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PubMedDate not supplied

Polymorphisms of angiotensin-converting enzyme and angiotensin II receptor type 1 genes in essential hypertension in a Polish population.

BACKGROUND: The angiotensin-converting enzyme gene and the angiotensin II type 1 receptor gene meet the criteria for candidate genes in the pathogenesis of essential hypertension. The aim of this study was to assess the possible association between polymorphisms of these genes and essential hypertension in a Polish population, to evaluate them as possible genetic markers of susceptibility to hypertension, and to search for interaction between the two polymorphisms. MATERIAL AND METHODS: The insertion/deletion polymorphism at the angiotensin-converting enzyme gene locus and the A1166C polymorphism at the angiotensin II type 1 receptor gene locus were detected using the polymerase chain reaction and restriction fragment length methods. 250 patients with stable essential hypertension lasting at least 1 year were compared to 150 individuals without signs and symptoms of cardiovascular disease or family history of hypertension. RESULTS: No association was found between the insertion/deletion polymorphism at the angiotensin-converting enzyme locus and essential hypertension in the study population, although the DD genotype occurred more often (p<0.01) among patients with hypertension and a negative family history of hypertension than among hypertensives with a positive family history. There was an association in our study population between hypertension and the A1166C polymorphism at the angiotensinogen II type 1 receptor gene locus. The frequency of occurrence of the C1166 variant was higher among patients with hypertension (0.29) than in control subjects (0.20). The CC genotype occurred more frequently among hypertensives (0.10) than in the control group (0.04). Both these differences were statistically significant. This association was stronger in males, patients with a negative family history of hypertension, and non-obese patients with a body mass index less than 26 kg/m2. To test the interaction between the polymorphisms in question, the distribution of the A1166 and C1166 variants among ACE genotypes was assessed. The A1166 variant occurs more often among DD genotype normotensives. CONCLUSIONS: There was no association in our study population between essential hypertension and the I/D polymorphism at the angiotensin-converting enzyme gene locus. The C1166 variant of the angiotensin II type 1 receptor gene was associated with hypertension in our study population, while the A1166 variant seems to be protective as regards susceptibility to hypertension.

Alleles↗
PubMed2006

The chicken Ig light chain 3'-enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A.

Expression of the rearranged chicken immunoglobulin light chain (IgL) gene is regulated by a V gene promoter, a matrix attachment region (MAR) in the J-C intron and an enhancer downstream of the Ig constant region. Using knockout analysis, we demonstrate that the 3'-enhancer is not only required for gene activation but is also essential for the maintenance of gene expression. Deletion of the MAR on the other hand increases IgL transcription, indicating that the MAR acts as negative regulator. We demonstrate that Id1 and Id3, dominant-negative regulators of basic-region helix-loop-helix (bHLH) transcription factors, are able to reduce chicken IgL 3'-enhancer activity in transient assays and strongly reduce the rate of gene conversion (GC) in DT40 clone 18 cells. Conversely, overexpression of avian E47, a bHLH transcription factor, leads to a dramatic increase in GC rates independent of IgL or activation-induced cytidine deaminase RNA levels. Thus, E47 is the first transcription factor to activate GC without an apparent increase in transcription.

Animals↗
PubMed2000

Sds22p is a subunit of a stable isolatable form of protein phosphatase 1 (Glc7p) from Saccharomyces cerevisiae.

Protein phosphatase 1 (PP1) is one of the major protein phosphatases in eukaryotic cells. PP1 activity is believed to be controlled by the interaction of PP1 catalytic subunit with various regulatory subunits. The essential gene GLC7 encodes the PP1 catalytic subunit in Saccharomyces cerevisiae. In this study, full-length GLC7(1-312), C-terminal deletion mutants, and C-terminally poly-his tagged mutants were constructed and expressed in a GLC7 knockout strain of S. cerevisiae. Viability studies of the GLC7 knockout strains carrying the plasmids expressing GLC7 C-terminal deletion mutants and their tagged forms showed that the mutants 1-295 and 1-304 were functional, whereas the mutant 1-245 was not. The C-terminally poly-his tagged Glc7p with and without an N-terminal hemagglutinin (HA) tag was partially purified by immobilized Ni(2+) affinity chromatography and further analyzed by gel filtration and ion exchange chromatography. Phosphatase activity assays, SDS-PAGE, and Western blot analyses of the chromatographic fractions suggested that the Glc7p associated with regulatory subunits in vivo. A 40-kDa protein was copurified with tagged Glc7p through several chromatographic procedures. Monoclonal antibody against the HA tag coimmunoprecipitated the tagged Glc7p and the 40-kDa protein. This protein was further purified by a reverse phase HPLC column. Analysis by CNBr digestion, peptide sequencing, and electrospray mass spectrometry showed that this 40-kDa protein is Sds22p, one of the proteins proposed to be a regulatory subunit of Glc7. These results demonstrate that Sds22p forms a complex with Glc7p and that Sds22p:Glc7p is a stable isolatable form of yeast PP1.

Catalytic Domain↗
PubMed1989

Characterization of the ColE1 mobilization region and its protein products.

A third of the 6.6 kb genome of ColE1 is devoted to mobilization (mob) genes necessary to promote its specific transfer in the presence of conjugative plasmids. The mob region is genetically complex: two mob genes are entirely overlapped by a third. Oligonucleotide-directed mutagenesis was used to insert an amber codon into one of the overlapped genes and make possible a full complementation analysis of mob. Four mob genes essential for mobilization by R64drd11 were thus identified. Fragments of mob were subcloned under control of the Ptac promoter in a suitable vector, overexpressed in minicells and the mobilization proteins visualized. A comprehensive alignment of the mob region of ColE1 with those of its close relatives ColK and ColA demonstrating that the four essential mob genes are conserved is also presented.

Amino Acid Sequence↗
PubMed2004

Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons.

Cilia play diverse roles in vertebrate and invertebrate sensory neurons. We show that a mutation of the zebrafish oval (ovl) locus affects a component of the ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia are generated but not maintained, producing the absence of photoreceptor outer segments. A loss of cilia also occurs in auditory hair cells and olfactory sensory neurons. In all three sense organs, cilia defects are followed by degeneration of sensory cells. Similar phenotypes are induced by the absence of the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A protein, ift140. The degeneration of mutant photoreceptor cells is caused, at least partially, by the ectopic accumulation of opsins. These studies reveal an essential role for IFT genes in vertebrate sensory neurons and implicate the molecular components of intraflagellar transport in degenerative disorders of these cells.

Algal Proteins↗
PubMed2003

Microbial genomics: all that you can't leave behind.

Projects designed to scan entire microbial genomes for essential genes have revealed a remarkably compact and conserved, but not universal, set of genes whose functions are necessary for survival or reproduction.

Bacillus subtilis↗
PubMed1987

Cancer genes: rare recombinants instead of activated oncogenes (a review).

The 20 known transforming (onc) genes of retroviruses are defined by sequences that are transduced from cellular genes termed protooncogenes or cellular oncogenes. Based on these sequences, viral onc genes have been postulated to be transduced cellular cancer genes, and proto-onc genes have been postulated to be latent cancer genes that can be activated from within the cell to cause virus-negative tumors. The hypothesis is popular because it promises direct access to cellular cancer genes. However, the existence of latent cancer genes presents a paradox, since such genes are clearly undesirable. The hypothesis predicts that viral onc genes and proto-onc genes are isogenic; that expression of proto-onc genes induces tumors; that activated proto-onc genes transform diploid cells upon transfection, like viral onc genes; and that diploid tumors exist. As yet, none of these predictions is confirmed. Instead: Structural comparisons between viral onc genes, essential retroviral genes, and proto-onc genes show that all viral onc genes are indeed new genes, rather than transduced cellular cancer genes. They are recombinants put together from truncated viral and truncated proto-onc genes. Proto-onc genes are frequently expressed in normal cells. To date, not one activated proto-onc gene has been isolated that transforms diploid cells. Above all, no diploid tumors with activated proto-onc genes have been found. Moreover, the probability of spontaneous transformation in vivo is at least 10(9) times lower than predicted from the mechanisms thought to activate proto-onc genes. Therefore, the hypothesis that proto-onc genes are latent cellular oncogenes appears to be an overinterpretation of sequence homology to structural and functional homology with viral onc genes. Here it is proposed that only rare truncations and illegitimate recombinations that alter the germ-line configuration of cellular genes generate viral and possibly cellular cancer genes. The clonal chromosome abnormalities that are consistently found in tumor cells are microscopic evidence for rearrangements that may generate cancer genes. The clonality indicates that the tumors are initiated with, and possibly by, these abnormalities, as predicted by Boveri in 1914.

Animals↗
PubMed1989

Chromatin configuration of the human CD2 gene locus during T-cell development.

To investigate the molecular basis for the tissue-specific expression of the human CD2 gene, its chromatin configuration was assessed by determining DNase I hypersensitivity and the degree of methylation during T-cell lineage commitment and development. Tissue-specific DNase I-hypersensitive sites were found within the 5' promoter region and a region 3' of the gene essential for gene expression. DNase I hypersensitivity of the 5' region correlated strictly with transcriptional activity, whereas hypersensitivity of the 3' region correlated with T-cell progenitor activity or lineage commitment but not necessarily with transcription. Hha I and Hpa II sites around the 5' and 3' regions were undermethylated in CD2-expressing T cells but were more extensively methylated in other cell types. These results define likely regulatory elements both upstream and downstream of the CD2 gene that control its tissue-specific expression. Further, they show that the 3' regulatory region adopts an open chromatin configuration prior to lineage commitment and during early stages of T-cell development before the CD2 gene is transcribed.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1996

Yeast homologues of higher eukaryotic TFIID subunits.

In eukaryotic cells the TATA-binding protein (TBP) associates with other proteins known as TBP-associated factors (TAFs) to form multisubunit transcription factors important for gene expression by all three nuclear RNA polymerases. Computer searching of the complete Saccharomyces cerevisiae genome revealed five previously unidentified yeast genes with significant sequence similarity to known human and Drosophila RNA polymerase II TAFs. Each of these genes is essential for viability. A sixth essential gene (FUN81) has previously been noted to be similar to human TAFII18. Coimmunoprecipitation experiments show that all six proteins are associated with TBP, demonstrating that they are true TAFs. Furthermore, these proteins are present in complexes containing the TAFII130 subunit, indicating that they are components of TFIID. Based on their predicted molecular weights, these genes have been designated TAF67, TAF61(68), TAF40, TAF23(25), TAF19(FUN81), and TAF17. Yeast TAF61 is significantly larger than its higher eukaryotic homologues, and deletion analysis demonstrates that the evolutionarily conserved, histone-like domain is sufficient and necessary to support viability.

Amino Acid Sequence↗
PubMed2002

Myogenic specification of side population cells in skeletal muscle.

Skeletal muscle contains myogenic progenitors called satellite cells and muscle-derived stem cells that have been suggested to be pluripotent. We further investigated the differentiation potential of muscle-derived stem cells and satellite cells to elucidate relationships between these two populations of cells. FACS(R) analysis of muscle side population (SP) cells, a fraction of muscle-derived stem cells, revealed expression of hematopoietic stem cell marker Sca-1 but did not reveal expression of any satellite cell markers. Muscle SP cells were greatly enriched for cells competent to form hematopoietic colonies. Moreover, muscle SP cells with hematopoietic potential were CD45 positive. However, muscle SP cells did not differentiate into myocytes in vitro. By contrast, satellite cells gave rise to myocytes but did not express Sca-1 or CD45 and never formed hematopoietic colonies. Importantly, muscle SP cells exhibited the potential to give rise to both myocytes and satellite cells after intramuscular transplantation. In addition, muscle SP cells underwent myogenic specification after co-culture with myoblasts. Co-culture with myoblasts or forced expression of MyoD also induced muscle differentiation of muscle SP cells prepared from mice lacking Pax7 gene, an essential gene for satellite cell development. Therefore, these data document that satellite cells and muscle-derived stem cells represent distinct populations and demonstrate that muscle-derived stem cells have the potential to give rise to myogenic cells via a myocyte-mediated inductive interaction.

Animals↗
PubMed2000

Characterization of mammalian RAD51 double strand break repair using non-lethal dominant-negative forms.

In contrast to yeast RAD51, mammalian mRAD51 is an essential gene. Its role in double strand break (DSB) repair and its consequences on cell viability remain to be characterized precisely. Here, we used a hamster cell line carrying tandem repeat sequences with an I-SCE:I cleavage site. We characterized conservative recombination after I-SCE:I cleavage as gene conversion or intrachromatid crossing over associated with random reintegration of the excised reciprocal product. We identified two dominant-negative RAD51 forms that specifically inhibit conservative recombination: the yeast ScRAD51 or the yeast-mouse chimera SMRAD51. In contrast, the mouse MmRAD51 stimulates conservative recombination. None of these RAD51 forms affects non-conservative recombination or global DSB healing. Consistently, although resistance to gamma-rays remains unaffected, MmRAD51 stimulates whereas ScRAD51 or SMRAD51 prevents radiation-induced recombination. This suggests that mRAD51 does not significantly affect the global DSB repair efficiency but controls the classes of recombination events. Finally, both ScRAD51 and SMRAD51 drastically inhibit spontaneous recombination but not cell proliferation, showing that RAD51-dependent spontaneous and DSB-induced conservative recombination can be impaired significantly without affecting cell viability.

Animals↗
PubMed2000

Functions of fission yeast orp2 in DNA replication and checkpoint control.

orp2 is an essential gene of the fission yeast Schizosaccharomyces pombe with 22% identity to budding yeast ORC2. We isolated temperature-sensitive alleles of orp2 using a novel plasmid shuffle based on selection against thymidine kinase. Cells bearing the temperature-sensitive allele orp2-2 fail to complete DNA replication at a restrictive temperature and undergo cell cycle arrest. Cell cycle arrest depends on the checkpoint genes rad1 and rad3. Even when checkpoint functions are wild type, the orp2-2 mutation causes high rates of chromosome and plasmid loss. These phenotypes support the idea that Orp2 is a replication initiation factor. Selective spore germination allowed analysis of orp2 deletion mutants. These experiments showed that in the absence of orp2 function, cells proceed into mitosis despite a lack of DNA replication. This suggests either that the Orp2 protein is a part of the checkpoint machinery or more likely that DNA replication initiation is required to induce the replication checkpoint signal.

Base Sequence↗
PubMed2003

Evolutionary dynamics of oncogenes and tumor suppressor genes: higher intensities of purifying selection than other genes.

Oncogenes and tumor suppressor genes (hereafter referred to as "cancer genes") result in cancer when they experience substitutions that prevent or distort their normal function. We examined evolutionary pressures acting on cancer genes and other classes of disease-related genes and compared our results to analyses of genes without known association to disease. We compared synonymous and nonsynonymous substitution rates in 3,035 human genes-approximately 10% of the genome-measuring the intensity of purifying selection on 311 human disease genes, including 122 cancer-related genes. Although the genes examined are similar to nondisease genes in product, expression, function, and pathway affiliation, we found intriguing differences in the selective pressures experienced by cancer genes relative to other (noncancer) disease-related and non-disease-related genes. We found a statistically significant increase in the intensity of purifying selection exerted on cancer genes (the average ratio of nonsynonymous to synonymous substitutions, omega, was 0.079) relative to all other disease-related genes groups (omega = 0.101) and non-disease-related genes (omega = 0.100). This difference indicates a striking increase in selection against nonsynonymous substitutions in oncogenes and tumor suppressor genes. This finding provides insight into the etiology of cancer and the differences between genes involved in cancer and those implicated in other human diseases. Specifically, we found a significant overlap between human oncogenes and tumor suppressor genes and "essential genes," human homologs of mouse lethal genes identified by knockout experiments. This insight may improve our ability to identify cancer-related genes and enhances our understanding of the nature of these genes.

Evolution, Molecular↗
PubMed2006

Identification of the Mycobacterium tuberculosis GlnE promoter and its response to nitrogen availability.

Adenylyltransferase, GlnE, has a predicted role in controlling the enzymic activity of glutamine synthetase, the key enzyme in ammonia assimilation. It was previously demonstrated that glnE is an essential gene in Mycobacterium tuberculosis. glnE is located downstream of glnA2, one of four glutamine synthetases. The expression of GlnE under various conditions was determined. Although a co-transcript of glnA2 and glnE was detectable, the major transcript was monocistronic. A transcriptional start site immediately upstream of glnE was identified and it was shown by site-directed mutagenesis that the predicted -10 region is a functional promoter. It was demonstrated that in a Mycobacterium smegmatis background M. tuberculosis P(glnE) was up-regulated in ammonia- or glutamine-containing media.

Gene Expression Regulation, Bacterial↗
PubMed1996

Regulators of aerobic and anaerobic respiration in Bacillus subtilis.

Two Bacillus subtilis genes, designated resD and resE, encode proteins that are similar to those of two-component signal transduction systems and play a regulatory role in respiration. The overlapping resD-resE genes are transcribed during vegetative growth from a very weak promoter directly upstream of resD. They are also part of a larger operon that includes three upstream genes, resABC (formerly orfX14, -15, and -16), the expression of which is strongly induced postexponentially. ResD is required for the expression of the following genes: resA, ctaA (required for heme A synthesis), and the petCBD operon (encoding subunits of the cytochrome bf complex). The resABC genes are essential genes which encode products with similarity to cytochrome c biogenesis proteins. resD null mutations are more deleterious to the cell than those of resE. resD mutant phenotypes, directly related to respiratory function, include streptomycin resistance, lack of production of aa3 or caa3 terminal oxidases, acid accumulation when grown with glucose as a carbon source, and loss of ability to grow anaerobically on a medium containing nitrate. A resD mutation also affected sporulation, carbon source utilization, and Pho regulon regulation. The data presented here support an activation role for ResD, and to a lesser extent ResE, in global regulation of aerobic and anaerobic respiration i B.subtilis.

Aerobiosis↗
PubMed2003

Molecular characterization of the essential response regulator protein YycF in Bacillus subtilis.

The response regulator YycF is essential for cell growth in gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus and Streptococcus pneumoniae. To study the function of YycF in the essential process, we characterized a YycF (H215P) mutation that caused temperature-sensitive growth in B. subtilis. The response regulators YycF and YycF (H215P) were analyzed using circular dichroism spectroscopy, whose T(m) values were 56.0 and 45.9 degrees C, respectively, suggesting that YycF (H215P) significantly affects the protein structure with an increase in temperature. Furthermore, using the gel mobility shift assay and DNase I footprinting, we investigated the effect of YycF (H215P) on binding to the YycF box of ftsAZ operon of B. subtilis. The replacement of the histidine 215 with proline resulted in a decrease of the DNA-binding ability of YycF in vitro. In vivo, using Escherichia coli two-hybrid and homodimerization assays, we clarified that His 215 of YycF plays a crucial role in the homodimerization of the protein. Thus the essential genes involved in growth of B. subtilis appear to be regulated by the homodimer of YycF. These results suggest that the YycF dimerization is an excellent target for the discovery of novel antibiotics.

Amino Acid Sequence↗
PubMed2003

Na,K-ATPase is essential for embryonic heart development in the zebrafish.

Na,K-ATPase is an essential gene maintaining electrochemical gradients across the plasma membrane. Although previous studies have intensively focused on the role of Na,K-ATPase in regulating cardiac function in the adults, little is known about the requirement for Na,K-ATPase during embryonic heart development. Here, we report the identification of a zebrafish mutant, heart and mind, which exhibits multiple cardiac defects, including the primitive heart tube extension abnormality, aberrant cardiomyocyte differentiation, and reduced heart rate and contractility. Molecular cloning reveals that the heart and mind lesion resides in the alpha1B1 isoform of Na,K-ATPase. Blocking Na,K-ATPase alpha1B1 activity by pharmacological means or by morpholino antisense oligonucleotides phenocopies the patterning and functional defects of heart and mind mutant hearts, suggesting crucial roles for Na,K-ATPase alpha1B1 in embryonic zebrafish hearts. In addition to alpha1B1, the Na,K-ATPase alpha2 isoform is required for embryonic cardiac patterning. Although the alpha1B1 and alpha2 isoforms share high degrees of similarities in their coding sequences, they have distinct roles in patterning zebrafish hearts. The phenotypes of heart and mind mutants can be rescued by supplementing alpha1B1, but not alpha2, mRNA to the mutant embryos, demonstrating that alpha1B1 and alpha2 are not functionally equivalent. Furthermore, instead of interfering with primitive heart tube formation or cardiac chamber differentiation, blocking the translation of Na,K-ATPase alpha2 isoform leads to cardiac laterality defects.

Animals↗
PubMed2005

Polycomb group protein complexes exchange rapidly in living Drosophila.

Fluorescence recovery after photobleaching (FRAP) microscopy was used to determine the kinetic properties of Polycomb group (PcG) proteins in whole living Drosophila organisms (embryos) and tissues (wing imaginal discs and salivary glands). PcG genes are essential genes in higher eukaryotes responsible for the maintenance of the spatially distinct repression of developmentally important regulators such as the homeotic genes. Their absence, as well as overexpression, causes transformations in the axial organization of the body. Although protein complexes have been isolated in vitro, little is known about their stability or exact mechanism of repression in vivo. We determined the translational diffusion constants of PcG proteins, dissociation constants and residence times for complexes in vivo at different developmental stages. In polytene nuclei, the rate constants suggest heterogeneity of the complexes. Computer simulations with new models for spatially distributed protein complexes were performed in systems showing both diffusion and binding equilibria, and the results compared with our experimental data. We were able to determine forward and reverse rate constants for complex formation. Complexes exchanged within a period of 1-10 minutes, more than an order of magnitude faster than the cell cycle time, ruling out models of repression in which access of transcription activators to the chromatin is limited and demonstrating that long-term repression primarily reflects mass-action chemical equilibria.

Animals↗