PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen L
PROVIDER: S-EPMC4832144 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Clock-regulated pathways coordinate the response of many developmental processes to changes in photoperiod and temperature. We model two of the best-understood clock output pathways in Arabidopsis, which control key regulators of flowering and elongation growth. In flowering, the model predicted regulatory links from the clock to cycling DOF factor 1 (CDF1) and flavin-binding, KELCH repeat, F-box 1 (FKF1) transcription. Physical interaction data support these links, which create threefold feed-forward motifs from two clock components to the floral regulator FT. In hypocotyl growth, the model described clock-regulated transcription of phytochrome-interacting factor 4 and 5 (PIF4, PIF5), interacting with post-translational regulation of PIF proteins by phytochrome B (phyB) and other light-activated pathways. The model predicted bimodal and end-of-day PIF activity profiles that are observed across hundreds of PIF-regulated target genes. In the response to temperature, warmth-enhanced PIF4 activity explained the observed hypocotyl growth dynamics but additional, temperature-dependent regulators were implicated in the flowering response. Integrating these two pathways with the clock model highlights the molecular mechanisms that coordinate plant development across changing conditions.
| S-EPMC4332151 | biostudies-literature
Project description:Circadian rhythms regulate physiology and behavior through transcriptional feedback loops of clock genes running within specific pacemaker cells. In Drosophila, molecular oscillations in the small ventral lateral neurons (sLNvs) command rhythmic behavior under free-running conditions releasing the neuropeptide PIGMENT DISPERSING FACTOR (PDF) in a circadian fashion. Electrical activity in the sLNvs is also required for behavioral rhythmicity. Yet, how temporal information is transduced into behavior remains unclear.Here we developed a new tool for temporal control of gene expression to obtain adult-restricted electrical silencing of the PDF circuit, which led to reversible behavioral arrhythmicity. Remarkably, PERIOD (PER) oscillations during the silenced phase remained unaltered, indicating that arrhythmicity is a direct consequence of the silenced activity. Accordingly, circadian axonal remodeling and PDF accumulation were severely affected during the silenced phase.Although electrical activity of the sLNvs is not a clock component, it coordinates circuit outputs leading to rhythmic behavior.
| S-EPMC3226771 | biostudies-literature
Project description:Organisms experience dramatic fluctuations in demands and stresses over the course of the day. In order to maintain biological processes within physiological boundaries, mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors have an integral role in homeostasis. Not only do circulating levels of various endocrine factors oscillate over the 24 h period, but so too does responsiveness of target tissues to these signals or stimuli. Emerging evidence suggests that these daily endocrine oscillations do not occur solely in response to behavioural fluctuations associated with sleep-wake and feeding-fasting cycles, but are orchestrated by an intrinsic timekeeping mechanism known as the circadian clock. Disruption of circadian clocks by genetic and/or environmental factors seems to precipitate numerous common disorders, including the metabolic syndrome and cancer. Collectively, these observations suggest that strategies designed to realign normal circadian rhythmicities hold potential for the treatment of various endocrine-related disorders.
| S-EPMC4304769 | biostudies-other
Project description:BACKGROUND:24-hour biological clocks are intimately connected to the cellular signalling network, which complicates the analysis of clock mechanisms. The transcriptional regulator TOC1 (TIMING OF CAB EXPRESSION 1) is a founding component of the gene circuit in the plant circadian clock. Recent results show that TOC1 suppresses transcription of multiple target genes within the clock circuit, far beyond its previously-described regulation of the morning transcription factors LHY (LATE ELONGATED HYPOCOTYL) and CCA1 (CIRCADIAN CLOCK ASSOCIATED 1). It is unclear how this pervasive effect of TOC1 affects the dynamics of the clock and its outputs. TOC1 also appears to function in a nested feedback loop that includes signalling by the plant hormone Abscisic Acid (ABA), which is upregulated by abiotic stresses, such as drought. ABA treatments both alter TOC1 levels and affect the clock's timing behaviour. Conversely, the clock rhythmically modulates physiological processes induced by ABA, such as the closing of stomata in the leaf epidermis. In order to understand the dynamics of the clock and its outputs under changing environmental conditions, the reciprocal interactions between the clock and other signalling pathways must be integrated. RESULTS:We extended the mathematical model of the plant clock gene circuit by incorporating the repression of multiple clock genes by TOC1, observed experimentally. The revised model more accurately matches the data on the clock's molecular profiles and timing behaviour, explaining the clock's responses in TOC1 over-expression and toc1 mutant plants. A simplified representation of ABA signalling allowed us to investigate the interactions of ABA and circadian pathways. Increased ABA levels lengthen the free-running period of the clock, consistent with the experimental data. Adding stomatal closure to the model, as a key ABA- and clock-regulated downstream process allowed to describe TOC1 effects on the rhythmic gating of stomatal closure. CONCLUSIONS:The integrated model of the circadian clock circuit and ABA-regulated environmental sensing allowed us to explain multiple experimental observations on the timing and stomatal responses to genetic and environmental perturbations. These results crystallise a new role of TOC1 as an environmental sensor, which both affects the pace of the central oscillator and modulates the kinetics of downstream processes.
| S-EPMC3614443 | biostudies-literature
Project description:The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock-DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs.
| S-EPMC4303322 | biostudies-other
Project description:The circadian clock is a master regulator of mammalian physiology, regulating daily oscillations of crucial biological processes and behaviors. Notably, circadian disruption has recently been identified as an independent risk factor for cancer and classified as a carcinogen. As such, it is imperative to discern the underpinning mechanisms by which circadian disruption alters cancer risk. Emergent data, reviewed herein, demonstrate that circadian regulatory functions play critical roles in several hallmarks of cancer, including control of cell proliferation, cell death, DNA repair, and metabolic alteration. Developing a deeper understanding of circadian-cancer regulation cross-talk holds promise for developing new strategies for cancer interception, prevention, and management.
| S-EPMC8121183 | biostudies-literature
Project description:The circadian clock is required for adaptive responses to daily and seasonal changes in environmental conditions. Light and the circadian clock interact to consolidate the phase of hypocotyl cell elongation to peak at dawn under diurnal cycles in Arabidopsis thaliana. Here we identify a protein complex (called the evening complex)--composed of the proteins encoded by EARLY FLOWERING 3 (ELF3), ELF4 and the transcription-factor-encoding gene LUX ARRHYTHMO (LUX; also known as PHYTOCLOCK 1)--that directly regulates plant growth. ELF3 is both necessary and sufficient to form a complex between ELF4 and LUX, and the complex is diurnally regulated, peaking at dusk. ELF3, ELF4 and LUX are required for the proper expression of the growth-promoting transcription factors encoded by PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PIF5 (also known as PHYTOCHROME INTERACTING FACTOR 3-LIKE 6) under diurnal conditions. LUX targets the complex to the promoters of PIF4 and PIF5 in vivo. Mutations in PIF4 and/or PIF5 are epistatic to the loss of the ELF4-ELF3-LUX complex, suggesting that regulation of PIF4 and PIF5 is a crucial function of the complex. Therefore, the evening complex underlies the molecular basis for circadian gating of hypocotyl growth in the early evening.
| S-EPMC3155984 | biostudies-literature
Project description:Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.
| S-EPMC8285898 | biostudies-literature
Project description:The circadian system is comprised three components: a network of core clock cells in the brain that keeps time, input pathways that entrain clock cells to the environment, and output pathways that use this information to ensure appropriate timing of physiological and behavioral processes throughout the day. Core clock cells can be divided into molecularly distinct populations that likely make unique functional contributions. Here we clarify the role of the dorsal neuron 1 (DN1) population of clock neurons in the transmission of circadian information by the Drosophila core clock network. Using an intersectional genetic approach that allowed us to selectively and comprehensively target DN1 cells, we show that suppressing DN1 neuronal activity alters the magnitude of daily activity and sleep without affecting overt rhythmicity. This suggests that DN1 cells are dispensable for both the generation of circadian information and the propagation of this information across output circuits.
| S-EPMC8413890 | biostudies-literature
Project description:Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor ? (ERR?, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERR? directly regulates all major components of the molecular clock. ERR?-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERR?-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERR? in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERR? corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERR?, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERR?, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERR?, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes.
| S-EPMC3121748 | biostudies-literature