scholarly journals Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation

2017 ◽  
Vol 28 (6) ◽  
pp. 834-842 ◽  
Author(s):  
Amol Chaudhari ◽  
Richa Gupta ◽  
Sonal Patel ◽  
Nikkhil Velingkaar ◽  
Roman Kondratov
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Skeletal Muscles ◽  
Cancer Metabolism ◽  
Reduced Body ◽  
Circadian Control ◽  
Cell Growth And Proliferation ◽  
Deficient Mice ◽  
Igf Signaling

Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)—transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone–induced, JAK2 kinase–mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.

scholarly journals Direct Association between Mouse PERIOD and CKIε Is Critical for a Functioning Circadian Clock

2004 ◽  
Vol 24 (2) ◽  
pp. 584-594 ◽  
Author(s):  
Choogon Lee ◽  
David R. Weaver ◽  
Steven M. Reppert
Keyword(s):  
Circadian Clock ◽  
Double Mutant ◽  
Mutant Mice ◽  
Chimeric Proteins ◽  
Posttranslational Regulation ◽  
Dependent Manner ◽  
Clock Proteins ◽  
Deficient Mice

ABSTRACT The mPER1 and mPER2 proteins have important roles in the circadian clock mechanism, whereas mPER3 is expendable. Here we examine the posttranslational regulation of mPER3 in vivo in mouse liver and compare it to the other mPER proteins to define the salient features required for clock function. Like mPER1 and mPER2, mPER3 is phosphorylated, changes cellular location, and interacts with other clock proteins in a time-dependent manner. Consistent with behavioral data from mPer2/3 and mPer1/3 double-mutant mice, either mPER1 or mPER2 alone can sustain rhythmic posttranslational events. However, mPER3 is unable to sustain molecular rhythmicity in mPer1/2 double-mutant mice. Indeed, mPER3 is always cytoplasmic and is not phosphorylated in the livers of mPer1-deficient mice, suggesting that mPER3 is regulated by mPER1 at a posttranslational level. In vitro studies with chimeric proteins suggest that the inability of mPER3 to support circadian clock function results in part from lack of direct and stable interaction with casein kinase Iε (CKIε). We thus propose that the CKIε-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock.

scholarly journals The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments

2021 ◽  
Vol 22 (6) ◽  
pp. 2974
Author(s):  
Marina Maria Bellet ◽  
Claudia Stincardini ◽  
Claudio Costantini ◽  
Marco Gargaro ◽  
Stefania Pieroni ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cancer Cells ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Antitumor Agents ◽  
Pharmacological Therapy ◽  
Drug Induced

The circadian clock driven by the daily light–dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other’s expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.

scholarly journals Machine Learning and In-Vivo Expression Analyses Reveal Circadian Clock Features Predictive of Anxiety in Humans

2021 ◽  
Author(s):  
Aziz Zafar ◽  
Rebeccah Overton ◽  
Ziad Attia ◽  
Ahmet Ay ◽  
Krista Ingram
Keyword(s):  
Machine Learning ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Gene ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Anxiety Symptoms ◽  
Circadian Phase ◽  
Functional Studies

Abstract Mood disorders, including anxiety, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3B-AG/CRY1-CG genotype being the strongest predictor of anxiety risk in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3B effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

scholarly journals Cancer clocks in tumourigenesis: the p53 pathway and beyond

2021 ◽  
Vol 28 (4) ◽  
pp. R95-R110
Author(s):  
Ewan M Stephenson ◽  
Laura E J Usselmann ◽  
Vinay Tergaonkar ◽  
David M Virshup ◽  
Robert Dallmann
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cancer Biology ◽  
Cell Cycle Progression ◽  
Clock Genes ◽  
Human Cancer ◽  
Epidemiologic Studies ◽  
Current Evidence

Circadian rhythms regulate a vast array of physiological and cellular processes, as well as the hormonal milieu, to keep our cells synchronised to the light–darkness cycle. Epidemiologic studies have implicated circadian disruption in the development of breast and other cancers, and numerous clock genes are dysregulated in human tumours. Here we review the evidence that circadian rhythms, when altered at the molecular level, influence cancer growth. We also note some common pitfalls in circadian-cancer research and how they might be avoided to maximise comparable results and minimise misleading data. Studies of circadian gene mutant mice, and human cancer models in vitro and in vivo, demonstrate that clock genes can impact tumourigenesis. Clock genes influence important cancer-related pathways, ranging from p53-mediated apoptosis to cell cycle progression. Confusingly, clock dysfunction can be both pro- or anti-tumourigenic in a model and cell type-specific manner. Due to this duality, there is no canonical mechanism for clock interaction with tumourigenic pathways. To understand the role of the circadian clock in patients’ tumours requires analysis of the molecular clock status compared to healthy tissue. Novel mathematical approaches are under development, but this remains largely aspirational, and is hampered by a lack of temporal information in publicly available datasets. Current evidence broadly supports the notion that the circadian clock is important for cancer biology. More work is necessary to develop an overarching model of this connection. Future studies would do well to analyse the clock network in addition to alterations in single clock genes.

scholarly journals Vascular circadian rhythms in a mouse vascular smooth muscle cell line (Movas-1)

2008 ◽  
Vol 295 (5) ◽  
pp. R1529-R1538 ◽  
Author(s):  
Jennifer A. Chalmers ◽  
Tami A. Martino ◽  
Nazneen Tata ◽  
Martin R. Ralph ◽  
Michael J. Sole ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Circadian Rhythms ◽  
Vascular Smooth Muscle ◽  
Circadian Clock ◽  
Smooth Muscle Cell ◽  
Cell Line ◽  
Cell Model ◽  
Muscle Cell Line

The circadian system in mammals is a hierarchy of oscillators throughout the organism that are coordinated by the circadian clock in the hypothalamic suprachiasmatic nucleus. Peripheral clocks act to integrate time-of-day information from neural or hormonal signals, regulating gene expression, and, subsequently, organ physiology. However, the mechanisms by which the central clock communicates with peripheral oscillators are not understood and are likely tissue specific. In this study, we establish a mouse vascular cell model suitable for investigations of these mechanisms at a molecular level. Using the immortalized vascular smooth muscle cell line Movas-1, we determined that these cells express the circadian clock machinery with robust rhythms in mRNA expression over a 36-h period after serum shock synchronization. Furthermore, norepinephrine and forskolin were able to synchronize circadian rhythms in bmal1. With synchronization, we observed cycling of specific genes, including the tissue inhibitor of metalloproteinase 1 and 3 ( timp1, timp3), collagen 3a1 ( col3a1), transgelin 1 ( sm22α), and calponin 1 ( cnn1). Diurnal expression of these genes was also found in vivo in mouse aortic tissue, using microarray and real-time RT-PCR analysis. Both of these revealed ultradian rhythms in genes similar to the cycling observed in Movas-1 in vitro. These findings highlight the cyclical nature of structurally important genes in the vasculature that is similar both in vivo and in vitro. This study establishes the Movas-1 cells as a novel cell model from which to further investigate the molecular mechanisms of clock regulation in the vasculature.

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

2005 ◽  
Vol 289 (3) ◽  
pp. R656-R662 ◽  
Author(s):  
J. P. Clark ◽  
Christopher S. Sampair ◽  
Paulo Kofuji ◽  
Avindra Nath ◽  
Jian. M. Ding
Keyword(s):  
Nmda Receptor ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Glutamate Release ◽  
Phase Shifts ◽  
Channel Blockers ◽  
Light Entrainment ◽  
Transactivator Of Transcription

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC50= 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-d-aspartate (NMDA) receptor [d-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase ( NG-nitro-l-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 μM), tetanus toxin (1 μM), P/Q/N type-calcium channel blockers (1 μM ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A1(1 μM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.

scholarly journals Circadian control of the secretory pathway is a central mechanism in tissue homeostasis

2018 ◽  
Author(s):  
Joan Chang ◽  
Richa Garva ◽  
Adam Pickard ◽  
Ching-Yan Chloé Yeung ◽  
Venkatesh Mallikarjun ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Collagen Synthesis ◽  
Secretory Pathway ◽  
Protein Homeostasis ◽  
Collagen Network ◽  
Rhythmic Expression ◽  
Circadian Control ◽  
Collagen Accumulation ◽  
Clock Mechanism

Collagen is the most abundant secreted protein in vertebrates that persists throughout life without renewal. The unchanging nature of collagen contrasts with observed continued collagen synthesis throughout adulthood and with conventional transcriptional and translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of procollagen transport from ER-to-Golgi and Golgi-to-plasma membrane by sequential rhythmic expression of SEC61, TANGO1, PDE4D and VPS33B. The result is nocturnal procollagen synthesis and daytime collagen fibril assembly in mice. Rhythmic collagen degradation by CTSK maintains collagen homeostasis. This circadian cycle of collagen synthesis, assembly and degradation affects only a pool of newly-synthesized collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes collagen accumulation and abnormal fibrils in vivo. In conclusion, our study has identified a circadian clock mechanism of protein homeostasis in which a sacrificial pool of collagen is synthesized and removed to maintain tissue function.

scholarly journals Direct and indirect inhibition of the circadian clock protein Per1: effects on ENaC and blood pressure

2019 ◽  
Vol 316 (5) ◽  
pp. F807-F813 ◽  
Author(s):  
Abdel Alli ◽  
Ling Yu ◽  
Meaghan Holzworth ◽  
Jacob Richards ◽  
Kit-Yan Cheng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Target Genes ◽  
Single Channel ◽  
Nuclear Entry ◽  
Altered Expression ◽  
Circadian Control ◽  
Underlying Mechanisms ◽  
Clock Protein

Circadian rhythms govern physiological functions and are important for overall health. The molecular circadian clock comprises several transcription factors that mediate circadian control of physiological function, in part, by regulating gene expression in a tissue-specific manner. These connections are well established, but the underlying mechanisms are incompletely understood. The overall goal of this study was to examine the connection among the circadian clock protein Period 1 (Per1), epithelial Na+ channel (ENaC), and blood pressure (BP) using a multipronged approach. Using global Per1 knockout mice on a 129/sv background in combination with a high-salt diet plus mineralocorticoid treatment, we demonstrated that loss of Per1 in this setting is associated with protection from hypertension. Next, we used the ENaC inhibitor benzamil to demonstrate a role for ENaC in BP regulation and urinary Na+ excretion in 129/sv mice. We targeted Per1 indirectly using pharmacological inhibition of Per1 nuclear entry in vivo to demonstrate altered expression of known Per1 target genes as well as a BP-lowering effect in 129/sv mice. Finally, we directly inhibited Per1 via genetic knockdown in amphibian distal nephron cells to demonstrate, for the first time, that reduced Per1 expression is associated with decreased ENaC activity at the single channel level.

scholarly journals Cryptochrome deficiency enhances transcription but reduces protein levels of pineal Aanat

2018 ◽  
Vol 61 (4) ◽  
pp. 219-229 ◽  
Author(s):  
Yujiro Yamanaka ◽  
Yoshiko Yamada ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Circadian Clock ◽  
The Body ◽  
Constant Darkness ◽  
Protein Levels ◽  
Circadian Fluctuation ◽  
Β Receptor ◽  
Β Adrenergic Receptors ◽  
Camp Levels ◽  
Deficient Mice

Cryptochrome (Cry) 1 and 2 are essential for circadian rhythm generation, not only in the suprachiasmatic nucleus, the site of the mammalian master circadian clock, but also in peripheral organs throughout the body. CRY is also known as a repressor of arylalkylamine-N-acetyltransferase (Aanat) transcription; therefore, Cry deficiency is expected to induce constantly high pineal melatonin content. Nevertheless, we previously found that the content was consistently low in melatonin-proficient Cry1 and Cry2 double-deficient mice (Cry1 − / − /Cry2 − / − ) on C3H background. This study aims to clarify the mechanism underlying this discrepancy. In the Cry1 − / − /Cry2 − / − pineal, expression levels of Aanat and clock gene Per1 were consistently high with no circadian fluctuation on the first day in constant darkness, demonstrating that CRY acts in vivo as a repressor of the pineal circadian clock and AANAT. In contrast, the enzyme activity and protein levels of AANAT remained low throughout the day, supporting our previous observation of continuously low melatonin. Thus, effects of Cry deficiency on the responses of β-adrenergic receptors were examined in cultured pineal glands. Isoproterenol, a β-adrenergic stimulant, significantly increased melatonin content, although the increase was smaller in Cry1 − / − /Cry2 − / − than in WT mice, during both the day and night. However, the increase in cAMP in response to forskolin was similar in both genotypes, indicating that CRY deficiency does not affect the pathway downstream of the β-adrenergic receptor. These results suggest that a lack of circadian adrenergic input due to CRY deficiency decreases β-receptor activity and cAMP levels, resulting in consistently low AANAT levels despite abundant Aanat mRNA.

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