A5028126403- Wnt/β-catenin signaling in development and cancer
- Cancer-related gene regulation
- Circadian rhythm and melatonin
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- Light effects on plants
- Cancer Cells and Metastasis
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Protein Kinase Regulation and GTPase Signaling
- Microtubule and mitosis dynamics
- Cancer-related molecular mechanisms research
- DNA Repair Mechanisms
- Peptidase Inhibition and Analysis
- Polyomavirus and related diseases
- Genetics, Aging, and Longevity in Model Organisms
- Cancer-related Molecular Pathways
- Bacteriophages and microbial interactions
- Transplantation: Methods and Outcomes
- Monoclonal and Polyclonal Antibodies Research
- Genetics and Neurodevelopmental Disorders
- Photoreceptor and optogenetics research
- Genomics and Chromatin Dynamics
- Phytase and its Applications
- Plant Molecular Biology Research
Duke-NUS Medical School
2016-2025
Duke University
2015-2024
National University of Singapore
2012-2024
Duke Medical Center
2015-2024
Duke University Hospital
2015-2024
RELX Group (United States)
2019
Agency for Science, Technology and Research
2012-2016
National Cancer Centre Singapore
2016
Institute of Medical Biology
2014
Queen's University Belfast
2013
Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization FASPS gene near telomere chromosome 2q. A strong candidate (hPer2), human homolog period in Drosophila, maps to same locus. Affected have serine glycine mutation within casein kinase Iepsilon (CKIepsilon) binding region hPER2, which causes...
The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation degradation. Although phosphorylation-regulated proteolysis these inhibitors is postulated to be essential for the function clock, inhibition this process has not yet been shown alter rhythm. We have developed cell-based model Murine (mPER2) hyperphosphorylation induced cell-permeable protein phosphatase inhibitor calyculin A rapidly ubiquitination degradation 26S...
Dysregulation of Wnt–β-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, glycogen synthase kinase 3β form a Wnt-regulated complex that mediates the phosphorylation-dependent degradation β-catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC yeast two-hybrid system. Expression B56 reduced abundance β-catenin inhibited transcription target genes...
Protein phosphatase 2A is a heterotrimeric protein serine/threonine consisting of 36-kDa catalytic C subunit, 65-kDa structural A and variable regulatory B subunit. The subunits determine the substrate specificity enzyme. There have been three families cellular identified to date: B55, B56 (B′), PR72/130. We now cloned five genes encoding human isoforms. Polypeptides encoded by all but one splice variant (B56γ1) are phosphoproteins, as shown mobility shift after treatment with alkaline...
Abstract Porcupine (PORCN) is a membrane bound O-acyltransferase that required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN their activity, suggesting inhibition of could be an effective treatment cancers dependent on excess In this study, we evaluated the inhibitor Wnt-C59 (C59), to determine its activity toxicity in cultured cells mice. C59 inhibits vitro at nanomolar concentrations, as assessed by interaction with carrier protein...
Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed Paneth cells as well other epithelial and stromal cells. Ex vivo, secreted can support stem when Wnt is enhanced with supplemental R-Spondin 1 (RSPO1). However, source of cell niche less clear. Genetic ablation Porcn, an endoplasmic reticulum resident O-acyltransferase that essential for secretion activity all vertebrate Wnts, confirmed role ex vivo culture....
Enhanced sensitivity to Wnts is an emerging hallmark of a subset cancers, defined in part by mutations regulating the abundance their receptors. Whether these identify clinical opportunity important question. Inhibition Wnt secretion blocking essential post-translational modification, palmitoleation, provides useful therapeutic intervention. We developed novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks and activity all Wnts. ETC-159...
Significance Tissue stem cells in vivo reside highly structured niches that provide signals for proliferation and differentiation. Understanding the role of niche requires identifying key cell types these regulators. In intestine, R-spondins Wnts are essential regulators stem-cell niche. Here we identify subepithelial myofibroblasts PDGF receptor α lineage as specific stromal type secretes ligands. These data demonstrate close interaction between epithelial underlying regulatory stroma...
AbstractThe molecular oscillator that keeps circadian time is generated by a negative feedback loop. Nuclear entry of regulatory proteins inhibit transcription from E-box-containing promoters appears to be critical component this loop in bothDrosophila and mammals. The Drosophila double-time gene product, casein kinase I ɛ (CKIɛ) homolog, has been reported interact with dPER regulate cycle length. We find mammalian CKIɛ binds phosphorylates the murine regulator mPER1. Unlike both mPER2,...
Study of the proteins involved in DNA replication a model system such as SV40 is first step understanding eukaryotic chromosomal replication. Using cell-free that capable replicating plasmid molecules containing origin replication, we conducted series systematic fractionation-reconstitution experiments for purpose identifying and characterizing cellular In addition to one viral-encoded protein, T antigen, have identified begun characterize at least six components from HeLa cytoplasmic...
Wnt signaling plays a key role in cell proliferation and development. Recently, casein kinase I (CKI) protein phosphatase 2A (PP2A) have emerged as positive negative regulators of the pathway, respectively. However, it is not clear how these two enzymes with opposing functions regulate signaling. Here we show that both CKI delta epsilon interacted directly Dvl-1, phosphorylated multiple components Wnt-regulated beta-catenin degradation complex vitro, including adenomatous polyposis coli...
Protein phosphatase 2A (PP2A) is a major intracellular protein that regulates multiple aspects of cell growth and metabolism. The ability this widely distributed heterotrimeric enzyme to act on diverse array substrates largely controlled by the nature its regulatory B subunit. Only two gene families encoding endogenous subunits have been cloned date, although existence several additional likely. We identified two-hybrid interaction new human family PP2A subunits. This family, denoted B56,...
Wnt proteins are secreted post-translationally modified that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number dedicated factors in the secreting cell whose coordinated functions not fully understood. A screen for small molecules identified inhibitors vacuolar acidification as potent secretion. Inhibition V-ATPase or disruption pH gradients by diverse drugs potently inhibited Wnt/β-catenin signaling both cultured human cells vivo,...
In resting cells, the NFAT1 transcription factor is kept inactive in cytoplasm by phosphorylation on multiple serine residues.These phosphorylated residues are primarily contained within two types of serine-rich motifs, SRR-1 and SP which conserved NFAT family.Several different kinases have been proposed to regulate NFAT, but no single candidate displays specificity required fully phosphorylate both motifs; thus, identity kinase that regulates activity remains unclear.Here we show motifs...
Biological clocks with a period of approximately 24 h (circadian) exist in most organisms and time variety functions, including sleep-wake cycles, hormone release, bioluminescence, core body temperature fluctuations. Much our understanding the clock mechanism comes from identification specific mutations that affect circadian behavior. A widely studied mutation casein kinase I (CKI), CKIepsilon(tau) mutant, has been shown to cause loss function vitro, but it difficult reconcile this current...