A5101736876- Prion Diseases and Protein Misfolding
- Acute Myeloid Leukemia Research
- Neurological diseases and metabolism
- Cytokine Signaling Pathways and Interactions
- Hematopoietic Stem Cell Transplantation
- Trace Elements in Health
- Retinoids in leukemia and cellular processes
- Bone and Joint Diseases
- Bone Metabolism and Diseases
- RNA regulation and disease
- Mesenchymal stem cell research
- Corneal Surgery and Treatments
- Pancreatic and Hepatic Oncology Research
- Cancer, Lipids, and Metabolism
- T-cell and B-cell Immunology
- interferon and immune responses
- Peroxisome Proliferator-Activated Receptors
- Immunotherapy and Immune Responses
- Acute Lymphoblastic Leukemia research
- Cancer Research and Treatments
- PARP inhibition in cancer therapy
- Caveolin-1 and cellular processes
- Neurogenesis and neuroplasticity mechanisms
- Lipoproteins and Cardiovascular Health
- Endoplasmic Reticulum Stress and Disease
Case Western Reserve University
2010-2022
The University of Tokyo
2021
University School
2012-2014
Cornell University
2010
Wuhan University
2002-2007
The cellular prion protein (PrP) is a highly conserved, widely expressed, glycosylphosphatidylinositol-anchored (GPI-anchored) cell surface glycoprotein. Since its discovery, most studies on PrP have focused role in neurodegenerative diseases, whereas function outside the nervous system remains unclear. Here, we report that human pancreatic ductal adenocarcinoma (PDAC) lines expressed PrP. However, was neither glycosylated nor GPI-anchored, existing as pro-PrP and retaining GPI anchor...
Resistance to standard therapy is a major reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Developing novel overcome PDAC drug-resistance urgently needed. CRABP-II was highly expressed in all but not normal tissues and chronic pancreatitis. shown promote migration metastasis while its potential role promoting known.A paired cohort human primary relapsing assessed expression by immunohistochemistry. CRISPR/cas9 gene editing used establish knockout cell lines MTT...
The RNA-binding protein HuR binds at 3' untranslated regions (UTRs) of target transcripts, thereby protecting them against degradation. We show that directly interacts with cellular retinoic acid-binding 2 (CRABP2), a known to transport RA from the cytosol nuclear acid receptor (RAR). Association CRABP2 dramatically increases affinity toward mRNAs and enhances stability such including Apaf-1, major in apoptosome. further its cooperation contributes ability suppress carcinoma cell...
Abstract More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain Notch1. Diffuse infiltration bone marrow commonly occurs T-ALL and relapsed B-cell patients, is associated with worse prognosis. However, mechanism outgrowth resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular molecular abnormalities stroma responsible for suppression normal using a mouse model...
Mutation in the prion gene PRNP accounts for 10-15% of human diseases. However, little is known about mechanisms by which mutant proteins (PrPs) cause disease. Here we investigated effects 10 different pathogenic mutations on conformation and ligand-binding activity recombinant PrP (rPrP). We found that rPrPs react more strongly with N terminus-specific antibodies, indicative a exposed terminus. The terminus contains glycosaminoglycan (GAG)-binding motif. Binding GAG important Accordingly,...
Filamin A (FLNA) is an integrator of cell mechanics and signaling. The spreading migration observed in FLNA sufficient A7 melanoma cells but not the parental deficient M2 have been attributed to FLNA. In cells, normal prion (PrP) exists as pro-PrP, retaining its glycosylphosphatidyl-inositol (GPI) anchor peptide signal sequence (GPI-PSS). GPI-PSS PrP has a binding motif binds Reducing expression alters spatial distribution organization actin diminishes migration. Integrin β1 also FLNA, PrP,...
Abstract Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal novel adhesive role of Notch-ligand engagement in hematopoietic progenitor cells (HSPCs). Using mice with conditional loss O-fucosylglycans on EGF-like repeats the binding ligands, report that HSPCs faulty ligand ability display enhanced cycling accompanied by increased egress from marrow, phenotype mainly attributed to their reduced adhesion...
Aberrant protein aggregation causes numerous neurological diseases including Creutzfeldt–Jakob disease (CJD), but the mechanisms remain poorly understood. Here, we report AFM results on formation pathways of β-oligomers and nonfibrillar aggregates from wild-type full-length recombinant human prion (WT) an insertion mutant (10OR) with five additional octapeptide repeats linked to familial CJD. Upon partial denaturing, seeds consisting 3–4 monomers quickly appeared. Oligomers ∼11–22 then...
Abstract Conventional dendritic cells (cDC) play a central role in T-cell antitumor responses. We studied the significance of Notch-regulated DC immune responses mouse model colitis-associated colorectal cancer which there is epithelial downregulation Notch/Hes1 signaling. This defect phenocopies that caused by GMDS (GDP-mannose 4,6-dehydratase) mutation human cancers. found that, although wild-type restrained dysplasia progression and decreased incidence adenocarcinoma chimeric mice, system...
We compared the biochemical properties of a wild type recombinant normal human cellular prion protein, rPrP(c), with mutant protein that has three additional octapeptide repeats, rPrP(8OR). Monoclonal antibodies are specific for N terminus rPrP(c) react much better rPrP(8OR) than suggesting is more exposed and hence available antibody binding. The PrP(c) contains glycosaminoglycan binding motif. Accordingly, also binds rPrP(c). In addition, divalent cation copper modulates conformations...
Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers progenitor cells (HPCs) into blood, precluding the procedure, or placed at increased risk complications due to slow reconstitution. Developing more efficacious HPC mobilization regimens and strategies enhance process improve patient outcome. Although Notch signaling is not essential homeostasis adult stem (HSCs), Notch-ligand adhesive...
Our previous study shows that cellular retinoic acid binding protein II (CRABP-II) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and pre-cancerous lesions, but not detected normal tissues. In this study, we show deletion of CRABP-II PDAC cells by CRISPR/Cas9 does affect cancer cell proliferation, decreases migration invasion. Gene expression microarray analysis reveals IL-8 one the top genes whose down-regulated upon deletion, while MMP-2 MMP-14, two targets are also...
Susceptibility to scrapie disease in sheep, the archetypal prion disease, correlates with polymorphisms within ovine PrP (prion-related protein) gene. The VRQ (Val136Arg154Gln171) and AL141RQ (Ala136Leu141Arg154Gln171) allelic variants are associated classical scrapie, whereas ARR (Ala136Arg154Arg171), AF141RQ (Ala136Phe141Arg154Gln171) AHQ (Ala136His154Gln171) atypical scrapie. Recent studies have suggested that there differences stability of PrPSc (abnormal disease-specific conformation...
Recombinant prion protein, rPrP, binds DNA. Both the KKRPK motif and octapeptide repeat region of rPrP are essential for maximal binding. with pathogenic insertional mutations more DNA than wild-type rPrP. promotes aggregation protects its N terminus from proteinase K digestion. When is mixed an expression plasmid Ca2+, rPrP·DNA complex taken up by mammalian cells leading to gene expression. In presence itself also in a temperature- pinocytosis-dependent manner. Cells do not take rPrPΔKKRPK,...
Mutation in the prion gene, PRNP, accounts for approx. 10-15% of human diseases. However, little is known about mechanisms by which a mutant protein (PrP) causes disease. We compared biochemical properties wild-type protein, rPrP(C) (recombinant PrP), has five octapeptide-repeats, with two recombinant proteins insertion mutations, one three more octapeptide repeats, rPrP(8OR), and other rPrP(10OR). found that are prone to aggregate, degree kinetics aggregation proportional number inserts....
Aggregation of the normal cellular prion protein, PrP, is important in pathogenesis disease. PrP binds glycosaminoglycan (GAG) and divalent cations, such as Cu 2+ Zn . Here, we report our findings that GAG promote aggregation recombinant human (rPrP). The protein has five octapeptide repeats. In presence either or , mutant rPrPs with eight ten repeats are more prone, exhibit faster kinetics form larger aggregates than wild‐type PrP. When GAG‐binding motif, KKRPK, deleted effect but not...
Pancreatic cancer is the fourth leading causing deaths in USA, with more than 30,000 per year. The overall median survival for all pancreatic 6 months and 5-year rate less 10%. This dismal outcome reflects inefficacy of chemotherapeutic agents, as well lack an early diagnostic marker. A protein known prion (PrP) expressed human cell lines. However, these lines, PrP incompletely processed exists pro-PrP. pro-PrP binds to a molecule inside cell, filamin (FLNa), which integrator signaling...
The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical highly proliferating cells potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL).Methods: this study, we assessed the transcriptomic phenotypic alterations UPR of bone marrow endothelial (ECs) mice engrafted with T-ALL specimens from patients who have T-ALL.We used PERK inhibitor generated specific knockout to study impact on...
Abstract Successful hematopoietic progenitor cell (HPC) transplant therapy is improved by mobilizing HPCs from the bone marrow niche in donors. Notch receptor–ligand interactions are known to retain marrow, and neutralizing antibodies against ligands, Jagged-1 or Delta-like ligand (DLL4), NOTCH2 receptor potentiates HPC mobilization. Notch–ligand dependent on posttranslational modification of receptors with O-fucose modulated Fringe-mediated extension moieties. We previously reported that...