A5043586163- Circadian rhythm and melatonin
- Light effects on plants
- Photoreceptor and optogenetics research
- Spaceflight effects on biology
- Genetics, Aging, and Longevity in Model Organisms
- Neurobiology and Insect Physiology Research
- Plant Molecular Biology Research
- Birth, Development, and Health
- Dietary Effects on Health
- Nuclear Structure and Function
- Ubiquitin and proteasome pathways
- Free Radicals and Antioxidants
- Photosynthetic Processes and Mechanisms
- Sleep and Wakefulness Research
- Glioma Diagnosis and Treatment
- Protein Kinase Regulation and GTPase Signaling
- DNA Repair Mechanisms
- Wnt/β-catenin signaling in development and cancer
- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Cancer, Hypoxia, and Metabolism
- thermodynamics and calorimetric analyses
- Chemical and Physical Studies
- Medicinal Plants and Bioactive Compounds
- Protein Degradation and Inhibitors
Nagoya University
2016-2025
Japan Science and Technology Agency
2015-2019
University of Southern California
2014-2015
The University of Tokyo
2003-2014
University of California, San Diego
2008-2014
Center for Systems Biology
2012
Tokyo University of Science
2010-2011
Tokyo Institute of Technology
2011
Genomics Institute of the Novartis Research Foundation
2008-2010
National Institute for Physiological Sciences
2001
Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate function might offer therapeutic approaches to such diseases, only a few compounds have identified selectively target core proteins. From an unbiased cell-based phenotypic screen, we KL001, molecule specifically interacts cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation CRY, resulting in lengthening period. In combination...
The circadian clock controls daily oscillations of gene expression at the cellular level. We report development a high-throughput functional assay system that consists luminescent reporter cells, screening automation, and data analysis pipeline. applied this to further dissect molecular mechanisms underlying mammalian using chemical biology approach. analyzed effect 1,280 pharmacologically active compounds with diverse structures on period length is indicative core mechanism. Our paradigm...
In mammals, peripheral circadian clocks are present in most tissues, but little is known about how these synchronized with the ambient 24-h cycles. By using rat-1 fibroblasts, a model cell system of clock, we found that an exchange culture medium triggered gene expression was preceded by slow down-regulation Per1 andPer2 mRNA levels. This profile contrasts to immediate up-regulation genes often observed for clock resetting. The screening factor(s) responsible revealed glucose as key...
The circadian clock underlies daily rhythms of diverse physiological processes, and alterations in function have been linked to numerous pathologies. To apply chemical biology methods modulate dissect the mechanism with new probes, we performed a screen ∼120,000 uncharacterized compounds on human cells containing reporter. analysis identified small molecule that potently lengthens period dose-dependent manner. Subsequent showed compound also lengthened variety from different tissues...
Cryptochrome 1 and 2 act as essential components of the central peripheral circadian clocks for generation rhythms in mammals. Here we show that mouse cryptochrome (mCRY2) is phosphorylated at Ser-557 liver, a well characterized clock tissue. The Ser-557-phosphorylated form accumulates liver during night parallel with mCRY2 protein, reaches its maximal level late night, preceding peak-time protein abundance by ∼4 h both light-dark cycle constant dark conditions. localized nucleus, whereas...
Circadian molecular oscillation is generated by a transcription/translation-based feedback loop in which CRY proteins play critical roles as potent inhibitors for E-box-dependent clock gene expression. Although CRY2 undergoes rhythmic phosphorylation its C-terminal tail, structurally distinct from the CRY1 little understood about how protein kinase(s) controls CRY2-specific and contributes to clockwork. Here we found that Ser557 tail of phosphorylated DYRK1A priming kinase subsequent GSK-3β...
Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we GO289, which strongly lengthened period, a potent and selective inhibitor of CK2. Phosphoproteomics multiple phosphorylation sites inhibited by GO289 on proteins, PER2 S693. Furthermore, exhibited cell type-dependent inhibition...
The circadian clock provides organisms with the ability to adapt daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for functions in fungi animals, but posttranslational that affect plant less understood. Here, using chemical biology strategies, we show Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved modification clock. Chemical screening demonstrated an...
Abstract Background It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) Circadian Locomotor Output Cycles Kaput (CLOCK), are essential for glioblastoma (GBM) stem cell (GSC) biology survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity. Methods We utilized GlioVis to determine genes differentially expressed in non-tumor versus GBM tissues. employed vitro vivo methods test...
Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles NRs as direct regulators circuitry. Here we show that receptor HNF4A strongly transrepresses CLOCK:BMAL1 heterodimer. We define central role for in maintaining cell-autonomous oscillations tissue-specific manner liver and colon cells. Not only transcript but also genome-wide chromosome binding...
Abstract The synthesis and functional analysis of KL001 derivatives, which are modulators the mammalian circadian clock, described. By using cutting‐edge CH activation chemistry, a focused library derivatives was rapidly constructed, enabled identification critical sites on that induce rhythm‐changing activity along with components trigger opposite modes action. first period‐shortening molecules target cryptochrome (CRY) were thus discovered. Detailed studies effects these compounds CRY...
Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), ultimately interact with to close the ~24 hr periodicity. Here we pinpoint key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind BMAL1 transactivation domain similarly sequester it from coactivators repress activity. However, find is recruited much higher...
The circadian clock controls daily rhythms of physiological processes. presence the mechanism throughout body is hampering its local regulation by small molecules. A photoresponsive modulator would enable precise and reversible using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design state-of-the-art photopharmacological tools, development visible light-responsive inhibitor casein kinase I (CKI) that period phase cellular tissue in manner. dark...
The circadian clock is phase-delayed or -advanced by light when given at early late subjective night, respectively. Despite the importance of time-of-day-dependent phase responses to light, underlying molecular mechanism poorly understood. Here, we performed a comprehensive analysis light-inducible genes in chicken pineal gland, which consists light-sensitive cells representing prototype system. Light stimulated expression 62 and 40 ESTs >2.5-fold, among responsive heat shock endoplasmic...
Significance Maintaining robust circadian rhythms has been linked to longevity and metabolic health. Because these are disturbed by factors such as jet lag, shift work, high-fat diets, there is interest in developing pharmacological control strategies modulate function. The design of therapeutic currently limited the lack a clear mechanistic understanding interactions between posttranslational regulators, efficient clock behavior will likely require several simultaneous modulations. Here we...
Abstract Small‐molecule probes have been playing prominent roles in furthering our understanding of the molecular underpinnings circadian clock. We previously discovered a carbazole derivative, KL001 ( N ‐(3‐(9 H ‐carbazol‐9‐yl)‐2‐hydroxypropyl)‐ ‐(furan‐2‐ylmethyl)methanesulfonamide), as stabilizer clock protein cryptochrome (CRY). Herein we describe an extensive structure–activity relationship analysis derivatives leading to development highly active derivative: 2‐(9 ‐carbazol‐9‐yl)‐...