PERIOD-TIMELESS interval timer may require an additional feedback loop.
Ontology highlight
ABSTRACT:
SUBMITTER: Kuczenski RS
PROVIDER: S-EPMC1937016 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with β-catenin in the cytoplasm, facilitated β-catenin degradation, and impaired the nuclear accumulation of β-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/β-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/β-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.
| S-EPMC6951841 | biostudies-literature
Project description:Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1delta and CK1varepsilon were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.
| S-EPMC2134962 | biostudies-literature
Project description:The level of rescue of clock function in genetically arrhythmic Drosophila melanogaster hosts using interspecific clock gene transformation was used to study the putative intermolecular coevolution between interacting clock proteins. Among them PER and TIM are the two important negative regulators of the circadian clock feedback loop. We transformed either the D. pseudoobscura per or tim transgenes into the corresponding arrhythmic D. melanogaster mutant (per01 or tim01) and observed >50% rhythmicity but the period of activity rhythm was either longer (D. pseudoobscura-per) or shorter than 24?h (D. pseudoobscura-tim) compared to controls. By introducing both transgenes simultaneously into double mutants, we observed that the period of the activity rhythm was rescued by the pair of hemizygous transgenes (~24?h). These flies also showed a more optimal level of temperature compensation for the period. Under LD 12:12 these flies have a D. pseudoobscura like activity profile with the absence of morning anticipation as well as a very prominent earlier evening peak of activity rhythm. These observation are consistent with the view that TIM and PER form a heterospecific coevolved module at least for the circadian period of activity rhythms. However the strength of rhythmicity was reduced by having both transgenes present, so while evidence for a coevolution between PER and TIM is observed for some characters it is not for others.
| S-EPMC5818170 | biostudies-other
Project description:The Drosophila circadian oscillator relies on a negative transcriptional feedback loop, in which the PERIOD (PER) and TIMELESS (TIM) proteins repress the expression of their own gene by inhibiting the activity of the CLOCK (CLK) and CYCLE (CYC) transcription factors. A series of posttranslational modifications contribute to the oscillations of the PER and TIM proteins but few posttranscriptional mechanisms have been described that affect mRNA stability. Here we report that down-regulation of the POP2 deadenylase, a key component of the CCR4-NOT deadenylation complex, alters behavioral rhythms. Down-regulating POP2 specifically increases TIM protein and tim mRNA but not tim pre-mRNA, supporting a posttranscriptional role. Indeed, reduced POP2 levels induce a lengthening of tim mRNA poly(A) tail. Surprisingly, such effects are lost in per 0 mutants, supporting a PER-dependent inhibition of tim mRNA deadenylation by POP2. We report a deadenylation mechanism that controls the oscillations of a core clock gene transcript.
| S-EPMC6431209 | biostudies-literature
Project description:Current DBS therapy delivers a train of electrical pulses at set stimulation parameters. This open-loop design is effective for movement disorders, but therapy may be further optimized by a closed loop design. The technology to record biosignals has outpaced our understanding of their relationship to the clinical state of the whole person. Neuronal oscillations may represent or facilitate the cooperative functioning of brain ensembles, and may provide critical information to customize neuromodulation therapy. This review addresses advances to date, not of the technology per se, but of the strategies to apply neuronal signals to trigger or modulate stimulation systems.
| S-EPMC4058859 | biostudies-other
Project description:Signaling pathways can behave as switches or rheostats, generating binary or graded responses to a given cell stimulus. We evaluated whether a single signaling pathway can simultaneously encode a switch and a rheostat. We found that the kinase Hog1 mediated a bifurcated cellular response: Activation and commitment to adaptation to osmotic stress are switchlike, whereas protein induction and the resolution of this commitment are graded. Through experimentation, bioinformatics analysis, and computational modeling, we determined that graded recovery is encoded through feedback phosphorylation and a gene induction program that is both temporally staggered and variable across the population. This switch-to-rheostat signaling mechanism represents a versatile stress adaptation system, wherein a broad range of inputs generate an "all-in" response that is later tuned to allow graded recovery of individual cells over time.
| S-EPMC4505820 | biostudies-literature
Project description:DNA nonhomologous end-joining (NHEJ) is the major pathway for repairing DNA double-strand breaks in mammalian cells. It also functions to carry out rearrangements at the specialized breaks introduced during V(D)J recombination. Here, we describe a patient with T(-)B(-) severe combined immunodeficiency, whose cells have defects closely resembling those of NHEJ-defective rodent cells. Cells derived from this patient show dramatic radiosensitivity, decreased double-strand break rejoining, and reduced fidelity in signal and coding joint formation during V(D)J recombination. Detailed examination indicates that the patient is defective neither in the known factors involved in NHEJ in mammals (Ku70, Ku80, DNA-dependent protein kinase catalytic subunit, Xrcc4, DNA ligase IV, or Artemis) nor in the Mre11/Rad50/Nbs1 complex, whose homologue in Saccharomyces cerevisiae functions in NHEJ. These results provide strong evidence that additional activities are crucial for NHEJ and V(D)J recombination in mammals.
| S-EPMC151363 | biostudies-literature
Project description:The remarkably stable circadian oscillations of single cyanobacteria enable a population of growing cells to maintain synchrony for weeks. The cyanobacterial pacemaker is a posttranslational regulation (PTR) circuit that generates circadian oscillations in the phosphorylation state of the clock protein KaiC. Layered on top of the PTR is transcriptional-translational feedback regulation (TTR), common to all circadian systems, consisting of a negative feedback loop in which KaiC regulates its own production. We found that the PTR circuit is sufficient to generate oscillations in growing cyanobacteria. However, in the absence of TTR, individual oscillators were less stable and synchrony was not maintained in a population of cells. Experimentally constrained mathematical modeling reproduced sustained oscillations in the PTR circuit alone and demonstrated the importance of TTR for oscillator synchrony.
| S-EPMC3696982 | biostudies-other
Project description:Nucleotide sequences of the circadian rhythm genes, period and timeless, were studied for the first time in mosquitoes Culex pipiens Linnaeus, 1758. In this work we evaluated variations of the studied genome fragments for the two forms of Culex pipiens (forma "pipiens" - mosquitoes common for aboveground habitats, forma "molestus" - underground mosquitoes). We compared Culex pipiens from Russia with transatlantic Culex pipiens and subtropical Culex quinquefasciatus Say, 1823. Our results show that intraspecies variability is higher for the gene period than for the gene timeless. The revealed substitutions in nucleotide sequences and especially in amino acid sequences grouped the individuals of the two forms into distinct clusters with high significance. The detected fixed amino acid substitutions may appear essential for functioning of the circadian rhythm proteins in Culex pipiens, and may be correlated with adaptations of the taxa within the group Culex pipiens. Our results suggest that natural selection favors fixed mutations and the decrease in diversity of the genes period and timeless in mosquitoes of the Culex pipiens f. "molestus" compared with the Culex pipiens f. "pipiens", is probably correlated with adaptive features of Culex pipiens f. "molestus". The studied genome regions may be considered as promising molecular-genetic markers for identification, population and phylogenetic analysis of similar species and forms of the Culex pipiens complex.
| S-EPMC5240504 | biostudies-literature
Project description:The transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly conserved at the amino acid level through evolution. Within this evolutionary frame, TIM represents a fascinating puzzle. While Drosophila contains two paralogs, dTIM and dTIM2, acting in clock/photoreception and chromosome integrity/photoreception respectively, mammals contain only one TIM homolog. Whereas TIM has been shown to regulate replication termination and cell cycle progression, its functional link to the circadian clock is under debate. Here we show that RNAi-mediated knockdown of TIM in NIH3T3 and U2OS cells shortens the period by 1 hour and diminishes DNA damage-dependent phase advancing. Furthermore, we reveal that the N-terminus of TIM is sufficient for interaction with CRY1 and CHK1 as well for homodimerization, and the C-terminus is necessary for nuclear localization. Interestingly, the long TIM isoform (l-TIM), but not the short (s-TIM), interacts with CRY1 and both proteins can reciprocally regulate their nuclear translocation in transiently transfected COS7 cells. Finally, we demonstrate that co-expression of PER2 abolishes the formation of the TIM/CRY1 complex through affinity binding competition to the C-terminal tail of CRY1. Notably, the presence of the latter protein region evolutionarily and structurally distinguishes mammalian from insect CRYs. We propose that the dynamic interaction between these three proteins could represent a post-translational aspect of the mammalian circadian clock that is important for its pace and adaption to external stimuli, such as DNA damage and/or light.
| S-EPMC3572085 | biostudies-literature