principle not require oscillatory homeostats. 24 30 control [8], alongside with integral feedback [9][10][11], and systems biology methods [12, 13]. 31 It became clear that certain reaction kinetic conditions are necessary for the occurrence 32December 24, 2019 1/17 of integral control leading to the robustness of the feedback controller. These conditions 33 include zero-order kinetics [9, 10,[14][15][16][17][18][19], autocatalysis [20][21][22], and second-order 34 (bimolecular/antithetic) reaction [23, 24], which were implemented into various controller 35 motifs, synthetic gene networks, and other negative feedback structures [18,[25][26][27]. 36A particular interesting aspect is that, under certain conditions, the homeostatic 37 controllers may become oscillatory and preserve, if integral control is present, their 38 homeostatic property by keeping the average value of the controlled variable at its 39 set-point [28]. While the occurrence of oscillations is generally avoided in control 40 engineering, natural systems show generally oscillatory behaviors, as found in circadian 41 or ultradian rhythms ...

Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation

“…Carpenter that the term homeostasis still stands as an unified approach [9]. We believe, that when multiple feedback and feedforward loops are studied theoretically in more detail, many of the above mentioned homeostatic facets can be accounted for, such as rheostatic control can be observed in a model of p53 regulation upon variable stress conditions [10].…”