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Frequency switching between oscillatory homeostats and the regulation of p53
- Source :
- PLoS ONE, Vol 15, Iss 5, p e0227786 (2020), PLoS ONE, PLOS ONE
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- 金沢大学国際基幹教育院<br />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.<br />Creative Commons Attribution License 4.0
- Subjects :
- Physiology
Regulator
døgnrytme
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Matematikk og Naturvitenskap: 400::Basale biofag: 470 [VDP]
Biochemistry
0302 clinical medicine
Medicine and Health Sciences
Homeostasis
Phosphorylation
Feedback, Physiological
0303 health sciences
Multidisciplinary
Cell Death
Chemistry
Mechanisms of Signal Transduction
Proto-Oncogene Proteins c-mdm2
Period Circadian Proteins
Circadian Rhythm
Nucleic acids
PER2
Circadian Oscillators
Circadian Rhythms
Cell Processes
Homeostatic Mechanisms
Medicine
Genetic Oscillators
Research Article
Signal Transduction
Feedback Regulation
DNA damage
Science
DNA-skade
cirkadiske rytmer
03 medical and health sciences
Downregulation and upregulation
Negative feedback
Genetics
Humans
Automatic gain control
Internal variable
030304 developmental biology
Ubiquitin
Maximum level
Biology and Life Sciences
DNA
Cell Biology
Models, Theoretical
homeostase
Cell stress
Gene Expression Regulation
Tumor Suppressor Protein p53
Physiological Processes
Chronobiology
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- PLoS ONE, Vol 15, Iss 5, p e0227786 (2020), PLoS ONE, PLOS ONE
- Accession number :
- edsair.doi.dedup.....c813b32ff4caf3f5ac93f671a75536b0
- Full Text :
- https://doi.org/10.1101/2019.12.31.891622