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PubMed1999

Ancestral origin of variation in the triosephosphate isomerase gene promoter.

A high frequency of nucleotide substitutions -5A/G, -8G/A, -24T/G in the triosephosphate isomerase (TPI) gene promoter has been demonstrated in African-Americans. The biological significance of these promoter variants, two of which, -8G/A and -24T/G, occur within regulatory elements essential for transcription, is controversial. The geographical distribution and frequency of allelic variation in the TPI promoter was determined in 378 unrelated normal subjects from sub-Saharan African (n = 103), Caribbean (n = 26), Northern European (n = 57), Mediterranean (n = 55), Middle Eastern (n = 42), Asian Indian (n = 48) and Oriental (n = 47) populations. Five haplotypes were identified: the common haplotype, -5A-8G-24T, -5G, -8A, -5G-8A, and -5G-8A-24G. All, with the exception of the -8A haplotype, were present in geographically dispersed populations. The -5G allele, which was found at varying frequency in all groups, has attained high frequency in the African, Caribbean and Oriental populations. Phylogenetic comparison suggests this may represent the ancestral promoter haplotype. Homozygosity for the -5G-8A haplotype identified in four subjects confirms that these variants are not responsible for a null allele as formerly postulated. Linkage disequilibrium between related TPI promoter haplotypes, -5G, -5G-8A and -5G-8A-24G, and a single nucleotide polymorphism at nt2262 of the TPI gene supports a single ancestral origin for these mutations which precedes the separation of African and non-African populations.

Africa↗

PubMed2002

Probing plant-pathogen interactions and downstream defense signaling using DNA microarrays.

The interaction between a plant and a pathogen activates a wide variety of defense responses. The recent development of microarray-based expression profiling methods, together with the availability of genomic and/or EST (expressed sequence tag) sequence data for some plant species, has allowed significant progress in the characterization of plant pathogenesis-related responses. The small number of expression profiling studies completed to date have already identified an amazing number of genes that had not previously been implicated in plant defense. Some of these genes can be associated with defense signal transduction or antimicrobial action, but the functional contribution of many others remains uncertain. Initial expression profiling work has also revealed similarities and distinctions between different defense signaling pathways, and cross-talk (both overlap and interference) between pathogenesis-related responses and plant responses to other stresses. Potential transcriptional cis-regulatory elements upstream of co-regulated genes can also be identified. Whole-genome arrays are only now becoming available, and many interactions remain to be studied (e.g. different pathogen species, plant genotypes, mutants, time-points after infection). Expression profiling technologies, in combination with other genomic tools, will have a substantial impact on our understanding of plant-pathogen interactions and defense signaling pathways.

Calcium↗

PubMed1992

Construction of a cassette enabling regulated gene expression in the presence of aromatic hydrocarbons.

A high-level expression cassette has been constructed from a TOL plasmid derived from Pseudomonas putida carrying all cis- and trans-acting regulatory elements necessary for transcriptional gene activation in the presence of aromatic hydrocarbons such as toluene. Foreign DNA can be inserted at unique KpnI, SacI, and EcoRI sites 7, 13, and 15 nucleotides downstream of a ribosome binding site. The cassette, flanked by BamHI and EcoRI restriction sites, was inserted into a broad-host-range vector and its efficacy demonstrated in various purple bacteria by monitoring the expression of a reporter gene spectrophotometrically and by SDS-PAGE. High-level induction (80- to 600-fold) was detected in Enterobacteriaceae and in Pseudomonas but was absent or low in Agrobacterium tumefaciens and Rhizobium leguminosarum.

Base Sequence↗

PubMed1980

Nucleotide sequence of the filamentous bacteriophage M13 DNA genome: comparison with phage fd.

The 6407 nucleotide-long sequence of bacteriophage M13 DNA has been determined using both the chemical degradation and chain-termination methods of DNA sequencing. This sequence has been compared with that of the closely related bacteriophage fd (Beck et al., 1978). M13 DNA appears to be only a single nucleotide shorter than fd DNA. There is an average of 3.0% of nucleotide-sequence differences between the two genomes, but the distribution of these changes is not random; the sequence of some genes is more conserved than of others. In contrast, the nucleotide sequences and positions of the regulatory elements involved in transcription, translation and replication appear to be identical in both filamentous phage DNA genomes.

Bacteriophages↗

PubMed2005

Vitamin D receptor regulation of the steroid/bile acid sulfotransferase SULT2A1.

SULT2A1 is a sulfo-conjugating phase II enzyme expressed at very high levels in the liver and intestine, the two major first-pass metabolic tissues, and in the steroidogenic adrenal tissue. SULT2A1 acts preferentially on the hydroxysteroids dehydroepiandrosterone, testosterone/dihydrotestosterone, and pregnenolone and on cholesterol-derived amphipathic sterol bile acids. Several therapeutic drugs and other xenobiotics, which include xenoestrogens, are also sulfonated by this cytosolic steroid/bile acid sulfotransferase. Nonsteroid nuclear receptors with key roles in the metabolism and detoxification of endobiotics and xenobiotics, such as bile acid-activated farnesoid X receptor, xenobiotic-activated pregnane X receptor and constitutive androstane receptor, and lipid-activated peroxisome proliferator-activated receptor-alpha, mediate transcription induction of SULT2A1 in the enterohepatic system. The ligand-activated vitamin D receptor (VDR) is another nuclear receptor that stimulates SULT2A1 transcription, and the regulatory elements in human, mouse, and rat promoters directing this induction have been characterized. Given that bile acid sulfonation is catalyzed exclusively by SULT2A1 and that the 3alpha-sulfate of the highly toxic lithocholic acid is a major excretory metabolite in humans, we speculate that a role for the VDR pathway in SULT2A1 expression may have emerged to shield first-pass tissues from the cytotoxic effects of a bile acid overload arising from disrupted sterol homeostasis triggered by endogenous and exogenous factors.

Animals↗

PubMed1999

Schizophrenia and bipolar disorder: findings from studies of the Stanley Foundation Brain Collection.

The Stanley Foundation Brain Collection contains a matched set of specimens from patients diagnosed with schizophrenia, bipolar disorder, non-psychotic depression and normal controls. Specimens have been shipped to investigators in more than 50 laboratories around the world. To date, results obtained from studies with this collection indicate that schizophrenia and bipolar disorder may both be characterized by abnormalities in frontal cortical interneurons, although different subpopulations of these neurons may be specifically affected in the two disorders. In samples from patients with familial bipolar disorder and major depression, there are alterations in glial density in cingulate cortex. Specific effects of antidepressant drugs on the transcription factor cAMP regulatory element binding protein and brain-derived neurotrophic factor have also been observed.

Antidepressive Agents↗

PubMed2006

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice.

OBJECTIVE: Cross-breeding experiments with different mouse strains have successfully been used by many groups to identify genetic loci that predispose for obesity. In order to provide a statistical assessment of these quantitative trait loci (QTL) as a basis for a systematic investigation of candidate genes, we have performed a meta-analysis of genome-wide linkage scans for body weight and body fat. DATA: From a total of 34 published mouse cross-breeding experiments, we compiled a list of 162 non-redundant QTL for body weight and 117 QTL for fat weight and body fat percentage. Collectively, these studies include data from 42 different parental mouse strains and >14,500 individual mice. METHODS: The results of the studies were analyzed using the truncated product method (TPM). RESULTS: The analysis revealed significant evidence (logarithm of odds (LOD) score >4.3) for linkage of body weight and adiposity to 49 different segments of the mouse genome. The most prominent regions with linkage for body weight and body fat (LOD scores 14.8-21.8) on chromosomes 1, 2, 7, 11, 15, and 17 contain a total of 58 QTL for body weight and body fat. At least 34 candidate genes and genetic loci, which have been implicated in regulation of body weight and body composition in rodents and/or humans, are found in these regions, including CCAAT/enhancer-binding protein alpha (C/EBPA), sterol regulatory element-binding transcription factor 1 (SREBP-1), peroxisome proliferator activator receptor delta (PPARD), and hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1). Our results demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control body weight and body composition. An interactive physical map of the QTL is available online at (http://www.obesitygenes.org).

Adipose Tissue↗

PubMed1993

Developmentally regulated transcription of the four liver-specific genes for inter-alpha-inhibitor family in mouse.

The inter-alpha-inhibitor family is composed of the plasma-protease inhibitors inter-alpha-inhibitor, pre-alpha-inhibitor and bikunin. Inter-alpha-inhibitor and pre-alpha-inhibitor are distinct assemblies of bikunin with distinct sets from three heavy (H) chains designated H1, H2 and H3. These H chains are encoded by a set of three evolutionarily related H genes, and bikunin by an alpha-1-microglobulin/bikunin precursor gene (AMBP). This precursor is cleaved to yield bikunin, a member of the Kunitz-type protease-inhibitor superfamily, and alpha-1-microglobulin, which belongs to the lipocalin superfamily. Northern-blot experiments with RNAs obtained from various tissues in fetal and in adult mice indicated that the transcription of the four AMBP and H genes is liver-restricted, although there is expression of H3 in brain. An analysis of the H1, H2, H3 and AMBP transcripts, as well as of transcripts for other control genes, in liver during development showed a progressive increase in the amounts of the H1, H2, H3 and AMBP RNAs, which all peak transiently at day 5 after birth. This was shown by a nuclear run-on experiment to originate from a change in transcription rate. The transient and postnatal increase in transcription could be explained neither by the liver-restricted expression nor by a common origin of these four genes, nor by a perinatal requirement for many lipocalins or protease inhibitors. This suggests that all four genes are perinatally triggered at the level of similar elements in their transcriptional regulatory regions, a conclusion strengthened by the weak expression of the four genes that is seen in a mutant mouse strain (albino) that is deficient in some liver-specific transcription factors.

Aging↗

PubMed1994

Structure, expression and gene sequence of a juvenile hormone esterase-related protein from metamorphosing larvae of Trichoplusia ni.

A carboxylesterase with an encoded molecular size of 61 kDa and a high sequence similarity to juvenile hormone esterase (JHE) has been cloned from cDNA prepared from final instar larvae of Trichoplusia ni. The absence of a recognizable encoded signal peptide suggests that the enzyme, JHER (for JHE-related) may not be secreted, in contrast to JHE. When the amino acid sequence of JHE, JHER and other esterases were mapped onto the secondary and tertiary structure determined crystallographically for acetylcholinesterase, certain structural features for the substrate binding/catalytic site were identified as common only to JHE and JHER. However, several differences between JHE and JHER were identified in residues at the binding/catalytic site, suggesting that although the two enzymes prefer similar natural substrates, these substrates are not identical. JHER is present as a single-copy gene, transcribed during the feeding stage of the final stage of the final larval stadium, but not after metamorphic commitment to the pupal developmental programme. The gene transcribes a single-size message of 2.0 kb. The genes for JHER and JHE appear to be physically juxtaposed in the T. ni genome. The 5' flanking sequence to the JHER gene possesses some sequences in common with the JHE gene, but is also missing some regulatory elements previously identified in the JHE gene. Sequences conserved between the promoters for the two genes were identified that were different from previously reported regulatory elements of eukaryotic transcription factors.

Acetylcholinesterase↗

PubMed2006

Regulation of acetyl-CoA carboxylase.

Acetyl-CoA carboxylase (ACC) catalyses the formation of malonyl-CoA, an essential substrate for fatty acid synthesis in lipogenic tissues and a key regulatory molecule in muscle, brain and other tissues. ACC contributes importantly to the overall control of energy metabolism and has provided an important model to explore mechanisms of enzyme control and hormone action. Mammalian ACCs are multifunctional dimeric proteins (530-560 kDa) with the potential to further polymerize and engage in multiprotein complexes. The enzymatic properties of ACC are complex, especially considering the two active sites, essential catalytic biotin, the three-substrate reaction and effects of allosteric ligands. The expression of the two major isoforms and splice variants of mammalian ACC is tissue-specific and responsive to hormones and nutritional status. Key regulatory elements and cognate transcription factors are still being defined. ACC specific activity is also rapidly modulated, being increased in response to insulin and decreased following exposure of cells to catabolic hormones or environmental stress. The acute control of ACC activity is the product of integrated changes in substrate supply, allosteric ligands, the phosphorylation of multiple serine residues and interactions with other proteins. This review traces the path and implications of studies initiated with Dick Denton in Bristol in the late 1970s, through to current proteomic and other approaches that have been consistently challenging and immensely rewarding.

Acetyl-CoA Carboxylase↗

PubMed1998

The cholinergic gene locus.

Messenger RNAs and the cognate gene(s) encoding choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) have been cloned from mammals and several other animal classes in the last decade. These have provided molecular tools for investigating acetylcholine synthesis and packaging into synaptic vesicles, the genesis of cholinergic vesicles, and the development and senescence of the cholinergic nervous system. VAChT and ChAT have been found to share a common gene locus and regulatory elements for gene transcription. The cholinergic gene locus represents a previously undiscovered type of neuronal transcriptional unit controlling chemically coded neurotransmission. In vitro assays for the transport function of VAChT have shed light on the bioenergetics of amine accumulation in secretory vesicles. Manipulation of VAChT expression in vivo has demonstrated unequivocally the primacy of vesicular exocytosis as the mode of transmitting quanta of acetylcholine at the neuromuscular junction, as in vivo manipulation of acetylcholinesterase levels has demonstrated the importance of acetylcholine metabolism in the regulation of complex functions such as cognition. Light and electron microscopic visualization of VAChT, complementing previous ChAT immunohistochemistry, has improved understanding of the genesis and function of the cholinergic vesicle, neuron, and synapse. These advances should accelerate the development of "cholinergic" pharmacological and gene therapeutic approaches to treatment of human diseases that are associated with cholinergic surfeit and insufficiency.

Acetylcholine↗

PubMed1999

Structural and functional organization of the gene encoding the human thyrotropin-releasing hormone receptor.

The thyrotropin-releasing hormone (TRH) receptor (TRHR) is widely distributed throughout the central and peripheral nervous systems. In addition to its role in controlling the synthesis and secretion of thyroid-stimulating hormone and prolactin from the anterior pituitary, TRH is believed to act as a neurotransmitter as well as a neuromodulator. We have isolated genomic lambda and P1-derived artificial chromosome clones encoding the human TRHR. The gene was found to be 35 kb with three exons and two introns. A 541-bp intron 1 (-629 to -89 relative to the translation start site) is conserved between human and mouse. A large intron 2 of 31 kb disrupts the open reading frame (starting in position +790) in the sequence encoding the supposed junction between the third intracellular loop and the putative sixth transmembrane domain. A similar intron was found in chimpanzee and sheep but not in rat and mouse. Promoter analysis of upstream regions demonstrated cell type-specific reporter activation, and sequencing of 2.5 kb of the promoter revealed putative cis-acting regulatory elements for several transcription factors that may contribute to the regulation of the TRHR gene expression. Functional analysis of potential response elements for the anterior pituitary-specific transcription factor Pit-1 revealed cell type-specific binding that was competed out with a Pit-1 response element from the GH gene promoter.

5' Untranslated Regions↗

PubMed2003

Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress.

BACKGROUND & AIMS: Ethanol impairs the mitochondrial transport of reduced glutathione (GSH), resulting in lower mitochondrial GSH (mGSH) levels. Our purpose was to evaluate the role of acetaldehyde on the regulation of mGSH in HepG2 cells. METHODS: mGSH levels and transport, mitochondrial membrane microviscosity, and lipid composition were determined in mitochondria isolated from acetaldehyde-treated HepG2 cells. RESULTS: The major ultrastructural changes of acetaldehyde-treated HepG2 cells included cytoplasmic lipid droplets and appearance of swollen mitochondria. Acetaldehyde depleted the mGSH pool size in a time- and dose-dependent fashion with spared cytosol GSH levels. Kinetics of GSH transport into isolated mitochondria from HepG2 cells showed 2 saturable, adenosine triphosphate-stimulated, high- and low-affinity components. Treatment with acetaldehyde increased the Michaelis constant for the high- and low-affinity components, with a greater impact on the former. These changes were due to increased mitochondrial microviscosity by enhanced cholesterol deposition because preincubation with the fluidizing agent, 2-(2-methoxyethoxy) ethyl 8-(cis-2-n-octylcyclopropyl) octanoate, normalized the initial transport rate of GSH into isolated mitochondria. Isolated mitochondria from rat liver enriched in free cholesterol reproduced the disturbing effects of acetaldehyde on GSH transport. The acetaldehyde-stimulated mitochondrial cholesterol content was preceded by increased levels of endoplasmic reticulum (ER)-responsive gene GADD153 and transcription factor sterol regulatory element-binding protein 1 and mimicked by the ER stress-inducing agents tunicamycin and homocysteine. Finally, the mGSH depletion induced by acetaldehyde sensitized HepG2 cells to tumor necrosis factor (TNF)-alpha-induced apoptosis that was prevented by cyclosporin A, GSH ethyl ester, and lovastatin. CONCLUSIONS: Acetaldehyde sensitizes HepG2 cells to TNF-alpha by impairing mGSH transport through an ER stress-mediated increase in cholesterol.

Acetaldehyde↗

PubMed2005

Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.

Proprotein convertase subtilisin kexin 9 (PCSK9) is a member of the subtilisin serine protease family with an important role in cholesterol metabolism. PCSK9 expression is regulated by dietary cholesterol in mice and cellular sterol levels in cell culture via the sterol regulatory element binding protein transcription factors, and mutations in PCSK9 are associated with a form of autosomal dominant hypercholesterolemia. Overexpression of PCSK9 in mice leads to increased total and low-density lipoprotein (LDL) cholesterol levels because of a decrease in hepatic LDL receptor (LDLR) protein with normal mRNA levels. To study the mechanism, PCSK9 was overexpressed in human hepatoma cells, HepG2, by adenovirus. Overexpression of PCSK9 in HepG2 cells caused a decrease in whole-cell and cell-surface LDLR levels. PCSK9 overexpression had no effect on LDLR synthesis but caused a dramatic increase in the degradation of the mature LDLR and a lesser increase in the degradation of the precursor LDLR. In contrast, overexpression of a catalytically inactive mutant PCSK9 prevented the degradation of the mature LDLR; whereas increased degradation of the precursor LDLR still occurred. The PCSK9-induced degradation of the LDLR was not affected by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases. The PCSK9-induced degradation of the LDLR was shown to require transport out of the endoplasmic reticulum. These results indicate that overexpression of PCSK9 induces the degradation of the LDLR by a nonproteasomal mechanism in a post-endoplasmic reticulum compartment.

Animals↗

PubMed2024

Clocking out and letting go to unleash green biotech applications in a photosynthetic host.

Cyanobacteria are photosynthetic bacteria whose gene expression patterns are globally regulated by their circadian (daily) clocks. Due to their ability to use sunlight as their energy source, they are also attractive hosts for "green" production of pharmaceuticals, renewable fuels, and chemicals. However, despite the application of traditional genetic tools such as the identification of strong promoters to enhance the expression of heterologous genes, cyanobacteria have lagged behind other microorganisms such as Escherichia coli and yeast as economically efficient cell factories. The previous approaches have ignored large-scale constraints within cyanobacterial metabolic networks on transcription, predominantly the pervasive control of gene expression by the circadian (daily) clock. Here, we show that reprogramming gene expression by releasing circadian repressor elements in the transcriptional regulatory pathways coupled with inactivation of the central oscillating mechanism enables a dramatic enhancement of expression in cyanobacteria of heterologous genes encoding both catalytically active enzymes and polypeptides of biomedical significance.

Photosynthesis↗

PubMed1984

Rapid mutational analysis of regulatory loci in Escherichia coli K-12 using bacteriophage M13.

A derivative of bacteriophage M13mp8 , designated M13mp8 /P, was prepared in which the promoter and NH2-terminal codons of bacterial genes may be fused to a portion of beta-galactosidase, resulting in an easily scorable phenotype. Because transcription from the inserted promoter remains responsive to the host regulatory system, it is simple to screen mutagenized phage for isolates with aberrant regulatory phenotypes and to determine the mutational changes by dideoxy sequence analysis. The feasibility of the method was demonstrated by isolation of a large number of mutations in the regulatory regions of two genes, lexA and recA. Base substitutions that altered the phenotype of recombinant phage were identified both in the single LexA repressor binding site of recA and in the two binding sites of lexA, as well as in other sites that likely affect translational efficiency. Our results suggest that this approach will be generally useful for mutational analysis of transcriptional and translational regulatory elements.

Bacterial Proteins↗

PubMed1995

The human medium chain Acyl-CoA dehydrogenase gene promoter consists of a complex arrangement of nuclear receptor response elements and Sp1 binding sites.

Expression of the gene encoding the mitochondrial fatty acid. beta-oxidation enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), is regulated among tissues during development and in response to alterations in substrate availability. To identify and characterize cis-acting MCAD gene promoter regulatory elements and corresponding transcription factors, DNA-protein binding studies and mammalian cell transfection analyses were performed with hjman MCAD gene promoter fragments. DNA:protein binding studies with nuclear protein extracts prepared from hepatoma G2 cells, 3T3 fibroblasts, or Y-1 adrenal tumor cells identified three sequences (nuclear receptor response element 1 or NRRE-1, NRRE-2, and NRRE-3) that bind orphan members of the steroid/thyroid nuclear receptor superfamily including chicken ovalbumin upstream promoter transcription factor and steroidogenic factor 1. Sp1 binding sites (A-C) were identified in close proximity to each of the NRREs. NRRE-3 conferred cell line-specific transcriptional repression by interacting with chicken ovalbumin upstream promoter transcription factor or activation via steroidogenic factor 1. In contrast, the Sp1 binding site A behaved as a transcriptional activator in all cell lines examined. We propose that multiple nuclear receptor transcription factors interact with MCAD gene promoter elements to differentially regulate transcription among a variety of cell types.

3T3 Cells↗

PubMed1995

NF-Y has a novel role in sterol-dependent transcription of two cholesterogenic genes.

The transcription of farnesyl diphosphate (FPP) synthase is regulated up to 30-fold by the sterol status of the cell. Point mutations in a 6-base pair ATTGGC sequence in the promoter disrupt both sterol-dependent transcription in vivo as well as binding of the transcription factor NF-Y in vitro. Co-transfection of cells with NF-YA29, a dominant negative form of NF-Y, and various promoter-reporter genes specifically inhibits the sterol-dependent regulation of FPP synthase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase. In contrast, NF-YA29 does not affect the regulation of reporter genes under the control of promoters derived from either the HMG-CoA reductase or the low density lipoprotein receptor gene. Transient expression of the 68-kDa transcriptionally active fragment of sterol regulatory element-binding protein in cells stimulates an HMG-CoA synthase-reporter gene over 90-fold. This induction is blocked in cells co-expressing NF-YA29. We hypothesize that NF-Y plays a novel role in sterol-dependent regulation of two key genes in the cholesterol biosynthetic pathway and that this role requires a specific interaction with the sterol regulatory element-binding protein or related transcription factors.

Alkyl and Aryl Transferases↗