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dc.contributor.authorRuoff, Peter
dc.contributor.authorNishiyama, Nobuaki
dc.date.accessioned2020-05-26T13:16:59Z
dc.date.available2020-05-26T13:16:59Z
dc.date.created2020-05-21T09:46:05Z
dc.date.issued2020-05
dc.identifier.citationRuoff P, Nishiyama N (2020) Frequency switching between oscillatory homeostats and the regulation of p53. PLoS ONE 15(5): e0227786en_US
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/11250/2655657
dc.description.abstractHomeostasis 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.en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.subjectdøgnrytmeen_US
dc.subjectcirkadiske rytmeren_US
dc.subjectDNA-skadeen_US
dc.subjecthomeostaseen_US
dc.titleFrequency switching between oscillatory homeostats and the regulation of p53en_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.rights.holder© 2020 Ruoff, Nishiyama.en_US
dc.subject.nsiVDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470en_US
dc.source.volume15en_US
dc.source.journalPLOS ONEen_US
dc.source.issue5en_US
dc.identifier.doi10.1371/journal.pone.0227786
dc.identifier.cristin1812029
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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