scholarly journals Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein MDM2

2018 ◽  
Author(s):  
JingJing Liu ◽  
Xianlin Zou ◽  
Tetsuya Gotoh ◽  
Anne M. Brown ◽  
Liang Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Biological Systems ◽  
Period Length ◽  
Circadian Period ◽  
Functional Elements ◽  
Post Translational Modifications ◽  
Independent Mechanism

ABSTRACTThe circadian clock relies on post-translational modifications to set the timing for degradation of core regulatory components and, thus, sets clock progression. Ubiquitin-modifying enzymes targeting clock components for degradation are known to mostly recognize phosphorylated substrates. A case in point is the circadian factor PERIOD 2 (PER2) whose phospho-specific turnover involves its recognition by β-transducin repeat containing proteins (β-TrCPs). Yet, the existence of this unique mode of regulation of PER2’s stability falls short of explaining persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery.In this study, we challenge the phosphorylation-centric view that PER2 degradation enhances circadian rhythm robustness by i) identifying the PER2:MDM2 endogenous complex, ii) establishing PER2 as a previously uncharacterized substrate for MDM2, iii) revealing an alternative phosphorylation-independent mechanism for PER2 ubiquitin-mediated degradation, iv) pinpointing residues for ubiquitin modification, and v) establishing the importance of MDM2-mediated PER2 turnover for defining the circadian period length. Our results not only expand MDM2’s suite of specific substrates beyond the cell cycle to include circadian components but also uncover novel regulatory players that likely impact our view of how other mechanisms crosstalk and modulate the clock itself.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

scholarly journals Survival is reduced when endogenous period deviates from 24 h in a non-human primate, supporting the circadian resonance theory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Clara Hozer ◽  
Martine Perret ◽  
Samuel Pavard ◽  
Fabien Pifferi
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Microcebus Murinus ◽  
Circadian Period ◽  
Biological Functions ◽  
Resonance Theory ◽  
Aging Research ◽  
Mouse Lemurs ◽  
Living Organisms ◽  
Human Primate

Abstract Circadian rhythms are ubiquitous attributes across living organisms and allow the coordination of internal biological functions with optimal phases of the environment, suggesting a significant adaptive advantage. The endogenous period called tau lies close to 24 h and is thought to be implicated in individuals’ fitness: according to the circadian resonance theory, fitness is reduced when tau gets far from 24 h. In this study, we measured the endogenous period of 142 mouse lemurs (Microcebus murinus), and analyzed how it is related to their survival. We found different effects according to sex and season. No impact of tau on mortality was found in females. However, in males, the deviation of tau from 24 h substantially correlates with an increase in mortality, particularly during the inactive season (winter). These results, comparable to other observations in mice or drosophila, show that captive gray mouse lemurs enjoy better fitness when their circadian period closely matches the environmental periodicity. In addition to their deep implications in health and aging research, these results raise further ecological and evolutionary issues regarding the relationships between fitness and circadian clock.

scholarly journals Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

2021 ◽  
Vol 15 ◽  
Author(s):  
Daisuke Ono ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cellular Networks ◽  
Clock Genes ◽  
Circadian System ◽  
Developmental Changes ◽  
Circadian Period ◽  
Functional Roles ◽  
Environmental Light

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

Minimally Invasive Ways of Determining Circadian Rhythms in Humans

Physiology ◽  
2021 ◽  
Vol 36 (1) ◽  
pp. 7-20 ◽  
Author(s):  
Sandra Crnko ◽  
Hilde Schutte ◽  
Pieter A. Doevendans ◽  
Joost P. G. Sluijter ◽  
Linda W. van Laake
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Minimally Invasive ◽  
Circadian Clock ◽  
Critical Role ◽  
Health And Disease

Circadian rhythm exerts a critical role in mammalian health and disease. A malfunctioning circadian clock can be a consequence, as well as the cause of several pathophysiologies. Clinical therapies and research may also be influenced by the clock. Since the most suitable manner of revealing this rhythm in humans is not yet established, we discuss existing methods and seek to determine the most feasible ones.

scholarly journals Circadian Rhythms in the Thermophilic Cyanobacterium Thermosynechococcus elongatus: Compensation of Period Length over a Wide Temperature Range

2004 ◽  
Vol 186 (15) ◽  
pp. 4972-4977 ◽  
Author(s):  
Kiyoshi Onai ◽  
Megumi Morishita ◽  
Shino Itoh ◽  
Kazuhisa Okamoto ◽  
Masahiro Ishiura
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Period Length ◽  
Oxygenic Photosynthesis ◽  
Dark Cycle ◽  
Bacterial Luciferase ◽  
X Ray ◽  
Gene Set ◽  
Thermophilic Cyanobacterium ◽  
Wide Range

ABSTRACT Proteins derived from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1, which performs plant-type oxygenic photosynthesis, are suitable for biochemical, biophysical, and X-ray crystallographic studies. We developed an automated bioluminescence real-time monitoring system for the circadian clock in the thermophilic cyanobacterium T. elongatus BP-1 that uses a bacterial luciferase gene set (Xl luxAB) derived from Xenorhabdus luminescens as a bioluminescence reporter gene. A promoter region of the psbA1 gene of T. elongatus was fused to the Xl luxAB gene set and inserted into a specific targeting site in the genome of T. elongatus. The bioluminescence from the cells of the psbA1-reporting strain was measured by an automated monitoring apparatus with photomultiplier tubes. The strain exhibited the circadian rhythms of bioluminescence with a 25-h period length for at least 10 days in constant light and temperature. The rhythms were reset by light-dark cycle, and their period length was almost constant over a wide range of temperatures (30 to 60°C). Theses results indicate that T. elongatus has the circadian clock that is widely temperature compensated.

scholarly journals Circadian rhythm and neurodegenerative disorders

2020 ◽  
Vol 6 (2) ◽  
pp. 71-80
Author(s):  
Michelle Werdann ◽  
Yong Zhang
Keyword(s):  
Circadian Rhythm ◽  
Early Intervention ◽  
Circadian Rhythms ◽  
Neurodegenerative Diseases ◽  
Circadian Clock ◽  
Neurodegenerative Disorders ◽  
Circadian Clocks ◽  
Daily Rhythms ◽  
Animal Physiology ◽  
And Behavior

The circadian clock controls daily rhythms in animal physiology, metabolism, and behavior, such as the sleep‐wake cycle. Disruption of circadian rhythms has been revealed in many diseases including neurodegenerative disorders. Interestingly, patients with many neurodegenerative diseases often show problems with circadian clocks even years before other symptoms develop. Here we review the recent studies identifying the association between circadian rhythms and several major neurodegenerative disorders. Early intervention of circadian rhythms may benefit the treatment of neurodegeneration.

scholarly journals Simulated Space Environmental Factors of Weightlessness, Noise and Low Air Pressure Differentially Affect the Circadian Rhythm and Gut Microbiome

2021 ◽  
Author(s):  
Huan Ma ◽  
Xihui Gan ◽  
Jianwei Zhao ◽  
Yin Zhang ◽  
Silin Li ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Community Structure ◽  
Circadian Rhythms ◽  
Environmental Factors ◽  
Circadian Clock ◽  
Gut Microbiome ◽  
Atmospheric Pressure ◽  
Clock Genes ◽  
Low Atmospheric Pressure ◽  
Space Capsule

Abstract Backgroundhe circadian clock extensively regulates physiology and behavior. In space, the astronauts encounter many environmental factors that are dramatically different from those on earth, however, the effects of these factors on circadian rhythms and the mechanisms remain largely unknown. The present study aimed to investigate the changes in the mouse circadian rhythm and gut microbiome under simulated space capsule conditions, including microgravity, noise and low atmospheric pressure.ResultsNoise and low atmospheric pressure were loaded in the capsule while the conditions in the animal room remained constant. The mice in the capsule showed disturbed locomotor rhythms and faster adaptation to a 6-h phase advance. RNA sequencing of hypothalamus samples revealed that microgravity simulated by hind limb unloading (HU) and exposure to noise and low atmospheric pressure led to decreases in the quantities of differentially expressed genes (DEGs), including circadian clock genes. Changes in the rhythmicity of genes implicated in pathways of cardiovascular deconditioning and more concentrated circadian phases were found under HU or noise and low atmospheric pressure. Furthermore, 16S rRNA sequencing revealed dysbiosis in the gut microbiome, and noise and low atmospheric pressure may repress the temporal discrepancy in the microbiome community structure induced by microgravity. Changes in diel oscillation were observed in a number of gut bacteria with critical physiological consequences in metabolism and immunodefense.ConclusionsOur data demonstrate that in addition to microgravity, exposure to noise and low atmospheric pressure affect the robustness of circadian rhythms and the community structure of the gut microbiome, and these factors may interfere with each other in their adaptation to respective conditions. These findings are important to further our understanding of the alteration of circadian rhythms in the space complex environment.

scholarly journals Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

GeroScience ◽  
2021 ◽  
Author(s):  
Maria Giulia Bacalini ◽  
Flavia Palombo ◽  
Paolo Garagnani ◽  
Cristina Giuliani ◽  
Claudio Fiorini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Successful Aging ◽  
Clock Genes ◽  
Association Studies ◽  
Italian Population ◽  
Age Related

AbstractMany physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

scholarly journals ISOLATION OF CIRCADIAN CLOCK MUTANTS OF NEUROSPORA CRASSA

Genetics ◽  
1973 ◽  
Vol 75 (4) ◽  
pp. 605-613
Author(s):  
Jerry F Feldman ◽  
Marian N Hoyle
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Neurospora Crassa ◽  
Nuclear Gene ◽  
Period Length ◽  
Continuous Darkness ◽  
Timing Mechanism

ABSTRACT Three mutants of Neurospora crassa have been isolated which have altered period lengths of their circadian rhythm of conidiation. The strains, designated "frequency" (frq), were obtained after mutagenesis of the band (bd) strain with N-methyl-N'-nitro-N-nitrosoguanidine. In continuous darkness at 25° bd has a period length of 21.6 ± 0.5 hours; under the same conditions the period length of frq-1 is 16.5 ± 0.5 hours; frq-2, 19.3 ± 0.4 hours; and frq-3, 24.0 ± 0.4 hours. Each of the mutants segregates as a single nuclear gene. All three mutants appear very tightly linked to each other, but it has not yet been determined whether the mutants are allelic. No major changes in the responses to light and temperature have been observed in any of the mutants. It is suggested that these mutants represent alterations in the basic timing mechanism of the circadian clock of Neurospora.

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