A5110044627- Pancreatic and Hepatic Oncology Research
- Chromatin Remodeling and Cancer
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Cellular transport and secretion
- Mechanisms of cancer metastasis
- Caveolin-1 and cellular processes
- Lipid Membrane Structure and Behavior
- Erythrocyte Function and Pathophysiology
- Sphingolipid Metabolism and Signaling
- Cell Adhesion Molecules Research
- Cancer Research and Treatments
- Lysosomal Storage Disorders Research
- Glycosylation and Glycoproteins Research
- Hedgehog Signaling Pathway Studies
- Acute Myeloid Leukemia Research
- Cancer-related Molecular Pathways
- Carbohydrate Chemistry and Synthesis
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Chronic Myeloid Leukemia Treatments
- Pancreatitis Pathology and Treatment
- Genomics and Chromatin Dynamics
- Calcium signaling and nucleotide metabolism
- RNA Research and Splicing
Novel (United States)
2015-2025
Mayo Clinic
2014-2024
Mayo Clinic in Florida
2019-2021
University of Utah
2007
University of Bristol
2007
Columbia University
2007
Tel Aviv University
2007
ProQuest (United States)
2006
Caprion (Canada)
2002
Boston University
1985-1988
We recently showed that human skin fibroblasts internalize fluorescent analogues of the glycosphingolipids lactosylceramide and globoside almost exclusively by a clathrin-independent mechanism involving caveolae. In contrast, sphingomyelin analogue is internalized approximately equally via clathrin-dependent caveolar routes. Here, we further characterized pathway for glycosphingolipids, showing Golgi targeting sphingolipids caveolae required microtubules phosphoinositol 3-kinases was...
We recently showed that human skin fibroblasts internalize fluorescent analogues of the glycosphingolipids lactosylceramide and globoside almost exclusively by a clathrin-independent mechanism involving caveolae. In contrast, sphingomyelin analogue is internalized approximately equally via clathrin-dependent caveolar routes. Here, we further characterized pathway for glycosphingolipids, showing Golgi targeting sphingolipids caveolae required microtubules phosphoinositol 3-kinases was...
Sphingolipids (SLs) are plasma membrane constituents in eukaryotic cells which play important roles a wide variety of cellular functions. However, little is known about the mechanisms their internalization from or subsequent intracellular targeting. We have begun to study these issues human skin fibroblasts using fluorescent SL analogues. Using selective endocytic inhibitors and dominant negative constructs dynamin epidermal growth factor receptor pathway substrate clone 15, we found that...
Internalization of some plasma membrane constituents, bacterial toxins, and viruses occurs via caveolae; however, the factors that regulate caveolar internalization are still unclear. Here, we demonstrate a brief treatment cultured cells with natural or synthetic glycosphingolipids (GSLs) elevation cholesterol (either by acute mbeta-cyclodextrin/cholesterol alteration growth conditions) dramatically stimulates endocytosis little no effect on other endocytic mechanisms. These treatments also...
We studied the endocytosis of fluorescent glycosphingolipid (GSL) analogs in various cell types using pathway-specific inhibitors and colocalization studies with endocytic markers DsRed caveolin-1 (cav-1). Based on inhibitor studies, all GSLs tested were internalized predominantly (>80%) by a clathrin-independent, caveolar-related mechanism, regardless type. In addition, lactosylceramide (LacCer) colocalized DsRed-cav-1 vesicular structures upon rat fibroblasts. The internalization mechanism...
We have previously demonstrated that glycosphingolipids are internalized from the plasma membrane of human skin fibroblasts by a clathrin-independent, caveolar-related mechanism and subsequently transported to Golgi apparatus process is dependent on microtubules, phosphatidylinositol 3-kinase, Rab7, Rab9. Here we characterized early steps intracellular transport fluorescent glycosphingolipid analog, BODIPY-lactosylceramide (LacCer), compared this transferrin (Tfn), well established marker...
Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. It accompanied an increased magnitude slow outward potassium ion current, I Ks . KCNQ1 KCNE1 subunits coassemble to form channel. Mutations in either subunit cause long QT syndrome, inherited arrhythmia associated with risk sudden death. Here we demonstrate that exocytosis proteins plasma membrane requires small GTPase RAB11, whereas...
Abstract Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS G12D , define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre - Nras mouse model. Further, these mutations promote transformation to acute myeloid leukemia. Using multiomics platform biochemical molecular studies we show that in are unique gene expression profile enriched mitotic...
BACKGROUNDA patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response gastrointestinal (GI) cancers.METHODSWe generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal cholangiocarcinoma. We compared PDO the observed donor same treatments.RESULTSWe report an approximately 80% concordance rate between...
In normal human skin fibroblasts (HSFs), fluorescent glycosphingolipid analogues are endocytosed and sorted into two pools, one that is recycled to the plasma membrane transported Golgi complex. Here, we investigated recycling in Niemann-Pick type A C lipid storage disease (NPFs). Cells were incubated with a analogue of lactosylceramide (LacCer) at 16 degrees label early endosomes (EEs), shifted 37 C, was quantified. Using dominant negative rabs, showed that, HSFs, LacCer rapid (t1/2...
Sphingolipids (SLs) play important roles in membrane structure and cell function. Here, we examine the SL requirements of various endocytic mechanisms using a mutant line pharmacological inhibitors to disrupt biosynthesis. First, demonstrated that Chinese hamster ovary cells could distinguish three distinct clathrin-independent endocytosis (caveolar, RhoA, Cdc42 dependent) which differed cargo, sensitivity agents, dominant negative proteins. General depletion SLs inhibited by each mechanism,...
Glycosphingolipids are endocytosed and targeted to the Golgi apparatus, but mistargeted lysosomes in numerous sphingolipidoses. Substrate reduction therapy utilizes imino sugars inhibit glucosylceramide synthase potentially abrogate effects of storage. Gaucher disease is a hereditary deficiency glucocerebrosidase leading accumulation; however, fibroblasts exhibited normal transport lactosylceramide. To better understand glycosphingolipid accumulation on intracellular trafficking use sugar...
We showed previously that the intracellular transport of sphingolipids (SLs) is altered in SL storage disease fibroblasts, due part to secondary accumulation free cholesterol. In present study we examined mechanism cholesterol elevation normal human skin fibroblasts induced by treatment with SLs. When cells were incubated various natural SLs for 44 h, levels increased 25–35%, and esterification was reduced. Catabolism exogenous not required because (i) a non-hydrolyzable degradable analog...
Glucosylceramide synthase (GCS) catalyzes the transfer of glucose from UDP-glucose to ceramide form glucosylceramide, precursor most higher order glycosphingolipids. Recently, we characterized GCS activity in highly enriched fractions rat liver Golgi membranes (Paul, P., Kamisaka, Y., Marks, D. L., and Pagano, R. E. (1996) J. Biol. Chem. 271, 2287–2293), human was cloned by others (Ichikawa, S., Sakiyama, H., Suzuki, G., Hidari, K. I.-P. J., Hirabayashi, Y. Proc. Natl. Acad. Sci. U. S. A....
Abstract Glycosphingolipids are known to play roles in integrin-mediated cell adhesion and migration; however, the mechanisms by which glycosphingolipids affect integrins unknown. Here, we show that addition of glycosphingolipid, C8-lactosylceramide (C8-LacCer), or free cholesterol human fibroblasts at 10°C causes formation glycosphingolipid-enriched plasma membrane domains as shown visualizing a fluorescent glycosphingolipid probe, BODIPY-LacCer, incorporated into living cells. Addition...
ABSTRACT Niemann‐Pick disease type C (NPC) is a genetic disorder in which patient cells exhibit lysosomal accumulation of cholesterol and sphingolipids (SLs) caused by defects either NPC1 or NPC2 proteins. We previously demonstrated that human skin fibroblasts overexpressing endosomal Rab proteins (Rab7 Rab9) showed correction the storage phenotype. In current study, we used protein transduction to further investigate Rab9‐mediated reduction stored lipids NPC cells. Recombinant Rab9 fused...