R W Hanson

Case Western Reserve University, Cleveland, Ohio, United States

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Publications (163)681.79 Total impact

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    ABSTRACT: Gene transfer systems targeting the asialo#{149} glycoprotein receptor have been developed to introduce functional genes into cells in culture and livers of intact animals. A synthetic neoglycoprotein carrier was con- structed and complexed to a chimeric gene containing the cDNA for human factor IX ligated to the promoter- regulatory region of the gene for phosphoenolpyruvate carboxykinase from the rat. The complex was used to transfect human hepatoma cells that express the asialoglycoprotein receptor. Human factor IX DNA se- quences were found in cells 10 days after treatment. A 1.4 levels of expression of the fully processed human factor IX were detected 30 days after introduction. The concentra- tion of factor IX in the blood returned to control levels 60 days after transfection. Factor IX production was in- duced as late as 96 days after treatment by feeding trans- fected animals a diet high in protein but devoid of carbo- hydrates. This DNA carrier system can be used to introduce functional genes into the livers of rats, and may be a useful technique for gene therapy targeting the liver.- Ferkol, T., Lindberg, G. L., Chen,J., Perales,J. C.,. Crawford, D. R., Ratnoff, 0. D., Hanson, R. W. Regula- tion of the phosphoenolpyruvate carboxykinase human factor IX gene introduced into the livers of adult rats by receptor-mediated gene transfer. FASEB J. 7: 1081-1091; 1993.
    07/2014;
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    ABSTRACT: The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
    Molecular Genetics and Metabolism 04/2014; · 2.83 Impact Factor
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    ABSTRACT: Hyaluronan, a macromolecular glycosaminoglycan, is normally synthesized by hyaluronan synthases at the plasma membrane using cytosolic UDP-GlcUA and UDP-GlcNAc substrates and extruding the elongating chain into the extracellular space. The cellular metabolism (synthesis and catabolism) of hyaluronan is dynamic. UDP-GlcNAc is also the substrate for O-GlcNAc transferase, which is central to control of many cytosolic pathways. This Perspective outlines recent data for regulation of hyaluronan synthesis and catabolism that support a model that hyaluronan metabolism can be a rheostat for controlling an acceptable normal range of cytosolic UDP-GlcNAc concentrations in order to maintain normal cell functions.
    Matrix biology: journal of the International Society for Matrix Biology 01/2014; · 3.56 Impact Factor
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    ABSTRACT: Hyaluronan, a macromolecular glycosaminoglycan, is normally synthesized by hyaluronan synthases at the plasma membrane using cytosolic UDP-GlcUA and UDP-GlcNAc substrates and extruding the elongating chain into the extracellular space. The cellular metabolism (synthesis and catabolism) of hyaluronan is dynamic. UDP-GlcNAc is also the substrate for O-GlcNAc transferase, which is central to control of many cytosolic pathways. This Perspective outlines recent data for regulation of hyaluronan synthesis and catabolism that support a model that hyaluronan metabolism can be a rheostat for controlling an acceptable normal range of cytosolic UDP-GlcNAc concentrations in order to maintain normal cell functions.
    Matrix Biology. 01/2014;
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    ABSTRACT: The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. As demonstration of a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
    Molecular Genetics and Metabolism 01/2014; · 2.83 Impact Factor
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    ABSTRACT: CBP/p300 interacting transactivator with glutamic acid (E) and aspartic acid (D)-tail 2 (Cited2) was recently shown to be essential for gluconeogenesis in the adult mouse. The metabolic function of Cited2 in mouse embryonic stem cells (mESCs) remains elusive. In the current study, the metabolism of glucose was investigated in mESCs, which contained a deletion in the gene for Cited2 (Cited2Δ/-). Compared to its parental wild type counterpart, Cited2Δ/- ESCs have enhanced glycolysis, alternations in mitochondria morphology, reduced glucose oxidation and decreased ATP content. Cited2 is recruited to the hexokinase 1 (HK1) gene promoter to regulate transcription of HK1, which coordinates glucose metabolism in wild type ESCs. Reduced glucose oxidation and enhanced glycolytic activity in Cited2Δ/- ESCs correlates with defective differentiation during hypoxia, which is reflected in an increased expression of pluripotency marker (Oct4) and epiblast marker (Fgf5) and decreased expression of lineage specification markers (T, Gata-6 and Cdx2). Knockdown of hypoxia inducible factor (HIF)-1α in Cited2Δ/- ESCs reinitiates the expression of differentiation markers T and Gata-6. Taken together, a deletion of Cited2 in mESCs results in abnormal mitochondrial morphology and impaired glucose metabolism, which correlates with a defective cell fate decision.
    Journal of Biological Chemistry 11/2013; · 4.65 Impact Factor
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    ABSTRACT: The promyelocytic leukemia protein (PML) is a well-known tumor suppressor, but its role in metabolism is largely unknown. Mice with a deletion in the gene for PML (KO mice) exhibit altered gene expression in liver, adipose tissue and skeletal muscle, an accelerated rate of fatty acid metabolism, abnormal glucose metabolism, constitutive AMP-activating kinase (AMPK) activation and insulin resistance in skeletal muscle. Lastly, an increased rate of energy expenditure protects PML KO mice from the effects of obesity induced by a western diet. Collectively, our study uncovers a previously unappreciated role of PML in the regulation of metabolism and energy balance in mice.
    Journal of Biological Chemistry 08/2013; · 4.65 Impact Factor
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    ABSTRACT: Caloric restriction (CR) markedly extends life span and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification, and life span analysis was used to determine how CR, which occurs in the Caenorhabditis elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes were detected. Life span analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the overexpression of the gene for the nematode analog of the cytosolic form of phosphoenolpyruvate carboxykinase caused a marked extension of the life span in C. elegans, presumably by enhancing energy metabolism via an altered rate of cataplerosis of tricarboxylic acid cycle anions. We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny.
    Journal of Biological Chemistry 07/2012; 287(37):31414-26. · 4.65 Impact Factor
  • Satish C Kalhan, Richard W Hanson
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    ABSTRACT: Serine is generally classified as a nutritionally nonessential (dispensable) amino acid, but metabolically, serine is indispensible and plays an essential role in several cellular processes. Serine is the major source of one-carbon units for methylation reactions that occur via the generation of S-adenosylmethionine. The regulation of serine metabolism in mammalian tissues is thus of critical importance for the control of methyl group transfer. In addition to the well known role of d-serine in the brain, l-serine has recently been implicated in breast cancer and other tumors due in part to the genomic copy number gain for 3-phosphoglycerate dehydrogenase, the enzyme that controls the entry of glycolytic intermediates into the pathway of serine synthesis. Here, we review recent information regarding the synthesis of serine and the regulation of its metabolism and discuss the role played by phosphoenolpyruvate carboxykinase in this process.
    Journal of Biological Chemistry 05/2012; 287(24):19786-91. · 4.65 Impact Factor
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    ABSTRACT: Overexpression of the Ski oncogene induces oncogenic transformation of chicken embryo fibroblasts (CEFs). However, unlike most other oncogene-transformed cells, Ski-transformed CEFs (Ski-CEFs) do not display the classical Warburg effect. On the contrary, Ski transformation reduced lactate production and glucose utilization in CEFs. Compared with CEFs, Ski-CEFs exhibited enhanced TCA cycle activity, fatty acid catabolism through β-oxidation, glutamate oxidation, oxygen consumption, as well as increased numbers and mass of mitochondria. Interestingly, expression of PPARγ, a key transcription factor that regulates adipogenesis and lipid metabolism, was dramatically elevated at both the mRNA and protein levels in Ski-CEFs. Accordingly, PPARγ target genes that are involved in lipid uptake, transport, and oxidation were also markedly up-regulated by Ski. Knocking down PPARγ in Ski-CEFs by RNA interference reversed the elevated expression of these PPARγ target genes, as well as the shift to oxidative metabolism and the increased mitochondrial biogenesis. Moreover, we found that Ski co-immunoprecipitates with PPARγ and co-activates PPARγ-driven transcription.
    Journal of Biological Chemistry 09/2011; 286(46):40013-24. · 4.65 Impact Factor
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    ABSTRACT: The plasma profile of subjects with nonalcoholic fatty liver disease (NAFLD), steatosis, and steatohepatitis (NASH) was examined using an untargeted global metabolomic analysis to identify specific disease-related patterns and to identify potential noninvasive biomarkers. Plasma samples were obtained after an overnight fast from histologically confirmed nondiabetic subjects with hepatic steatosis (n = 11) or NASH (n = 24) and were compared with healthy, age- and sex-matched controls (n = 25). Subjects with NAFLD were obese, were insulin resistant, and had higher plasma concentrations of homocysteine and total cysteine and lower plasma concentrations of total glutathione. Metabolomic analysis showed markedly higher levels of glycocholate, taurocholate, and glycochenodeoxycholate in subjects with NAFLD. Plasma concentrations of long-chain fatty acids were lower and concentrations of free carnitine, butyrylcarnitine, and methylbutyrylcarnitine were higher in NASH. Several glutamyl dipeptides were higher whereas cysteine-glutathione levels were lower in NASH and steatosis. Other changes included higher branched-chain amino acids, phosphocholine, carbohydrates (glucose, mannose), lactate, pyruvate, and several unknown metabolites. Random forest analysis and recursive partitioning of the metabolomic data could separate healthy subjects from NAFLD with an error rate of approximately 8% and separate NASH from healthy controls with an error rate of 4%. Hepatic steatosis and steatohepatitis could not be separated using the metabolomic profile. Plasma metabolomic analysis revealed marked changes in bile salts and in biochemicals related to glutathione in subjects with NAFLD. Statistical analysis identified a panel of biomarkers that could effectively separate healthy controls from NAFLD and healthy controls from NASH. These biomarkers can potentially be used to follow response to therapeutic interventions.
    Metabolism: clinical and experimental 03/2011; 60(3):404-13. · 3.10 Impact Factor
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    ABSTRACT: We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7–10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ∼50% increase in serine de novo synthesis. Pyruvate was the primary (∼90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/S-adenosylhomocysteine ratio and lower cystathione β-synthase and cystathionine γ-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.
    Journal of Biological Chemistry 02/2011; 286(7):5266-5277. · 4.65 Impact Factor
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    ABSTRACT: We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ∼50% increase in serine de novo synthesis. Pyruvate was the primary (∼90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/S-adenosylhomocysteine ratio and lower cystathione β-synthase and cystathionine γ-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.
    Journal of Biological Chemistry 02/2011; 286(7):5266-77. · 4.65 Impact Factor
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    Ali Cakmak, Gultekin Ozsoyoglu, Richard W Hanson
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    ABSTRACT: Metabolism is a representation of the biochemical principles that govern the production, consumption, degradation, and biosynthesis of metabolites in living cells. Organisms respond to changes in their physiological conditions or environmental perturbations (i.e. constraints) via cooperative implementation of such principles. Querying inner working principles of metabolism under different constraints provides invaluable insights for both researchers and educators. In this paper, we propose a metabolism query language (MQL) and discuss its query processing. MQL enables researchers to explore the behavior of the metabolism with a wide-range of predicates including dietary and physiological condition specifications. The query results of MQL are enriched with both textual and visual representations, and its query processing is completely tailored based on the underlying metabolic principles.
    Journal of Bioinformatics and Computational Biology 04/2010; 8(2):247-93. · 0.93 Impact Factor
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    ABSTRACT: Endoplasmic reticulum (ER)-bound transcription factor families are shown to be involved in the control of various metabolic pathways. Here, we report a critical function of ER-bound transcription factor, CREBH, in the regulation of hepatic gluconeogenesis. Expression of CREBH is markedly induced by fasting or in the insulin-resistant state in rodents in a dexamethasone- and PGC-1alpha-dependent manner, which results in the accumulation of active nuclear form of CREBH (CREBH-N). Overexpression of constitutively active CREBH activates transcription of PEPCK-C or G6Pase by binding to its enhancer site that is distinct from the well-characterized CREB/CRTC2 regulatory sequences in vivo. Of interest, knockdown of CREBH in liver significantly reduces blood glucose levels without altering expression of genes involved in the ER stress signaling cascades in mice. These data suggest a crucial role for CREBH in the regulation of hepatic glucose metabolism in mammals.
    Cell metabolism 04/2010; 11(4):331-9. · 17.35 Impact Factor
  • Ali Cakmak, Gultekin Özsoyoglu, Richard W. Hanson
    J. Bioinformatics and Computational Biology. 01/2010; 8:247-293.
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    ABSTRACT: The emerging field of metabolomics enables researchers to measure concentrations of large numbers of metabolites in biofluids, and to interpret them in connection with the underlying metabolic network, which poses a significant challenge for manual analysis. Given a set of observations on metabolite concentration changes, our goal in this study is to employ automated reasoning, and provide researchers with possible metabolic action scenarios that may have occurred in the body to produce the observed metabolite changes. Our proposed methodology, called the Observed Metabolite Analysis, is to (1) computationally chase the implications of a given a set of metabolite concentration change observations in body fluids, relative to a control subject, (2) eliminate metabolic action scenarios, called hypothesis, that are invalid (i.e., those scenarios that could not have happened) (e.g., increased protein turnover), and (3) rank possibly valid metabolic action scenarios on the basis of pre-defined flux ratio information. We computationally evaluate the proposed methodology with typical metabolomics data, and demonstrate that (a) through consistency analysis against a small number of measured metabolite concentration changes, over 90% of the automatically generated hypotheses are invalidated with no manual analysis, (b) using summarization techniques, the entire hypothesis set is represented by a much smaller (2% of the original) hypothesis set, and (c) performing hypothesis generation and consistency checking in an interleaved manner leads to over 95% improvement in running time.
    Proceedings of the First ACM International Conference on Bioinformatics and Computational Biology, BCB 2010, Niagara Falls, NY, USA, August 2-4, 2010; 01/2010
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    ABSTRACT: We have developed, for the Case 3D Cryo-imaging system, a specialized, multiscale visualization scheme which provides color-rich volume rendering and multiplanar reformatting enabling one to visualize an entire mouse and zoom in to organ, tissue, and microscopic scales. With this system, we have anatomically characterized, in 3D, from whole animal to tissue level, a transgenic mouse and compared it with its control. The transgenic mouse overexpresses the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) in its skeletal muscle and is capable of greatly enhanced physical endurance and has a longer life-span and reproductive life as compared to control animals. We semiautomatically analyzed selected organs such as kidney, heart, adrenal gland, spleen, and ovaries and found comparatively enlarged heart, much less visceral, subcutaneous, and pericardial adipose tissue, and higher tibia-to-femur ratio in the transgenic animal. Microscopically, individual skeletal muscle fibers, fine mesenteric blood vessels, and intestinal villi, among others, were clearly seen.
    International Journal of Biomedical Imaging 01/2010; 2010:105984.
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    ABSTRACT: With the development of improved and cost-effective technologies, it is now possible to detect thousands of metabolites in biofluids or specific organs, and reliably quantify their amounts. Metabolomics focuses on studying the concentrations of metabolites in a cell or a tissue. In this paper, we describe a prototype Web-based metabolomics data analysis system, PathCase<sup>MAW</sup> (pathcase metabolomics analysis workbench), which features (1) A Web-accessible metabolic pathway database that supports online browsing and querying, and is novel in that it includes tissue and subcompartment information for pathways, and models transport processes, (2) Tissue-aware visualization support for viewing processes, pathways, or groups of pathways in PathCase<sup>MAW</sup> database, and (3) An online metabolomics data analysis tool, called automated consequence prediction tool, which allows users to upload their own observed/measured metabolite level changes, and computationally invalidates or M(aybe)-validates those biological mechanisms that produce the observed metabolite changes.
    Computer and Information Sciences, 2009. ISCIS 2009. 24th International Symposium on; 10/2009
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    ABSTRACT: The SIRT1 activators isonicotinamide (IsoNAM), resveratrol, fisetin, and butein repressed transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C). An evolutionarily conserved binding site for hepatic nuclear factor (HNF) 4alpha (-272/-252) was identified, which was required for transcriptional repression of the PEPCK-C gene promoter caused by these compounds. This site contains an overlapping AP-1 binding site and is adjacent to the C/EBP binding element (-248/-234); the latter is necessary for hepatic transcription of PEPCK-C. AP-1 competed with HNF4alpha for binding to this site and also decreased HNF4alpha stimulation of transcription from the PEPCK-C gene promoter. Chromatin immunoprecipitation experiments demonstrated that HNF4alpha and AP-1, but not C/EBPbeta, reciprocally bound to this site prior to and after treating HepG2 cells with IsoNAM. IsoNAM treatment resulted in deacetylation of HNF4alpha, which decreased its binding affinity to the PEPCK-C gene promoter. In HNF4alpha-null Chinese hamster ovary cells, IsoNAM and resveratrol failed to repress transcription from the PEPCK-C gene promoter; overexpression of HNF4alpha in Chinese hamster ovary cells re-established transcriptional inhibition. Exogenous SIRT1 expression repressed transcription, whereas knockdown of SIRT1 by RNA interference reversed this effect. IsoNAM decreased the level of mRNA for PEPCK-C but had no effect on mRNA for glucose-6-phosphatase in AML12 mouse hepatocytes. We conclude that SIRT1 activation inhibited transcription of the gene for PEPCK-C in part by deacetylation of HNF4alpha. However, SIRT1 deacetylation of other key regulatory proteins that control PEPCK-C gene transcription also likely contributed to the inhibitory effect.
    Journal of Biological Chemistry 09/2009; 284(40):27042-53. · 4.65 Impact Factor

Publication Stats

5k Citations
681.79 Total Impact Points

Institutions

  • 1980–2014
    • Case Western Reserve University
      • • Department of Biochemistry
      • • Department of Molecular Medicine
      • • Department of Electrical Engineering and Computer Science
      • • School of Medicine
      • • Division of Hospital Medicine (MetroHealth Medical Center)
      • • Department of Medicine (University Hospitals Case Medical Center)
      Cleveland, Ohio, United States
  • 1990–2011
    • Case Western Reserve University School of Medicine
      • • Department of Biochemistry
      • • Department of Pediatrics
      Cleveland, Ohio, United States
    • University of Saskatchewan
      • Department of Biochemistry
      Saskatoon, Saskatchewan, Canada
  • 2009
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2008
    • Cleveland Clinic
      • Department of Hospital Medicine
      Cleveland, Ohio, United States
  • 2007
    • Wyeth
      New Johnsonville, Tennessee, United States
  • 1997–2005
    • Hebrew University of Jerusalem
      • Institute of Biochemistry, Food Science and Nutrition
      Jerusalem, Jerusalem District, Israel
  • 1993–1996
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, PA, United States
  • 1995
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1992
    • Autonomous University of Barcelona
      • Departamento de Bioquímica y Biología Molecular
      Cerdanyola del Vallès, Catalonia, Spain