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J Ericsson

Publications and source records attributed to J Ericsson.

At least 19 recordsLinked to original sources
PubMed2006

Scaling of the low-temperature dephasing rate in Kondo systems.

We present phase coherence time measurements in quasi-one-dimensional Ag wires doped with Fe Kondo impurities of different concentrations n_{s}. Because of the relatively high Kondo temperature T_{K} approximately 4.3 K of this system, we are able to explore a temperature range from above T_{K} down to below 0.01T_{K}. We show that the magnetic contribution to the dephasing rate gamma_{m} per impurity is described by a single, universal curve when plotted as a function of T/T_{K}. For T>0.1T_{K}, the dephasing rate is remarkably well described by recent numerical results for spin S=1/2 impurities. At lower temperature, we observe deviations from this theory. Based on a comparison with theoretical calculations for S>1/2, we discuss possible explanations for the observed deviations.

Journal Article↗
PubMed2001

CTP:phosphocholine cytidylyltransferase, a new sterol- and SREBP-responsive gene.

The CTP:phosphocholine cytidylyltransferase (CT) gene encodes the rate-controlling enzyme in the phosphatidylcholine biosynthesis pathway. CTalpha mRNA levels, like farnesyl diphosphate synthase and the LDL receptor, are repressed when human or rodent cells are incubated with exogenous sterols and induced when cells are incubated in lipid-depleted medium. A putative sterol response element (SRE) was identified 156 bp upstream of the transcription start site of the CTalpha gene. Electrophoretic mobility shift assays demonstrate that recombinant SREBP-1a binds to the wild-type SRE identified in the CTalpha promoter but not to oligonucleotides containing two mutations in the SRE. In other studies, a luciferase reporter construct under the control of the murine CTalpha proximal promoter was transiently transfected into cells. The activity of the reporter was repressed after addition of sterols to the medium and induced when the cells were incubated in lipid-depleted medium. The activity of the CTalpha-luciferase reporter was also induced when cells were cotransfected with plasmids encoding either SREBP-1a or SREBP-2. In contrast, no induction was observed under the same conditions when the CTalpha promoter-reporter gene contained two mutations in the SRE. In addition, the induction of the wild-type CTalpha promoter-reporter gene that occurs in cells incubated in lipid-depleted medium is attenuated when dominant-negative SREBP is cotransfected into the cells. These studies demonstrate that transcription of the CTalpha gene is inhibited by sterols and activated by mature forms of SREBP. We conclude that SREBP-regulated genes are involved not only in the synthesis of cholesterol, fatty acids, triglycerides, and NADPH, but also, as shown here, in the synthesis of phospholipids.

Adipocytes↗
PubMed2000

The transcriptional co-activator P/CAF potentiates TGF-beta/Smad signaling.

Smads perform pivotal functions in the intracellular signaling of transforming growth factor-beta (TGF-beta). TGF-beta-mediated activation of TGF-beta type I receptor stimulates the phosphorylation of Smad2 and Smad3 and subsequent heteromeric complex formation with Smad4. The heteromeric Smad complexes translocate into the nucleus where they, in co-operation with co-activators and co-repressors, regulate transcriptional responses. Here we investigated the possible co-activator function of P/CAF in TGF-beta/Smad signaling. P/CAF was found to interact directly with Smad3 in vitro. Moreover, Smad2 and Smad3 interacted with P/CAF upon TGF-beta type I receptor activation in cultured mammalian cells. The interaction involves the MH2 domain of Smad3 and the N-terminal region of P/CAF. P/CAF potentiated the transcriptional activity of heterologous Gal4-Smad2 and Gal4-Smad3 fusion proteins. In addition, P/CAF potentiated the TGF-beta/Smad3-induced transcriptional responses, which could be further enhanced by co-activators p300 and Smad4. P/CAF may, therefore, activate Smad-mediated transcriptional responses independently or in co-operation with p300/CBP. Our results indicate a direct physical and functional interplay between two negative regulators of cell proliferation, Smad3 and P/CAF.

Acetyltransferases↗
PubMed1999

YY1 is a negative regulator of transcription of three sterol regulatory element-binding protein-responsive genes.

Ying Yang 1 (YY1) is shown to bind to the proximal promoters of the genes encoding 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, farnesyl diphosphate (FPP) synthase, and the low density lipoprotein (LDL) receptor. To investigate the potential effect of YY1 on the expression of SREBP-responsive genes, HepG2 cells were transiently transfected with luciferase reporter constructs under the control of promoters derived from either HMG-CoA synthase, FPP synthase, or the LDL receptor genes. The luciferase activity of each construct increased when HepG2 cells were incubated in lipid-depleted media or when the cells were cotransfected with a plasmid encoding mature sterol regulatory element-binding protein (SREBP)-1a. In each case, the increase in luciferase activity was attenuated by coexpression of wild-type YY1 but not by coexpression of mutant YY1 proteins that are known to be defective in either DNA binding or in modulating transcription of other known YY1-responsive genes. In contrast, incubation of cells in lipid-depleted media resulted in induction of an HMG-CoA reductase promoter-luciferase construct by a process that was unaffected by coexpression of wild-type YY1. Electromobility shift assays were used to demonstrate that the proximal promoters of the HMG-CoA synthase, FPP synthase, and the LDL receptor contain YY1 binding sites and that YY1 displaced nuclear factor Y from the promoter of the HMG-CoA synthase gene. We conclude that YY1 inhibits the transcription of specific SREBP-dependent genes and that, in the case of the HMG-CoA synthase gene, this involves displacement of nuclear factor Y from the promoter. We hypothesize that YY1 plays a regulatory role in the transcriptional regulation of specific SREBP-responsive genes.

Alkyl and Aryl Transferases↗
PubMed1999

Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway.

Compounds derived from the isoprenoid/cholesterol biosynthetic pathway have recently been shown to have novel biological activities. These compounds include certain sterols, oxysterols, farnesol, and geranylgeraniol, as well as the diphosphate derivatives of isopentenyl, geranyl, farnesyl, geranylgeranyl, and presqualene. They regulate transcriptional and post-transcriptional events that in turn affect lipid synthesis, meiosis, apoptosis, developmental patterning, protein cleavage, and protein degradation.

Cholesterol↗
PubMed1998

Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MS.

We have used reversed phase-high performance liquid chromatography-mass spectrometry (RP-HPLC-MS) with an ion trap mass spectrometer to study the metabolism of arachidonic and linoleic acids by human recombinant cytochrome P450 (CYP) enzymes. We first recorded the MS2 spectra of the carboxylate anions of epoxides, diols, omega-side chain, and bisallylic hydroxy fatty acids of arachidonic, octadeuterated arachidonic, and linoleic acids. The metabolites formed by CYP2C9 and CYP2C19 were then studied. CYP2C9 converted arachidonic and linoleic acids to epoxides/diols and monohydroxy fatty acids. Some hydroxyeicosatetraenoic acids (HETEs) were studied in detail to investigate the oxygenation mechanism. Incubation of CYP2C9 under oxygen-18 gas showed that all HETEs had incorporated oxygen-18 to the same degree. Chiral HPLC showed that CYP2C9 formed 15R-HETE (72% of the R enantiomer), 13S-HETE (90%), and 11R-HETE (57%). RP-HPLC-MS analysis revealed that CYP2C19 oxygenated arachidonic acid to 19-HETE, 14,15-epoxyeicosatrienoic acid (EET), and 8,9-EET as main metabolites. The method was sufficiently sensitive to identify arachidonic acid metabolites formed by some other isozymes. RP-HPLC-MS with MS2 seems to be useful for rapid identification of fatty acid metabolites in complex mixtures formed by cytochrome P450.

Arachidonic Acids↗
PubMed1998

CBP is required for sterol-regulated and sterol regulatory element-binding protein-regulated transcription.

Cells were transfected with luciferase reporter genes, under the control of promoters derived from either the farnesyl diphosphate (FPP) synthase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, or low density lipoprotein receptor genes. The increase in luciferase activity that occurred when cells were either incubated in sterol-depleted medium or cotransfected with a cDNA encoding sterol regulatory element-binding protein (SREBP)-1a was prevented by coexpression of wild-type E1A or a Gal4-CBP (1-451) fusion protein. The inhibitory effect of E1A was overcome by coexpression of CBP. The increase in reporter gene activity noted above was not affected when the cells were cotransfected with cDNAs that encoded either a mutant E1A that is unable to interact with the transcriptional activator CBP or Gal4-CBP fusion proteins encoding separate fragments of CBP, which span the remainder of the CBP molecule. A preformed SREBP-1a:[32P]DNA complex bound specifically to membrane-immobilized GST-CBP fusion proteins that contained amino-terminal portions of CBP. In order to investigate the role of CBP in the regulation of endogenous genes, we isolated stable transformants that express Gal4-CBP(1-451) in response to added doxycycline. Induction of endogenous FPP synthase and HMG-CoA synthase mRNAs, in response to cellular cholesterol depletion, was prevented when cells expressed Gal4-CBP(1-451). We conclude that when cells are incubated in the absence of sterols, the transcriptional activation of the HMG-CoA synthase, HMG-CoA reductase, FPP synthase, and low density lipoprotein receptor genes is dependent on a specific interaction between SREBP, which is bound to the promoter DNA, and the amino-terminal domain (amino acids 1-451) of CBP.

Adenovirus E1A Proteins↗
PubMed1998

Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease.

The association of high plasma cholesterol levels with the development of atherosclerosis is well known. The metabolic pathways that are regulated by cholesterol and the mechanisms involved are less well understood. Recent studies have identified not only cholesterol, but also oxysterols and isoprenoids, derived from the cholesterol biosynthetic pathway, as new signaling molecules. The transcriptional and post-transcriptional regulation of specific genes and metabolic pathways by these newly discovered signaling molecules may be important in the development of human disease and forms the topic of this review.

Abnormalities, Multiple↗
PubMed1998

Synergistic activation of transcription by nuclear factor Y and sterol regulatory element binding protein.

The current studies define the role of three distinct cis-elements in the proximal promoter of the rat farnesyl diphosphate (FPP) synthase gene. The three cis-elements, a sterol regulatory element 3 (SRE-3) flanked by an ATTGG motif (inverted CCAAT box), and a CCAAT box, form a sterol regulatory unit that is necessary and sufficient for sterol-regulated expression of FPP synthase promoter-reporter genes. FPP synthase promoter-reporter genes, that contain promoters with either wild-type nucleotide sequences or mutations in one or more of the three cis-elements, were transiently transfected into CV-1 cells. The activity of the wild-type promoter-reporter gene increased when the cells were incubated in sterol-depleted media or when the cells were co-transfected with a plasmid encoding the mature form of SRE binding protein (SREBP-1a). The results with the mutant promoter-reporter genes demonstrated that all three cis-elements were necessary for normal expression/regulation of the reporter gene by either sterols or by co-expressed SREBP-1a. Gel mobility shift assays demonstrated that the synergistic binding of SREBP-1a to SRE-3 was dependent on the binding of recombinant nuclear factor Y (NF-Y) to the DNA, consistent with the in vivo regulation studies.

Alkyl and Aryl Transferases↗
PubMed1998

Human geranylgeranyl diphosphate synthase: isolation of the cDNA, chromosomal mapping and tissue expression.

We report the nucleotide sequence of human geranylgeranyl diphosphate (GGPP) synthase cDNA isolated from a fetal heart library. The 2.5 kb cDNA encodes a protein of 34 kDa. The protein contains six domains that have been identified previously in many other prenyltransferases. Recombinant, purified histidine-tagged protein exhibited the enzymatic properties associated with GGPP synthase, namely the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. Transient transfection of mammalian cells with a plasmid encoding the putative GGPP synthase resulted in a 55-fold increase in GGPP synthase activity. Taken together, these results establish that the cDNA encodes the mammalian GGPP synthase protein. The mRNA for GGPP synthase was expressed ubiquitously. Of the 16 human tissues examined, the highest expression of the mRNA was in testis. The mRNA levels in cultured HeLa cells were unaffected by alterations in cellular sterol levels and contrasted with the significant regulation of isopentenyl diphosphate synthase mRNA under these same conditions. Fluorescent in situ hybridization was used to map the single gene encoding human GGPP synthase to chromosome 1q43.

Amino Acid Sequence↗
PubMed1997

Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1- and sterol regulatory element-binding protein-responsive gene.

We demonstrate that the mRNA levels of glycerol-3-phosphate acyltransferase (GPAT), a mitochondrial enzyme catalyzing the initial step in glycerolipid synthesis, are induced during the differentiation of 3T3-L1 preadipocytes to adipocytes and following ectopic expression of rat adipocyte determination and differentiation factor 1 (ADD1), a protein with high homology to the human sterol regulatory element-binding protein-1 (SREBP-1). The increase in GPAT mRNA levels that occurs during differentiation is partially prevented by ectopic expression of a dominant negative form of ADD1. Nucleotide sequences corresponding to the proximal promoter of the murine mitochondrial GPAT gene (Jerkins, A. A., Liu, W. R., Lee, S., and Sul, H. S. (1995) J. Biol. Chem. 270, 1416-1421) bound SREBP-1a and NF-Y in electromobility shift assays. In addition, GPAT promoter-luciferase reporter genes were stimulated by co-expression of SREBP-1a. This increase was attenuated when either a dominant negative form of NF-Y was co-transfected into the cells or when the GPAT promoter contained mutations in the putative binding sites for SREBP-1a or NF-Y. These studies demonstrate that the regulated expression of the mitochondrial GPAT gene requires both NF-Y and ADD1/SREBPs. Thus, SREBPs/ADD1 regulate not only genes involved in cholesterol homeostasis and fatty acid synthesis but also a key enzyme in glycerolipid synthesis.

Adipocytes↗
PubMed1997

Administration of G-CSF to healthy subjects: the effects on eosinophil counts and mobilization of eosinophil granule proteins.

Any influence of G-CSF on eosinophils is mostly negative, although reports which have studied this relationship are few with varied results. The aim of this study was to investigate the influence of G-CSF administration to healthy subjects on eosinophils in peripheral blood. Blood eosinophil counts, serum levels of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil protein X (EPX), as well as cell morphology were studied. 14 healthy volunteers received 7.5 microg (n = 8) or 10 microg/kg body weight (n = 6) G-CSF daily for six consecutive days. ECP and EPX were assessed by specific RIAs and EPO by a specific FEIA. Cell morphology was examined by electron microscopy. During G-CSF administration, eosinophil counts increased from 0.22 +/- 0.04 x 10(9)/l to 0.61 +/- 0.098 x 10(9)/l (P = 0.001), serum ECP from 12.39 +/- 2.45 microg/l to 61.82 +/- 7.38 microg/l (P = 0.0014), serum EPX from 28.05 +/- 4.54 microg/l to 87.86 +/- 9.84 microg/l (P = 0.002) and serum EPO from 8.89 +/- 2.2 microg/l to 19.98 +/- 5.1 microg/l (P = 0.003). All variables returned gradually to initial values after discontinuation of G-CSF. Distinct changes in the morphology of secondary granules were observed 24 h after G-CSF administration. The granules became irregular and their matrix less electron dense. We conclude that administration of G-CSF to healthy humans increases the number of circulating eosinophils and affects the mobilization of eosinophil granule proteins.

Adult↗
PubMed1997

Multiple primary malignant tumors in a national cancer registry--reliability of reporting.

During the years 1958-1988, 808,522 individuals were registered in the Swedish national population-based cancer register with a total of 933,900 primary malignant tumors. Roughly 11% of the tumors reported to the Swedish Cancer Registry in 1988 were found in persons earlier registered for another primary malignancy. One hundred of the individuals registered with multiple primary malignant tumors were randomly selected for a study of the reliability of reporting of multiple malignancies. Medical records and when necessary histopathological slides and other relevant diagnostic material for each malignancy were collected and the diagnoses reevaluated. Three persons had to be excluded; thus 97 cases with 209 reported malignancies were analysed. Of these, 94% of the first, 98% of the second and 79% of the third malignancy were accepted. Twelve of the reported tumors were not accepted as malignant, five were benign or cancer in situ, five were incorrectly reported as new primaries and two were a second incorrect registration of a previously registered malignancy. All 97 persons had at least one malignant tumor, in 90% of the persons all reported diagnoses were accepted and 93% had multiple primary malignancies. The results of this quality control study indicate that suitable data are available in the Swedish Cancer Registry for investigations related to the occurrence of multiple primary malignancies in a large unselected population. The Swedish Cancer Registry, to which all newly diagnosed malignancies by law have to be reported, comprise today close to one million individuals with registered malignancies.

Breast Neoplasms↗
PubMed1996

Synergistic binding of sterol regulatory element-binding protein and NF-Y to the farnesyl diphosphate synthase promoter is critical for sterol-regulated expression of the gene.

Sterol-regulated transcription of the farnesyl diphosphate (FPP) synthase gene is dependent on two cis elements in the proximal promoter. These elements, an inverted CCAAT box and sterol regulatory element 3 (SRE-3), bind NF-Y and sterol regulatory element-binding protein 1 (SREBP-1), respectively. We now demonstrate that the binding of recombinant SREBP-1 to its cognate site (SRE-3) within the FPP synthase promoter in vitro is enhanced by binding of NF-Y to the upstream inverted CCAAT box. Using an FPP synthase promoter fragment containing the binding sites for both NF-Y and SREBP-1 in gel mobility shift assays, we demonstrate that the addition of NF-Y increases the binding of SREBP-1 to SRE-3 over 20-fold. In contrast, NF-Y does not stimulate the binding of SREBP-1 to SRE-3 when the inverted CCAAT box is either mutated or 4 base pairs (bp) are inserted between the inverted CCAAT box and SRE-3. Promoter-reporter genes, containing either the wild-type FPP synthase promoter sequence or containing the 4-bp insertion between the inverted CCAAT box and SRE-3, were transiently transfected into cells. The activity of the wild-type promoter-reporter gene increased when the cells were either incubated in sterol-depleted medium or were co-transfected with an expression vector encoding transcriptionally active SREBP-1. This increase in activity was attenuated when the promoter contained the 4-bp insert, consistent with defective binding of SREBP to the promoter in vivo. These studies suggest that the binding of SREBP-1 to SRE-3 in the FPP synthase promoter, and subsequent stimulation of transcription, is dependent on synergistic binding and a functional interaction between SREBP-1 and NF-Y.

Alkyl and Aryl Transferases↗
PubMed1996

Sterol regulatory element binding protein binds to a cis element in the promoter of the farnesyl diphosphate synthase gene.

Sterol-regulated transcription of the gene for rat farnesyl diphosphate (FPP) synthase (geranyl-diphosphate:isopentenyl-diphosphate geranyltranstransferase, EC 2.5.1.10) is dependent in part on the binding of the ubiquitous transcription factor NF-Y to a 6-bp element within the proximal promoter. Current studies identify a second element in this promoter that is also required for sterol-regulated transcription in vivo. Mutation of three nucleotides (CAC) within this element blocks the 8-fold induction of FPP synthase promoter-reporter genes that normally occurs when the transfected cells are incubated in medium deprived of sterols. Gel mobility-shift assays demonstrate that the transcriptionally active 68-kDa fragment of the sterol regulatory element (SRE-1)-binding protein assays (SREBP-1) binds to an oligonucleotide containing the wild-type sequence but not to an oligonucleotide in which the CAC has been mutated. DNase 1 protection pattern (footprint) analysis indicates that SREBP-1 binds to nucleotides that include the CAC. Both the in vivo and in vitro assays are affected by mutagenesis of nucleotides adjacent to the CAC. Coexpression of SREBP with a wild-type FPP synthase promoter-reporter gene in CV-1 cells results in very high levels of reporter activity that is sterol-independent. In contrast, the reporter activity remained low when the promoter contained a mutation in the CAC trinucleotide. We conclude that sterol-regulated transcription of FPP synthase is controlled in part by the interaction of SREBP with a binding site that we have termed SRE-3. Identification of this element may prove useful in the identification of other genes that are both regulated by SREBP and involved in lipid biosynthesis.

Alkyl and Aryl Transferases↗