A5070538781- Circadian rhythm and melatonin
- Light effects on plants
- Dietary Effects on Health
- Invertebrate Immune Response Mechanisms
- Neurobiology and Insect Physiology Research
- Photoreceptor and optogenetics research
- Plant Molecular Biology Research
- interferon and immune responses
- NF-κB Signaling Pathways
- Sleep and Wakefulness Research
- Muscle metabolism and nutrition
- Algal biology and biofuel production
- Viral Infectious Diseases and Gene Expression in Insects
- Phytase and its Applications
- Exercise and Physiological Responses
- Chromatin Remodeling and Cancer
- Protein Hydrolysis and Bioactive Peptides
- Cancer Mechanisms and Therapy
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Spaceflight effects on biology
- Phytochemical and Pharmacological Studies
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Cancer-related gene regulation
Duke-NUS Medical School
2017-2025
National University of Singapore
2024
Salk Institute for Biological Studies
2012-2016
University of Zurich
2005-2009
Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, cancer. Increased inflammation is one of common underlying mechanisms these diseases, thus raising a hypothesis that circadian-oscillator components may regulate immune response. Here we show absence core component protein cryptochrome (CRY) leads constitutive elevation proinflammatory cytokines in cell-autonomous manner. We observed NF–κB kinase A (PKA) signaling...
Significance Our innate circadian clocks control myriad aspects of behavior and physiology. Disruption our by shift work, jet lag, or inherited mutation leads to metabolic dysregulation contributes diseases, including diabetes cancer. A central step in clock is phosphorylation the PERIOD 2 (PER2) protein. Here we conclusively identify elusive PER2 priming kinase find it be well-known kinase, casein 1 (CK1). Surprisingly, different forms CK1 have differing abilities phosphorylate site, adding...
Inhibition of the transcription factor NF-κB or its target genes should be considered for treatment patients with glioblastoma multiforme.
Significance The most abundant modification in mRNA is the N 6 -methylation of internal adenosines (m6A), but m6A’s physiological function unknown for mRNAs. Here we show that Casein Kinase 1 Delta ( Ck1δ ), coding a critical kinase control circadian rhythms, regulated by m6A. When m6A inhibited, expression two CK1δ isoforms, uncharacterized until now, increases due to enhanced translation. This increase CK1δs leads slower clock because increased phosphorylation protein PER2 at key residue,...
PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability repressive activity in the molecular clock. CK1δ phosphorylation of familial advanced sleep phase (FASP) serine cluster embedded within 1 binding domain (CK1BD) mammalian PER1/2 inhibits its on phosphodegrons to stabilize extend period. Here, we show phosphorylated FASP region (pFASP) PER2 directly interacts with CK1δ. Co-crystal structures conjunction dynamics simulations reveal...
Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation CK1 eukaryotes, little is known about its regulation factors that influence substrate selectivity on functionally antagonistic sites directly period. Here we describe molecular switch involving highly conserved anion binding site CK1. This controls conformation kinase activation loop determines which mammalian...
Casein kinase 1 (CK1) plays a central role in regulating the period of circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On other hand, recent studies have questioned whether degradation core machinery critical step clock regulation. Prior cell-based found that CK1 at Ser478 recruits ubiquitin E3 ligase β-TrCP, leading to Creation this phosphodegron phosphoswitch also implicated temperature compensation. However,...
Background The JNK pathway is a mitogen-activated protein (MAP) kinase involved in the regulation of numerous physiological processes during development and response to environmental stress. activity controlled by two MAPK kinases (MAPKK), Mkk4 Mkk7. Mkk7 plays prominent role upon Tumor Necrosis Factor (TNF) stimulation. Eiger, unique TNF-superfamily ligand Drosophila, potently activates signaling through activation MAPKKK Tak1. Methodology/Principal Findings In dominant suppressor screen...
Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated not well understood. CK1δ inhibited by autophosphorylation of intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 δ2, are known to have very different effects on rhythms. These variants differ only in the last 16 residues tail, referred as extreme C termini (XCT), with marked changes potential...
Circadian rhythms in mammals are tightly regulated through phosphorylation of Period (PER) proteins by Casein Kinase 1 (CK1, subtypes δ and ε). CK1 acts on at least two different regions PER with opposing effects: phosphodegron (pD) leads to degradation, while the Familial Advanced Sleep Phase (FASP) region stabilization. To investigate how substrate selectivity is encoded conformational dynamics CK1, we performed a large set independent molecular (MD) simulations wildtype tau mutant (R178C)...
Signaling by tumor necrosis factors (TNFs) plays a prominent role in mammalian development and disease. To fully understand this complex signaling pathway it is important to identify all regulators transduction components. A single TNF family member, Eiger, encoded the Drosophila genome, offering possibility of applying genetic approaches for pursuing goal. Here we present screen isolation novel genes involved TNF/Eiger pathway. On basis Eiger's ability potently activate Jun-N-terminal...
Abstract Casein kinase 1 δ (CK1δ) controls essential biological processes including circadian rhythms and Wnt signaling, but how its activity is regulated not well understood. CK1δ inhibited by autophosphorylation of intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 δ2, are known to have very different effects on rhythms. These variants differ only in the last 16 residues tail, referred as extreme C-termini (XCT), with marked changes potential phosphorylation sites. Here...
Abstract Casein kinase 1 (CK1) plays a central role in regulating the period of circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On other hand, recent studies have questioned whether degradation core machinery critical step clock regulation. Prior cell-based found that CK1 at Ser478 recruits ubiquitin E3 ligase β-TrCP, leading to Creation this phosphodegron phosphoswitch also implicated temperature compensation....
Summary Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation CK1 eukaryotes, little is known about its regulation factors that influence substrate selectivity on functionally antagonistic sites directly period. Here we describe molecular switch involving highly conserved anion binding site CK1. This controls conformation activation loop to define mammalian PER2,...
Summary PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability repressive activity in the molecular clock. CK1δ phosphorylation of Familial Advanced Sleep Phase (FASP) serine cluster embedded within 1 binding domain (CK1BD) mammalian PER1/2 inhibits its on phosphodegrons to stabilize extend period. Here, we show phosphorylated FASP region (pFASP) PER2 directly interacts with CK1δ. Co-crystal structures conjunction accelerated dynamics...
Abstract Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. In last century we have accumulated tremendous amounts data on this type cancer, but despite extensive study, few therapeutic targets been identified for GBM. We established a lentiviral-induced mouse model malignant gliomas, which faithfully captures pathophysiology molecular signatures human RNAseq analysis these tumors revealed high NFκB activation showing enrichment known target genes. Depletion IKK2 in...