A5080097084- Cholesterol and Lipid Metabolism
- Lipid Membrane Structure and Behavior
- Drug Transport and Resistance Mechanisms
- Cellular transport and secretion
- Peroxisome Proliferator-Activated Receptors
- Sphingolipid Metabolism and Signaling
- Endoplasmic Reticulum Stress and Disease
- DNA Repair Mechanisms
- Receptor Mechanisms and Signaling
- Immune Cell Function and Interaction
- Lipid metabolism and biosynthesis
- Carcinogens and Genotoxicity Assessment
- Phagocytosis and Immune Regulation
- Autophagy in Disease and Therapy
- Aortic aneurysm repair treatments
- Peptidase Inhibition and Analysis
- Calcium signaling and nucleotide metabolism
- RNA regulation and disease
- Pancreatic function and diabetes
- interferon and immune responses
- Photochromic and Fluorescence Chemistry
- Cancer-related gene regulation
- Immune cells in cancer
- Lysosomal Storage Disorders Research
- Genomics, phytochemicals, and oxidative stress
St George's, University of London
2007-2022
Harvard University Press
2008
Harvard University
2002-2007
Cincinnati Children's Hospital Medical Center
2005
The University of Texas Southwestern Medical Center
1996-2000
University of Victoria
1996-1997
Southwestern Medical Center
1997
Hebrew University of Jerusalem
1997
Institut Curie
1994
Centre National de la Recherche Scientifique
1994
The proteolytic cleavage of sterol regulatory element-binding proteins (SREBPs) is regulated by SREBP cleavage-activating protein (SCAP), which forms complexes with SREBPs in membranes the endoplasmic reticulum (ER). In sterol-depleted cells, SCAP facilitates Site-1 protease, thereby initiating release active NH 2 -terminal fragments from ER membrane so that they can enter nucleus and activate gene expression. sterol-overloaded activity blocked, remain bound to membranes, transcription...
SREBP cleavage-activating protein (SCAP) stimulates the proteolytic cleavage of membrane-bound SREBPs, thereby initiating release NH2-terminal fragments from cell membranes. The liberated enter nucleus and stimulate transcription genes involved in synthesis uptake cholesterol fatty acids. Sterols repress apparently by interacting with membrane attachment domain SCAP. In present studies we show that SCAP, like is located membranes endoplasmic reticulum nuclear envelope. COOH-terminal on...
Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that promote lipid synthesis in animal cells. They embedded the membranes of endoplasmic reticulum (ER) a helical hairpin orientation and released from ER by two-step proteolytic process. Proteolysis begins when SREBPs cleaved at Site-1, which is located leucine residue middle hydrophobic loop lumen ER. Sterols suppress Site-1 cleavage, apparently interacting with polytopic membrane protein...
The NH<sub>2</sub>-terminal fragments of sterol regulatory element-binding proteins (SREBPs) are released from endoplasmic reticulum membranes by proteases whose activities depend upon SREBP cleavage-activating protein (SCAP), a polytopic membrane protein. activity SCAP is inhibited sterols, which appear to interact with the domain SCAP. Here, we use protease protection and <i>N</i>-linked glycosylation site-mapping techniques define topology eight membrane-spanning domains data indicate...
SREBP cleavage activating protein (SCAP), a membrane-bound glycoprotein, regulates the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which are transcription factors that control lipid synthesis in animal cells. SCAP-stimulated proteolysis releases active fragments SREBPs from membranes endoplasmic reticulum and allows them to enter nucleus where they activate transcription. Sterols such as 25-hydroxycholesterol inactivate SCAP, suppressing turning off...
In the process of membrane biogenesis several dozen proteins must operate in precise concert to generate ≈100 lipids at appropriate concentrations. To study regulation bilayer assembly a cell cycle-independent manner, we have exploited fact that phagocytes replenish membranes expended during particle engulfment rapid phase lipid synthesis. response phagocytosis latex beads, human embryonic kidney 293 cells synthesized cholesterol and phospholipids amounts equivalent surface area internalized...
Oxygenated sterols such as 25-hydroxycholesterol kill Chinese hamster ovary cells because they inhibit the proteolytic processing of sterol regulatory element binding proteins (SREBPs), a pair membrane-bound transcription factors that activate genes controlling cholesterol synthesis and uptake from lipoproteins. The unprocessed SREBPs remain membrane-bound, cannot biosynthetic pathway, die deprivation. Several sterol-resistant cell lines have been isolated previously by chemical mutagenesis...
Abstract The spontaneously immortalised DF-1 cell line is rapidly replacing its progenitor primary chicken embryo fibroblasts (CEFs) for studies on avian viruses such as influenza but no comprehensive study has yet been reported comparing their innate immunity phenotypes. We conducted microarray analyses of and CEFs, under both normal stimulated conditions using interferon-α (chIFN-α) the attenuated infectious bursal disease virus vaccine strain PBG98. found that have an response compared to...
Fusion of phagosomes with late endocytic organelles is essential for cellular digestion microbial pathogens, senescent cells, apoptotic bodies, and retinal outer segment fragments. To further elucidate the biochemistry targeting process, we developed a scintillation proximity assay to study stepwise association lysosomes in vitro. Incubation tritium-labeled containing scintillant latex beads led light emission reaction requiring cytosol, ATP, low Ca(2+) concentrations. The nascent complex...
Lipid metabolism in mammals is orchestrated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control the expression genes required for uptake and synthesis cholesterol, fatty acids, triglycerides. SREBPs are thus essential insulin-induced lipogenesis cellular membrane homeostasis biogenesis. Although multiple players have been identified activation SREBPs, gaps remain our understanding how coordinated with other physiological pathways.To...
An important role of IgG antibodies in the defense against microbial infections is to promote ingestion and killing microbes by phagocytes. Here, we developed vivo vitro approaches ask whether opsonization particles with enhances intracellular targeting lysosomes phagosomes. To eliminate effect on process, cells were exposed latex beads at 15-20 degrees C, which allows engulfment both IgG-coated uncoated but prevents fusion Upon shifting temperature 37 phagosomes containing matured...
Lysosomes play important roles in multiple aspects of physiology, but the problem how transcription lysosomal genes is coordinated remains incompletely understood. The goal this study was to illuminate physiological contexts which are coordinately regulated and identify factors involved control.As their target often co-regulated, we performed meta-analyses array-based expression data regulators whose mRNA profiles highly correlated with those a core set genes. Among ~50 that rank highest by...
Alkylating agents damage DNA and proteins are widely used in cancer chemotherapy. While cellular responses to alkylation-induced have been explored, knowledge of how alkylation affects global stress is sparse. Here, we examined the effects alkylating agent methylmethane sulfonate (MMS) on gene expression mouse liver, using mice deficient alkyladenine glycosylase (Aag), enzyme that initiates repair alkylated bases. MMS induced a robust transcriptional response wild-type liver included markers...
Peroxisome proliferator-activated receptor &#947; agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration the vascular wall is an early event in this pathology, and therefore we explored effects of peroxisome agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling phorbol ester-stimulated THP-1 cells, found that a number aneurysm-related gene changes effected by AngII were...
Cells acquire cholesterol in part by endocytosis of cholesteryl ester containing lipoproteins. In endosomes and lysosomes is hydrolyzed acidic hydrolase producing fatty acids. Under certain pathological conditions, however, such as atherosclerosis, excessive levels accumulate for reasons that are poorly understood. Here, we have studied endosomal lysosomal metabolism cultured mouse macrophages with cell-free extracts. We show net hydrolysis coupled to the transfer membranes. When membrane...
We investigated the effects of gamma-ray exposures at high dose-rate (HDR, 23.2 Gy/min) and low (LDR, 0.47 on survival induction DNA double-strand breaks (dsb) in a diploid wild-type (D7) repair-deficient mutant strain rad52/rad52 Saccharomyces cerevisiae. Analysis by pulsed-field gel electrophoresis (PFGE) using contour homogeneous electric field apparatus revealed that, HDR, range 0-400 Gy, dsb are induced as linear function dose. Liquid holding recovery non-nutrient medium (LHR) for 48 h...
A scintillation proximity assay has been developed to study the endosomal trafficking of radiolabeled cholesterol in living cells. Mouse macrophages were cultured presence tritiated and scintillant microspheres. Microspheres taken up by phagocytosis stored phagolysosomes. Absorption tritium beta particles produces light signals that can be measured standard counters. Because short range for geometric reasons, microspheres detect only fraction localized inside phagolysosomes or within a...
We have characterized 54 HPRT- point mutations in T-lymphocytes from 17 individuals exposed to ionizing radiation of 137Cs Goiânia, Brazil and compared this spectrum that 30 mutants 9 unexposed Brazilian controls. The average internal exposure the group was 205 mCi, external 1.7 Gy. mutant frequency for 13.3 × 10-5, approximately a 10-fold increase over controls, which 1.56 10-5. types included base substitutions, small deletions, frameshifts, in-sertions, complex mutations, losses exon...