A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints

Circadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological pr...

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Autores principales: Zou, Xianlin, Kim, Dae Wook, Gotoh, Tetsuya, Liu, Jingjing, Kim, Jae Kyoung, Finkielstein, Carla V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176909/
https://www.ncbi.nlm.nih.gov/pubmed/32372973
http://dx.doi.org/10.3389/fphys.2020.00327
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author Zou, Xianlin
Kim, Dae Wook
Gotoh, Tetsuya
Liu, Jingjing
Kim, Jae Kyoung
Finkielstein, Carla V.
author_facet Zou, Xianlin
Kim, Dae Wook
Gotoh, Tetsuya
Liu, Jingjing
Kim, Jae Kyoung
Finkielstein, Carla V.
author_sort Zou, Xianlin
collection PubMed
description Circadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological processes run on a 24 h timescale. The hierarchical nature of the clock manifests itself in multiple points of control on the daily cell division cycle, which relies on synthesis, degradation, and post-translational modification for progression. This relationship is particularly important for understanding the role of clock components in sensing stress conditions and triggering checkpoint signals that stop cell cycle progression. A case in point is the interplay among the circadian factor PERIOD2 (PER2), the tumor suppressor p53, and the oncogenic mouse double minute-2 homolog protein (MDM2), which is the p53’s negative regulator. Under unstressed conditions, PER2 and p53 form a stable complex in the cytosol and, along with MDM2, a trimeric complex in the nucleus. Association of PER2 to the C-terminus end of p53 prevents MDM2-mediated ubiquitylation and degradation of p53 as well as p53’s transcriptional activation. Remarkably, when not bound to p53, PER2 acts as substrate for the E3-ligase activity of MDM2; thus, PER2 is degraded in a phosphorylation-independent fashion. Unexpectedly, the phase relationship between PER2 and p53 are opposite; however, a systematic modeling approach, inferred from the oscillatory time course data of PER2 and p53, aided in identifying additional regulatory scenarios that explained, a priori, seemingly conflicting experimental data. Therefore, we advocate for a combined experimental/mathematical approach to elucidating multilevel regulatory cellular processes.
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spelling pubmed-71769092020-05-05 A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints Zou, Xianlin Kim, Dae Wook Gotoh, Tetsuya Liu, Jingjing Kim, Jae Kyoung Finkielstein, Carla V. Front Physiol Physiology Circadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological processes run on a 24 h timescale. The hierarchical nature of the clock manifests itself in multiple points of control on the daily cell division cycle, which relies on synthesis, degradation, and post-translational modification for progression. This relationship is particularly important for understanding the role of clock components in sensing stress conditions and triggering checkpoint signals that stop cell cycle progression. A case in point is the interplay among the circadian factor PERIOD2 (PER2), the tumor suppressor p53, and the oncogenic mouse double minute-2 homolog protein (MDM2), which is the p53’s negative regulator. Under unstressed conditions, PER2 and p53 form a stable complex in the cytosol and, along with MDM2, a trimeric complex in the nucleus. Association of PER2 to the C-terminus end of p53 prevents MDM2-mediated ubiquitylation and degradation of p53 as well as p53’s transcriptional activation. Remarkably, when not bound to p53, PER2 acts as substrate for the E3-ligase activity of MDM2; thus, PER2 is degraded in a phosphorylation-independent fashion. Unexpectedly, the phase relationship between PER2 and p53 are opposite; however, a systematic modeling approach, inferred from the oscillatory time course data of PER2 and p53, aided in identifying additional regulatory scenarios that explained, a priori, seemingly conflicting experimental data. Therefore, we advocate for a combined experimental/mathematical approach to elucidating multilevel regulatory cellular processes. Frontiers Media S.A. 2020-04-16 /pmc/articles/PMC7176909/ /pubmed/32372973 http://dx.doi.org/10.3389/fphys.2020.00327 Text en Copyright © 2020 Zou, Kim, Gotoh, Liu, Kim and Finkielstein. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Zou, Xianlin
Kim, Dae Wook
Gotoh, Tetsuya
Liu, Jingjing
Kim, Jae Kyoung
Finkielstein, Carla V.
A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title_full A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title_fullStr A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title_full_unstemmed A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title_short A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints
title_sort systems biology approach identifies hidden regulatory connections between the circadian and cell-cycle checkpoints
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176909/
https://www.ncbi.nlm.nih.gov/pubmed/32372973
http://dx.doi.org/10.3389/fphys.2020.00327
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