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1.
J Chem Phys ; 158(3): 034303, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681637

RESUMO

Cryptochrome photoreceptors contain a photochemically generated radical pair, which is thought to mediate sensing of the geomagnetic field direction in many living organisms. To gain insight into the response of the cryptochrome to a weak magnetic field, we have studied the quantum-mechanical hyperfine spin states of the radical pair. We identify quantum states responsible for the precise detection of the magnetic field direction, taking into account the strongly axial hyperfine interactions of each radical in the radical pair. The contribution of these states to the formation of the cryptochrome signaling state sharply increases when the magnetic field becomes orthogonal to the hyperfine axis of either radical. Due to such a response, the radical pair may be able to detect the particular field direction normal to the plane containing the hyperfine axes of the radicals.


Assuntos
Criptocromos , Campos Magnéticos , Criptocromos/química , Transporte de Elétrons , Anisotropia
2.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675058

RESUMO

The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock's circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.


Assuntos
Fatores de Transcrição ARNTL , Relógios Circadianos , Gravidez , Feminino , Humanos , Camundongos , Animais , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos/genética , Placenta/metabolismo , Regulação da Expressão Gênica , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , Ritmo Circadiano/fisiologia , Reprodução
3.
Phys Chem Chem Phys ; 25(2): 975-982, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36519379

RESUMO

Magnetic field effects on the yields of radical pair reactions are often characterised by the "half-field" parameter, B1/2, which encodes useful information on spin relaxation, radical recombination kinetics and electron-electron couplings as well as electron-nuclear hyperfine interactions. Here we use a variety of spin dynamics simulation methods to estimate the hyperfine-only values of B1/2 for the flavin-tryptophan radical pair, [FAD˙- TrpH˙+], thought to be the detector in the magnetic compass sense of migratory songbirds. The main findings are: (a) in the absence of fast recombination and spin relaxation, [FAD˙- TrpH˙+] radical pairs in solution and in the putative magnetoreceptor protein, cryptochrome, have B1/2 ≈ 1.89 mT and 2.46 mT, respectively. (b) The widely used expression for B1/2 due to Weller et al. (Chem. Phys. Lett, 1983, 96, 24-27) is only applicable to small, short-lived (∼5 ns), rapidly tumbling radical pairs in solution, and is quantitatively unreliable in the context of magnetoreception. (c) In the absence of molecular tumbling, the low-field effect for [FAD˙- TrpH˙+] is predicted to be abolished by the anisotropic components of the hyperfine interactions. Armed with the 2.46 mT "base value" for cryptochrome, measurements of B1/2 can be used to understand the impact of spin relaxation on its performance as a magnetic compass sensor.


Assuntos
Criptocromos , Triptofano , Triptofano/metabolismo , Compostos Orgânicos , Campos Magnéticos , Flavinas
4.
Nat Commun ; 13(1): 6742, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36347873

RESUMO

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53-/- mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.


Assuntos
Relógios Circadianos , Criptocromos , Animais , Camundongos , Relógios Circadianos/genética , Ritmo Circadiano/genética , Criptocromos/genética , Criptocromos/metabolismo , Longevidade , Mamíferos/metabolismo , Camundongos Knockout , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética
5.
Aging (Albany NY) ; 14(22): 9056-9089, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36385012

RESUMO

The period (PER) and cryptochrome (CRY) families play critical roles in circadian rhythms. The imbalance of circadian factors may lead to the occurrence of cancer. Expressions of PER and CRY family members decrease in various cancers. Nevertheless, expression levels, genetic variations, and molecular mechanisms of PER and CRY family members in lung adenocarcinoma (LUAD) and their correlations with prognoses and immune infiltration in LUAD patients are still unclear. In this study, to identify their biological functions in LUAD development, comprehensive high-throughput techniques were applied to analyze the relationships of expressions of PER and CRY family members with genetic variations, molecular mechanisms, and immune infiltration. The present results showed that transcription levels of PER1 and CRY2 in LUAD were significantly downregulated. High expression levels of PER2, PER3, CRY1, and CRY2 indicated longer overall survival. Some cancer signaling pathways were related to PER and CRY family members, such as cell-cycle, histidine metabolism, and progesterone-mediated oocyte maturation pathways. Expressions of PER and CRY family members significantly affected the infiltration of different immune cells. In conclusion, our findings may help better understand the molecular basis of LUAD, and provide new perspectives of PER and CRY family members as novel biomarkers for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Criptocromos/genética , Criptocromos/metabolismo , Ritmo Circadiano/genética , Prognóstico , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética
6.
F1000Res ; 11: 1016, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226040

RESUMO

Background: Impairment of the circadian clock has been associated with numerous diseases, including sleep disorders and metabolic disease. Although small molecules that modulate clock function may form the basis of drug discovery of clock-related diseases, only a few compounds that selectively target core clock proteins have been identified. Three scaffolds were previously discovered as small-molecule activators of the clock protein Cryptochrome (CRY), and they have been providing powerful tools to understand and control the circadian clock system. Identifying new scaffolds will expand the possibilities of drug discovery. Methods: A methylbenzimidazole derivative TH401 identified from cell-based circadian screens was characterized. Effects of TH401 on circadian rhythms were evaluated in cellular assays. Functional assays and X-ray crystallography were used to elucidate the effects of the compound on CRY1 and CRY2 isoforms. Results: TH401 lengthened the period of circadian rhythms and stabilized both CRY1 and CRY2. The compound repressed Per2 reporter activity, which was reduced by Cry1 or Cry2 knockout and abolished by Cry1/Cry2 double knockout, indicating the dependence on CRY isoforms. Thermal shift assays showed slightly higher interaction of TH401 with CRY2 over CRY1. The crystal structure of CRY1 in complex with TH401 revealed a conformational change of the gatekeeper W399, which is involved in isoform-selectivity determination. Conclusions: The present study identified a new small molecule TH401 that targets both CRY isoforms. This compound has expanded the chemical diversity of CRY activators, and will ultimately aid in the development of therapeutics against circadian clock-related disorders.


Assuntos
Relógios Circadianos , Criptocromos , Animais , Criptocromos/química , Criptocromos/metabolismo , Ritmo Circadiano/fisiologia , Relógios Circadianos/fisiologia , Mamíferos/metabolismo , Isoformas de Proteínas
7.
Nat Commun ; 13(1): 7045, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396657

RESUMO

Cryptochromes (CRYs) are evolutionarily conserved photolyase-like photoreceptors found in almost all species, including mammals. CRYs regulate transcription by modulating the activity of several transcription factors, but whether and how they affect pre-mRNA processing are unknown. Photoperiod and temperature are closely associated seasonal cues that influence reproductive timing in plants. CRYs mediate photoperiod-responsive floral initiation, but it is largely unknown whether and how they are also involved in thermosensory flowering. We establish here that blue light and CRY2 play critical roles in thermosensory flowering in Arabidopsis thaliana by regulating RNA alternative splicing (AS) to affect protein expression and development. CRY2 INTERACTING SPLICING FACTOR 1 (CIS1) interacts with CRY2 in a blue light-dependent manner and promotes CRY2-mediated thermosensory flowering. Blue light, CRYs, and CISs affect transcriptome-wide AS profiles, including those of FLOWERING LOCUS M (FLM), which is critical for temperature modulation of flowering. Moreover, CIS1 binds to the FLM pre-mRNA to regulate its AS, while CRY2 regulates the RNA-binding activity of CIS1. Thus, blue light regulates thermosensory flowering via a CRY2-CIS1-FLM signaling pathway that links flowering responses to both light and ambient temperature.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Processamento Alternativo , Regulação da Expressão Gênica de Plantas , Flores , Precursores de RNA/metabolismo , Arabidopsis/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , Proteínas de Domínio MADS/genética
8.
Int J Oral Sci ; 14(1): 53, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376275

RESUMO

Bone regeneration remains a great clinical challenge. Low intensity near-infrared (NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However, the effect and underlying mechanism of NIR on bone regeneration remain unclear. We demonstrated that bone regeneration in the rat skull defect model was significantly accelerated with low-intensity NIR stimulation. In vitro studies showed that NIR stimulation could promote the osteoblast differentiation in bone mesenchymal stem cells (BMSCs) and MC3T3-E1 cells, which was associated with increased ubiquitination of the core circadian clock protein Cryptochrome 1 (CRY1) in the nucleus. We found that the reduction of CRY1 induced by NIR light activated the bone morphogenetic protein (BMP) signaling pathways, promoting SMAD1/5/9 phosphorylation and increasing the expression levels of Runx2 and Osterix. NIR light treatment may act through sodium voltage-gated channel Scn4a, which may be a potential responder of NIR light to accelerate bone regeneration. Together, these findings suggest that low-intensity NIR light may promote in situ bone regeneration in a CRY1-dependent manner, providing a novel, efficient and non-invasive strategy to promote bone regeneration for clinical bone defects.


Assuntos
Regeneração Óssea , Relógios Circadianos , Criptocromos , Animais , Ratos , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular , Criptocromos/metabolismo , Osteoblastos/metabolismo , Osteogênese , Fatores de Transcrição/metabolismo
9.
J Phys Chem Lett ; 13(45): 10500-10506, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36332112

RESUMO

The mechanism underlying magnetoreception has long eluded explanation. A popular hypothesis attributes this sense to the quantum coherent spin dynamics and spin-selective recombination reactions of radical pairs in the protein cryptochrome. However, concerns about the validity of the hypothesis have been raised because unavoidable inter-radical interactions, such as the strong electron-electron dipolar coupling, appear to suppress its sensitivity. We demonstrate that sensitivity can be restored by driving the spin system through a modulation of the inter-radical distance. It is shown that this dynamical process markedly enhances geomagnetic field sensitivity in strongly coupled radical pairs via Landau-Zener-Stückelberg-Majorana transitions between singlet and triplet states. These findings suggest that a "live" harmonically driven magnetoreceptor can be more sensitive than its "dead" static counterpart.


Assuntos
Criptocromos , Campos Magnéticos , Criptocromos/metabolismo , Movimento (Física) , Elétrons
10.
Int J Oncol ; 61(6)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36263655

RESUMO

The circadian rhythm is generated at the cellular level by a molecular clock system that involves specific genes. Studies have revealed that circadian clock disruption is a control point in cancer progression. Colorectal cancer (CRC) is one of the cancers closely associated with circadian disruption. In the present review, the involvement of the circadian clock in CRC development was summarized. Abnormal expression of certain clock genes has been found in patients with CRC and their correlation with clinicopathological features has also been explored. The period and cryptochrome 2 (Cry2), Sirtuin1 (SIRT1) and neuronal PAS domain protein 2 (NPAS2) genes were reported to have tumour suppressor properties. Conversely, Cry1, brain and muscle ARNT­like­1, circadian locomotor output cycles kaput (CLOCK) and timeless may aggravate CRC progression, but these findings are not consistent and require to be confirmed by further research. Circadian scheduling also indicated advantages in chemotherapy treatments for patients with CRC by increasing the maximum tolerated doses and decreasing toxicities. Dysfunction of the molecular CLOCK system disrupted cellular processes to accelerate colon tumorigenesis, such as metabolism, cell cycle, DNA damage repair, proliferation and apoptosis, epithelial­mesenchymal transition and stemness. The clock gene network and how the dynamics of the system influence CRC were discussed.


Assuntos
Relógios Circadianos , Neoplasias Colorretais , Humanos , Relógios Circadianos/genética , Criptocromos , Sirtuína 1 , Ciclo Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ritmo Circadiano/genética
11.
Commun Biol ; 5(1): 1103, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36257983

RESUMO

Cryptochromes are blue light receptors that mediate circadian rhythm and magnetic sensing in various organisms. A typical cryptochrome consists of a conserved photolyase homology region domain and a varying carboxyl-terminal extension across species. The structure of the flexible carboxyl-terminal extension and how carboxyl-terminal extension participates in cryptochrome's signaling function remain mostly unknown. In this study, we uncover the potential missing link between carboxyl-terminal extension conformational changes and downstream signaling functions. Specifically, we discover that the blue-light induced opening of carboxyl-terminal extension in C. reinhardtii animal-like cryptochrome can structurally facilitate its interaction with Rhythm Of Chloroplast 15, a circadian-clock-related protein. Our finding is made possible by two technical advances. Using single-molecule Förster resonance energy transfer technique, we directly observe the displacement of carboxyl-terminal extension by about 15 Å upon blue light excitation. Combining structure prediction and solution X-ray scattering methods, we propose plausible structures of full-length cryptochrome under dark and lit conditions. The structures provide molecular basis for light active conformational changes of cryptochrome and downstream regulatory functions.


Assuntos
Relógios Circadianos , Desoxirribodipirimidina Fotoliase , Animais , Criptocromos/metabolismo , Desoxirribodipirimidina Fotoliase/química , Desoxirribodipirimidina Fotoliase/metabolismo , Luz , Ritmo Circadiano
12.
Nat Commun ; 13(1): 5869, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36198686

RESUMO

Circadian pace is modulated by light intensity, known as the Aschoff's rule, with largely unrevealed mechanisms. Here we report that photoreceptor CRY2 mediates blue light input to the circadian clock by directly interacting with clock core component PRR9 in blue light dependent manner. This physical interaction dually blocks the accessibility of PRR9 protein to its co-repressor TPL/TPRs and the resulting kinase PPKs. Notably, phosphorylation of PRR9 by PPKs is critical for its DNA binding and repressive activity, hence to ensure proper circadian speed. Given the labile nature of CRY2 in strong blue light, our findings provide a mechanistic explanation for Aschoff's rule in plants, i.e., blue light triggers CRY2 turnover in proportional to its intensity, which accordingly releasing PRR9 to fine tune circadian speed. Our findings not only reveal a network mediating light input into the circadian clock, but also unmask a mechanism by which the Arabidopsis circadian clock senses light intensity.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Relógios Circadianos , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ritmo Circadiano , Proteínas Correpressoras/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , DNA/metabolismo , Regulação da Expressão Gênica de Plantas , Luz
13.
Cells ; 11(19)2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231018

RESUMO

The avian magnetic compass allows orientation during migration and is shown to function properly under short-wavelength but not long-wavelength visible light. Therefore, the magnetoreceptive system is assumed to be light- and wavelength-dependent and localized in the retina of the eye. Putative candidates for the role of primary magnetosensory molecules are the cryptochromes that are known to be expressed in the avian retina and must be able to interact with phototransduction proteins. Previously, we reported that in migratory birds change in magnetic field direction induces significant effects on electroretinogram amplitude in response to blue flashes, and such an effect was observed only in the nasal quadrant of the retina. Here, we report new electroretinographic, microscopic and microspectrophotometric data on European robins, confirming the magnetosensitivity of the retinal nasal quadrant after applying the background illumination. We hypothesized that magnetoreceptive distinction of this region may be related to its morphology and analyzed the retinal distribution and optical properties of oil droplets, the filtering structures within cones. We found that the nasal quadrant contains double cones with the most intensely colorized oil droplets compared to the rest of the retina, which may be related to its magnetosensory function.


Assuntos
Migração Animal , Criptocromos , Migração Animal/fisiologia , Animais , Aves , Criptocromos/metabolismo , Campos Magnéticos , Retina/metabolismo
14.
Plant Sci ; 325: 111483, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36183809

RESUMO

Iron-sulfur (Fe-S) clusters are involved in fundamental biological reactions and represent a highly regulated process involving a complex sequence of mitochondrial, cytosolic and nuclear-catalyzed protein-protein interactions. Iron-sulfur complex assembly (ISCA) scaffold proteins are involved in Fe-S cluster biosynthesis, nitrogen and sulfur metabolism. ISCA proteins are involved in abiotic stress responses and in the pigeon they act as a magnetic sensor by forming a magnetosensor (MagS) complex with cryptochrome (Cry). MagR gene exists in the genomes of humans, plants, and microorganisms and the interaction between Cry and MagR is highly conserved. Owing to the extensive presence of ISCA proteins in plants and the occurrence of homology between animal and human MagR with at least four Arabidopsis ISCAs and several ISCAs from different plant species, we believe that a mechanism similar to pigeon magnetoperception might be present in plants. We suggest that plant ISCA proteins, homologous of the animal MagR, are good candidates and could contribute to a better understanding of plant magnetic induction. We thus urge more studies in this regard to fully uncover the plant molecular mechanisms underlying MagR/Cry mediated magnetic induction and the possible coupling between light and magnetic induction.


Assuntos
Proteínas Ferro-Enxofre , Ferro , Animais , Humanos , Ferro/metabolismo , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Enxofre/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , Fenômenos Magnéticos
15.
Parasit Vectors ; 15(1): 374, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36258200

RESUMO

BACKGROUND: The study of behavioral and physiological traits in mosquitoes has been mainly focused on females since males are not hematophagous and thus do not transfer the parasites that cause diseases in human populations. However, the performance of male mosquitoes is key for the expansion of populations and the perpetuation of mosquito species. Pre-copulatory communication between males and females is the initial and essential step for the success of copulation and studying the male facet of this interaction provides fertile ground for the improvement of vector control strategies. Like in most animals, reproduction, feeding, and oviposition are closely associated with locomotor activity in mosquitoes. Rhythmic cycles of locomotor activity have been previously described in Aedes aegypti, and in females, they are known to be altered by blood-feeding and arbovirus infection. In previous work, we found that males in the presence of females significantly change their locomotor activity profiles, with a shift in the phase of the activity peak. Here, we investigated whether this shift is associated with changes in the expression level of three central circadian clock genes. METHODS: Real-time PCR reactions were performed for the gene period, cycle, and cryptochrome 2 in samples of heads, antennae, and abdominal tips of solitary males and males in the presence of females. Assays with antennae-ablated males were also performed, asking whether this is an essential organ mediating the communication and the variation in activity profiles. RESULTS: The gene period showed a conserved expression pattern in all tissues and conditions, while the other two genes varied according to the male condition. A remarking pattern was observed in cry2, where the difference between the amplitude of expression at the beginning of photophase and the expression peak in the scotophase was greater when males were in the presence of females. Antennae ablation in males did not have a significant effect on the expression profiles, suggesting that female recognition may involve other senses besides hearing and olfaction. CONCLUSION: Our results suggest that the expression of gene cryptochrome 2 varies in association with the interaction between males and females.


Assuntos
Aedes , Animais , Humanos , Feminino , Masculino , Aedes/fisiologia , Mosquitos Vetores/fisiologia , Transcriptoma , Criptocromos/genética , Oviposição
16.
Proc Natl Acad Sci U S A ; 119(40): e2203936119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161947

RESUMO

The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 "in" orientation and also a close "further in" conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.


Assuntos
Relógios Circadianos , Glioblastoma , Animais , Carbazóis , Ritmo Circadiano/fisiologia , Criptocromos/metabolismo , Glioblastoma/tratamento farmacológico , Mamíferos/metabolismo , Isoformas de Proteínas/genética , Sulfonamidas
17.
Proc Natl Acad Sci U S A ; 119(40): e2205755119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161962

RESUMO

Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [ßOHB]) that correlated with liver ßOHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic ßOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood ßOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock-deficient Cry1,2-/- mice. These data suggest that blood ßOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.


Assuntos
Relógios Circadianos , Redes Reguladoras de Genes , Corpos Cetônicos , PPAR alfa , Ácido 3-Hidroxibutírico/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Criptocromos/metabolismo , Corpos Cetônicos/metabolismo , Fígado/metabolismo , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo
18.
Genes (Basel) ; 13(9)2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36140781

RESUMO

The cryptochrome/photolyase (CRY/PL) family represents an ancient group of proteins fulfilling two fundamental functions. While photolyases repair UV-induced DNA damages, cryptochromes mainly influence the circadian clock. In this study, we took advantage of the large number of already sequenced and annotated genes available in databases and systematically searched for the protein sequences of CRY/PL family members in all taxonomic groups primarily focusing on metazoans and limiting the number of species per taxonomic order to five. Using BLASTP searches and subsequent phylogenetic tree and motif analyses, we identified five distinct photolyases (CPDI, CPDII, CPDIII, 6-4 photolyase, and the plant photolyase PPL) and six cryptochrome subfamilies (DASH-CRY, mammalian-type MCRY, Drosophila-type DCRY, cnidarian-specific ACRY, plant-specific PCRY, and the putative magnetoreceptor CRY4. Manually assigning the CRY/PL subfamilies to the species studied, we have noted that over evolutionary history, an initial increase of various CRY/PL subfamilies was followed by a decrease and specialization. Thus, in more primitive organisms (e.g., bacteria, archaea, simple eukaryotes, and in basal metazoans), we find relatively few CRY/PL members. As species become more evolved (e.g., cnidarians, mollusks, echinoderms, etc.), the CRY/PL repertoire also increases, whereas it appears to decrease again in more recent organisms (humans, fruit flies, etc.). Moreover, our study indicates that all cryptochromes, although largely active in the circadian clock, arose independently from different photolyases, explaining their different modes of action.


Assuntos
Relógios Circadianos , Desoxirribodipirimidina Fotoliase , Animais , Relógios Circadianos/genética , Criptocromos/genética , Criptocromos/metabolismo , Dano ao DNA , Desoxirribodipirimidina Fotoliase/genética , Desoxirribodipirimidina Fotoliase/metabolismo , Humanos , Mamíferos , Filogenia
19.
Adv Exp Med Biol ; 1390: 143-153, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107317

RESUMO

All life of Earth has evolved mechanisms to track time. This permits anticipation of predictable changes in light/dark, and in most cases also directs fed/fasted cycles, and sleep/wake. The nuclear receptors enjoy a close relationship with the molecular machinery of the clock. Some play a core role within the circadian machinery, other respond to ligands which oscillate in concentration, and physical cross-talk between clock transcription factors, eg cryptochromes, and multiple nuclear receptors also enable coupling of nuclear receptor function to time of day. Essential processes including inflammation, and energy metabolism are strongly regulated by both the circadian machinery, and rhythmic behaviour, and also by multiple members of the nuclear receptor family. An emerging theme is reciprocal regulation of key processes by different members of the nuclear receptor family, for example NR1D1/2, and NR1F1, in regulation of the core circadian clock transcription factor BMAL1.


Assuntos
Relógios Circadianos , Ritmo Circadiano , Fatores de Transcrição ARNTL/genética , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Criptocromos/genética , Ligantes
20.
Nat Commun ; 13(1): 5220, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064778

RESUMO

The moon's monthly cycle synchronizes reproduction in countless marine organisms. The mass-spawning bristle worm Platynereis dumerilii uses an endogenous monthly oscillator set by full moon to phase reproduction to specific days. But how do organisms recognize specific moon phases? We uncover that the light receptor L-Cryptochrome (L-Cry) discriminates between different moonlight durations, as well as between sun- and moonlight. A biochemical characterization of purified L-Cry protein, exposed to naturalistic sun- or moonlight, reveals the formation of distinct sun- and moonlight states characterized by different photoreduction- and recovery kinetics of L-Cry's co-factor Flavin Adenine Dinucleotide. In Platynereis, L-Cry's sun- versus moonlight states correlate with distinct subcellular localizations, indicating different signaling. In contrast, r-Opsin1, the most abundant ocular opsin, is not required for monthly oscillator entrainment. Our work reveals a photo-ecological concept for natural light interpretation involving a "valence interpreter" that provides entraining photoreceptor(s) with light source and moon phase information.


Assuntos
Criptocromos , Lua , Luz , Opsinas , Reprodução , Luz Solar
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