Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CLOCK”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2006

Multiple phytohormones influence distinct parameters of the plant circadian clock.

Circadian systems coordinate endogenous events with external signals. In mammals, hormone-clock feedbacks are a well-known integration system. Here, we investigated phytohormone effects on plant-circadian rhythms via the promoter:luciferase system. We report that many hormones control specific features of the plant-circadian system, and do so in distinct ways. In particular, cytokinins delay circadian phase, auxins regulate circadian amplitude and clock precision, and brassinosteroid and abscisic acid modulate circadian periodicity. We confirmed the pharmacology in hormone synthesis and perception mutants, as rhythmic expression is predictably altered in an array of hormone-related mutants. We genetically dissected one mechanism that integrates hormone signals into the clock, and showed that the hormone-activated ARABIDOPSIS RESPONSE REGULATOR 4 and the photoreceptor phytochrome B are elements in the input of the cytokinin signal to circadian phase. Furthermore, molecular-expression targets of this signal were found. Collectively, we found that plants have multiple input/output feedbacks, implying that many hormones can function on the circadian system to adjust the clock to external signals to properly maintain the clock system.

Arabidopsis↗
PubMed2004

MAP kinases in the mammalian circadian system--key regulators of clock function.

Over the past 7 years, there has been spectacular progress in our understanding of the molecular basis of the circadian pacemaker in many species, from yeast to mammals. However, the biochemical signalling mechanisms that underpin synchronization of the clock to environmental cues are still poorly understood. Recently, attention has been focused on the role of mitogen-activated protein (MAP) kinase in biological timekeeping. It has been proposed that signal transduction via the MAP kinase cascades allows environmental information to be assimilated intracellularly within the circadian clock to produce changes in the phasing of clock gene expression, which, in turn, underlies clock-controlled phase-resetting of biological rhythms. This review examines the evidence for MAP kinase, particularly extracellular regulated kinases 1/2, involvement in the circadian clock and looks at the putative upstream regulators and downstream substrates of this signalling system.

Animals↗
PubMed2003

A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors.

Although many biochemical, morphological and physiological processes in the vertebrate retina are controlled by a circadian (24 h) clock, the location of the clock and how the clock alters retinal function are unclear. For instance, several observations have suggested that dopamine, a retinal neuromodulator, may play an important role in retinal rhythmicity but the link between dopamine and a clock located within or outside the retina remains to be established. We found that endogenous dopamine release from isolated goldfish retinae cultured in continuous darkness for 56 h clearly exhibited a circadian rhythm with high values during the subjective day. The continuous presence of melatonin (1 nM) in the culture medium abolished the circadian rhythm of dopamine release and kept values constantly low and equal to the night-time values. The selective melatonin antagonist luzindole (1 microM) also abolished the dopamine rhythm but the values were high and equal to the daytime values. Melatonin application during the late subjective day introduced rod input and reduced cone input to fish cone horizontal cells, a state usually observed during the subjective night. In contrast, luzindole application during the subjective night decreased rod input and increased cone input. Prior application of dopamine or spiperone, a selective dopamine D(2)-like antagonist, blocked the above effects of melatonin and luzindole, respectively. These findings indicate that a circadian clock in the vertebrate retina regulates dopamine release by the activation of melatonin receptors and that endogenous melatonin modulates rod and cone pathways through dopamine-mediated D(2)-like receptor activation.

Animals↗
PubMed2001

Reciprocal regulation between TOC1 and LHY/CCA1 within the Arabidopsis circadian clock.

The interactive regulation between clock genes is central for oscillator function. Here, we show interactions between the Arabidopsis clock genes LATE ELONGATED HYPOCOTYL (LHY), CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), and TIMING OF CAB EXPRESSION 1 (TOC1). The MYB transcription factors LHY and CCA1 negatively regulate TOC1 expression. We show that both proteins bind to a region in the TOC1 promoter that is critical for its clock regulation. Conversely, TOC1 appears to participate in the positive regulation of LHY and CCA1 expression. Our results indicate that these interactions form a loop critical for clock function in Arabidopsis.

Arabidopsis↗
PubMed2005

Obesity and metabolic syndrome in circadian Clock mutant mice.

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

Adipocytes↗
PubMed2001

Signaling to the mammalian circadian clocks: in pursuit of the primary mammalian circadian photoreceptor.

The mammalian circadian system is critical for the proper regulation of behavioral and physiological rhythms. The central oscillator, or master clock, is located in the hypothalamic suprachiasmatic nucleus (SCN). Additional circadian clocks are dispersed throughout most organs and tissues of an animal. The most prominent stimuli capable of synchronizing circadian oscillations to the environment is light. This occurs through daily photic signaling to the SCN, which ultimately results in the appropriate phasing of the various biological rhythms. Two critical aspects of circadian biology that will be discussed here are photic signaling and the communication between central and peripheral clocks. After 10 years of investigation, the primary mammalian circadian photoreceptor remains elusive. Recent findings suggest that multiple photoreceptive molecules may contribute to the perception of environmental light cycles. In addition, the relatively recent identification of cell-autonomous peripheral clocks has opened up an entirely new area of investigation. Deciphering the communication networks responsible for harmonious central and peripheral clock function is a critical step toward the development of effective therapies for circadian-related disorders.

Animals↗
PubMed2006

The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function.

It is becoming increasingly clear that the intrinsic properties of both the heart and vasculature exhibit dramatic oscillations over the course of the day. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e., neurohumoral factors) and intracellular (i.e., circadian clock) influences. The intracellular circadian clock is composed of a series of transcriptional modulators that together allow the cell to perceive the time of day, thereby enabling preparation for an anticipated stimulus. These molecular timepieces have been characterized recently within both vascular smooth muscle cells and cardiomyocytes, giving rise to a multitude of hypotheses relating to the potential role(s) of the circadian clock as a modulator of physiological and pathophysiological cardiovascular events. For example, evidence strongly supports the hypothesis that the circadian clock within the heart modulates myocardial metabolism, which in turn facilitates anticipation of diurnal variations in workload, substrate availability, and/or the energy supply-to-demand ratio. The purpose of this review is therefore to summarize our current understanding of the molecular events governing diurnal variations in the intrinsic properties of the heart, with special emphasis on the intramyocardial circadian clock. Whether impairment of this molecular mechanism contributes toward cardiovascular disease associated with hypertension, diabetes mellitus, shift work, sleep apnea, and/or obesity will be discussed.

Animals↗
PubMed1999

The search for circadian clock and sleep genes.

In recent years, there has been extraordinary progress in elucidating the molecular components of the mammalian circadian clock system. The discovery of circadian clock genes in lower organisms (such as fruit flies and fungi), which show many similarities with clock genes in mammals, together with advances in mouse molecular genetics have led to major new discoveries on the molecular and genetic basis of mammalian circadian rhythms. This article reviews both of these lines of research from an historical perspective and discusses how these lines have merged to provide unique insights into the molecular mechanisms of circadian function. The review also speculates on how the discovery of circadian clock genes may lead directly or indirectly to the discovery of mammalian sleep genes. The determination of the molecular mechanisms via which circadian clock genes (and their protein products) regulate the timing and the need for sleep, and the identification of new genes involved in sleep regulation, may produce new information on the genetic and molecular control of sleep which could ultimately lead to the development of new treatments for sleep disorders.

Animals↗
PubMed2002

Restoration of self-sustained circadian rhythmicity by the mutant clock allele in mice in constant illumination.

Mice mutant for the Clock gene display abnormal circadian behavior characterized by long circadian periods and a tendency to become rapidly arrhythmic in constant darkness (DD). To investigate whether this result is contingent on the absence of light, the authors studied the circadian behavior of homozygous Clock mutant mice under conditions of both constant light and DD. Fourteen of 15 Clock/Clock mice stayed rhythmic in constant light of 70 to 170 lux, where 10 of 15 wild-type mice became arrhythmic. In contrast, only 5 of 15 Clock/ Clock mice and 15 of 15 wild-type mice remained rhythmic after 60 cycles when released in DD (dim red light of < 1.5 lux) after 8 days of entrainment. The restoration of self-sustained rhythmicity by the Clock allele cannot be attributed to reduced sensitivity of the system to light It underscores the fact that self-sustainment is not a secure guide to functional organization.

Alleles↗
PubMed2004

Retinal circadian clocks and control of retinal physiology.

Retinas of all classes of vertebrates contain endogenous circadian clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis, and cellular events such as rod disk shedding, intracellular signaling pathways, and gene expression. The vertebrate retina is an example of a "peripheral" oscillator that is particularly amenable to study because this tissue is well characterized, the relationships between the various cell types are extensively studied, and many local clock-controlled rhythms are known. Although the existence of a photoreceptor clock is well established in several species, emerging data are consistent with multiple or dual oscillators within the retina that interact to control local physiology. A prominent example is the antiphasic regulation of melaton in and dopamine in photoreceptors and inner retina, respectively. This review focuses on the similarities and differences in the molecular mechanisms of the retinal versus the SCN oscillators, as well as on the expression of core components of the circadian clockwork in retina. Finally, the interactions between the retinal clock(s) and the master clock in the SCN are examined.

Animals↗
PubMed2004

Posttranscriptional and posttranslational regulation of clock genes.

Circadian rhythms have been observed in diverse organisms, including plants, animals, bacteria, and fungi. In such organisms, the circadian clock is primarily composed of a cell-autonomous transcriptional feedback loop. In addition to transcriptional regulation, the modification of core clock transcripts and proteins can dramatically affect the circadian clock. In this review, the authors discuss some of the posttranscriptional and posttranslational modifications and their effects on the circadian clock. The combined outcome of these modifications is to adjust the timing of the clock to produce a circadian oscillator that takes approximately 24 h.

Animals↗
PubMed2004

It's all in the timing: many clocks, many outputs.

It is thought that circadian regulation of physiology and behavior imparts survival advantages to organisms that use clocks. In mammals, a master clock resident in the SCN synchronizes other central and peripheral oscillators to evoke this regulation. This master oscillator consists of interlocking transcriptional-translational feedback loops, and it regulates both core clock genes necessary for oscillator maintenance as well as specific output genes that directly or indirectly mediate physiology under circadian control. It is now clear that both neuroanatomic and molecular outputs of the clock are necessary for proper circadian clock function. Recent technology has improved our understanding of these processes, elucidating the anatomic outputs of the SCN, as well as the molecular outputs of both central and peripheral oscillators that mediate observed physiological changes.

Animals↗
PubMed2006

Restoration of circadian rhythmicity in circadian clock-deficient mice in constant light.

In mammals, circadian rhythms in behavior and physiology are controlled by a central pacemaker, the SCN, and subordinated clocks throughout the body. On the molecular level, these clocks are based on transcriptional/translational feedback loops involving a set of clock genes that regulate their own transcription. Among the components driving the mammalian circadian clock are the Period 1 and 2 (Per1 and Per2) and Cryptochrome 1 and 2 (Cry1 and Cry2) genes. In the present study, the authors characterize the behavioral and molecular rhythms of Per2/Cry1 double mutant mice under 3 different lighting conditions. In an LD cycle, the activity of these animals is masked by light, while in DD, the mutants lose circadian rhythmicity but exhibit strong ultradian rhythms. In LL of higher intensity, circadian rhythms are restored on the behavioral level with a drastically shortened endogenous period. Furthermore, both in the SCN and in the periphery, clock gene rhythms are restored. Based on these observations and also on the fact that light-mediated induction of Per gene expression is preserved in these mutants, the authors propose a mechanism by which endogenous ultradian rhythms may relay timed light exposure to the SCN, leading to a reinitiation of self-sustained circadian rhythms in LL.

Animals↗
PubMed1990

The quail's eye: a biological clock.

The site (intraocular vs. extraocular) of the biological clock driving a rhythm in melatonin content in the eyes of Japanese quail was investigated by alternately patching the left and right eyes of individual birds, otherwise held in constant light, for 12-hr periods. This patching protocol, therefore, exposed each eye to a light-dark cycle (LD 12:12) 180 degrees (12 hr) out of phase with the LD cycle experienced by the other eye. The optic nerves to both eyes were transected prior to initiating the patching protocol. The ocular melatonin rhythm (OMR) of the left eyes of quail could be entrained by this procedure 180 degrees out of phase with the rhythm expressed by the right eyes. Since optic nerve section would have deprived any putative extraocular clocks of photic entrainment information, the results show conclusively that the clock driving the OMR is located within the eye itself. In addition, the OMR of Japanese quail is remarkably unaffected by removing two potential neural inputs to the eye (sympathetic innervation from the superior cervical ganglia, and input from the isthmo-optic nucleus of the midbrain); this suggests that these inputs are not required to maintain the OMR. Finally, the clock driving the OMR of one eye does not appear to be coupled to the clock driving the OMR in the other eye, since permanently patching one eye abolished the ability of the patched eye to re-entrain to an 8-hr shift in the phase of an LD 12:12 cycle, whereas the exposed eye rapidly re-entrained to the phase-shifted cycle.

Animals↗
PubMed1996

An ultradian clock controls locomotor behaviour and cell division in isolated cells of Paramecium tetraurelia.

An ultradian clock operates in fast growing cells of the large ciliate, Paramecium tetraurelia. The period of around 70 minutes is well temperature-compensated over the temperature range tested, i.e. between 18 degrees C and 33 degrees C. The Q10 between 18 degrees C and 27 degrees C is 1.08; above 27 degrees C there is a slight overcompensation. The investigation of individual cells has revealed that two different cellular functions are under temporal control by this ultradian clock. First, locomotor behaviour, which is an alternation between a phase of fast swimming with only infrequent turning, and a phase of slow swimming with frequent spontaneous changes of direction. In addition, the ultradian clock is involved in the timing of cell division. Generation times are not randomly distributed, but occur in well separated clusters. At all of the six temperatures tested, the clusters are separated by around 70 minutes which corresponds well to the period of the locomotor behaviour rhythm at the respective temperatures. Whereas the interdivision times were gradually lengthened both above and below the optimum growth temperature, the underlying periodicity remained unaffected. Also cells of different clonal age had identical periods, suggesting that neither the differences in DNA content, not other changes associated with ageing in Paramecium have an effect on the clock. A constant phase relationship was observed between the rhythm in locomotor behaviour and the time window for cell division; this strongly suggests that the same ultradian clock exerts temporal control over both processes.

Animals↗
PubMed2003

Interactions between photic and nonphotic stimuli to synchronize the master circadian clock in mammals.

The master circadian clock is located in the suprachiasmatic nuclei (SCN) in mammals. The most powerful synchronizer of the SCN clock is the daily variation in light intensity. Several other nonphotic cues are well known to be able to shift or synchronize the circadian clock in the absence of photic cues. Some results obtained at systems, cellular and molecular levels provide evidence in contrast to the view that nonphotic signals reset the SCN clock independently of the mechanisms of photic synchronization. Rather, the SCN appear to integrate a wide range of information from the environment to fine-tune photic synchronization. The neuronal mechanisms underlying this integration are far from being understood. Nevertheless, in real-life situations, multiple interactions between photic and nonphotic cues could be of importance for the daily phase adjustment of the circadian clock and its control of the 24-h temporal organization of the whole organism.

Animals↗
PubMed2006

Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES.

Mammalian CLOCK(NPAS2), BMAL1 and CRYPTOCHROMEs are core components of the circadian oscillatory mechanism. The active CLOCK/BMAL1 or NPAS2/BMAL1 complexes regulate expression of numerous genes including two Cryptochromes. The products of these genes, CRY1 and CRY2, in turn repress CLOCK/BMAL1 transcriptional activity by an unknown mechanism. We have examined the effect of CRYPTOCHROMEs on posttranslational modifications and intracellular distribution of endogenous and ectopically expressed CLOCK(NPAS2) and BMAL1 proteins. We found that ectopic coexpression with CRY led to stabilization and nuclear accumulation of unphosphorylated forms of the proteins, which directly correlated with the inhibition of their transcriptional activity. This effect was CRY-specific, as other known repressors of CLOCK/BMAL1 and NPAS2/ BMAL1 transcriptional activity were not able to induce similar effects. CRYs had no effect on CLOCK(NPAS2)/BMAL1 complex formation or its ability to bind DNA. Altogether, these results demonstrate that CRYs regulate the functional activity of circadian transcriptional complex at the posttranslational level. Importantly, the posttranslational modifications and intracellular distribution of CLOCK and BMAL1 proteins were critically impaired in the tissues of mice with targeted disruption of both Cry genes, thus confirming the suggested role of CRY in clock function in vivo. Based on these findings we propose a modified model of the circadian transcriptional control, which implies CRY-mediated periodic rotation of transcriptionally active and inactive forms of CLOCK/BMAL1 on the promoter. This model provides mechanistic explanation for previously reported dual functional activity of CLOCK/BMAL1 and highlights the involvement of the circadian system in modulating the organism's response to various types of genotoxic stress, including chemotherapy and radiation.

ARNTL Transcription Factors↗
PubMed1999

[Molecular mechanisms of the biological clock].

Considerable progress has been made in elucidating the mechanisms underlying the generation of circadian rhythmicity. This review describes recent observations and hypothesis on the nature of circadian biological clock in different organisms, such as cyanobacteria (Synechococcus; in which the first noneukaryotic clock was described), Neurospora and Drosophila (representing respectively a fungal and insect system of crucial value for the molecular dissection of circadian timing systems), as well as mammals. Being specific for particular group of organisms, a common model of the circadian biological clock can be depicted which involves a negative transcription/translation-based feedback loop, containing positive and negative elements, and clock genes, as well as clock controlled genes that are directly related to rhythmic metabolism and behavior.

Animals↗