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  • 1
  • 2
    Keywords: CELLS ; EXPRESSION ; Germany ; INHIBITION ; KINASE ; PATHWAY ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; PROTEINS ; SACCHAROMYCES-CEREVISIAE ; transcription ; COMPLEX ; RESPONSES ; COMPLEXES ; DNA ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; cell cycle ; CELL-CYCLE ; CYCLE ; fibroblasts ; PHOSPHORYLATION ; PROTEIN-KINASE ; ASSOCIATION ; CHROMATIN ; chromatin remodeling ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; YEAST ; BUDDING YEAST ; PROMOTER ; NUMBER ; LINE ; Jun ; DEGRADATION ; ORGANIZATION ; nutrition ; REPRESSION ; expression profiling ; CYCLE CONTROL ; C-FOS EXPRESSION ; ASSOCIATIONS ; assembly ; MUTANTS ; HUMAN-CELLS ; ACTIVATOR MET4 ; CK2 knockouts ; HMGB PROTEINS ; MET genes ; PHO genes ; REGULATORY SUBUNITS ; transcription regulation
    Abstract: Protein kinase CK2 has diverse links to gene control and cell cycle. Comparative genome-wide expression profiling of CK2 mutants of the budding yeast Saccharomyces cerevisiae at cell cycle entry has revealed that a significant proportion of cell-cycle genes are affected by CK2. Here, we examine how CK2 realizes this effect. We show that the CK2 action may be directed to gene promoters causing genes with promoter homologies to respond comparably to CK2 perturbation. Examples are metabolic pathway and nutrition supply genes such as the PHO and MET regulon genes, responsible for phosphate maintenance and methionine biosynthesis, respectively. CK2 perturbation affects both regulons permanently and both via repression of a central transcription factor, but with different mechanisms: In the PHO regulon, the gene encoding the central transcription factor Pho4 is repressed and, in addition, Pho4 and/or the cyclin-dependent kinase of the regulon's control complex may be affected by CK2 phosphorylation. In the MET regulon, the repression of the central transcription factor Met4 occurs not by expression inhibition, but rather by availability tuning via a CK2-mediated phosphorylation of a degradation complex. On the other hand, the CK2 action may be directed to the chromatin regulon, thus affecting globally the expression of genes, i.e., the CK2 perturbation results either in comparable responses of genes which have no promoter homologies or in deviating responses despite promoter homologies. The effect is rather transient and concerns aside various cell cycle control genes a notable number of genes encoding chromatin remodeling and modification proteins with functions in chromatin assembly and (anti-)silencing as well as in histone (de-)acetylation, and frequently are also substrates of CK2, suggesting additional tuning at protein level. In line with these findings, we observe in human cells sequence-independent but cell-cycle-dependent CK2 associations with promoters of cell-cycle-regulated genes at periods of extensive gene expression alterations, including cell cycle entry. Our observations are compatible with the idea that the gene control by CK2 is achieved via different mechanisms and at different levels of organization and includes a global role in transcription-related chromatin remodelling and modification
    Type of Publication: Journal article published
    PubMed ID: 16335538
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  • 3
    Keywords: CELLS ; SURVIVAL ; IN-VIVO ; PATHWAY ; PROTEIN ; radiation ; BIOLOGY ; PROTEIN-KINASE ; PROGRESSION ; REPAIR ; COMET ASSAY ; SIGNALING PATHWAYS ; DNA repair ; DOUBLE-STRAND BREAKS ; HUMAN-CELLS ; OXIDATIVE DNA-DAMAGE ; B COMPLEX ; Hat1 ; HZE particles
    Abstract: Hat1 was the first histone acetyltransferase identified; however, its biological function is still unclear. In this report, it is shown for the first time that human Hat1 has two isoforms. Isoform a has 418 amino acids (aa) and is localized exclusively in the nuclear matrix of normal human keratinocytes (NHKs). Isoform b has 334 aa and is located in the cytoplasm, the nucleoplasm, attached to the chromatin and to the nuclear matrix. Immunohistochemical analyses revealed that the bulk of Hat1 is confined to the nucleus, with much lesser amounts in the cytoplasm. Cells undergoing mitotic division have an elevated amount of Hat1 compared to those that are non-mitotic. Senescent cells, however, exhibit a higher concentration of Hat1 in the cytoplasm compare to proliferating cells and the amount of Hat1 in the nucleus decreases with the progression of senescence. NHKs exposed to hydrogen peroxide (H(2)O(2)) or to a beam of high mass and energy ion particles displayed bright nuclear staining for Hat1, a phenotype that was not observed in NHKs exposed to gamma-rays. We established that the enhanced nuclear staining for Hat1 in response to these treatments is regulated by the PI3K and the mitogen-activated protein kinase signaling pathways. Our observations clearly implicate Hat1 in the cellular response assuring the survival of the treated cells.
    Type of Publication: Journal article published
    PubMed ID: 20148353
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  • 4
    Keywords: Germany ; KINASE ; CDNA ; GENE ; transcription ; SEQUENCE ; IDENTIFICATION ; ASSAY ; DATABASE ; BETA ; LOCALIZATION ; CRYSTAL-STRUCTURE ; Alu repeat ; ALU REPEATS ; BLAST ; CK2-ALPHA ; Ets1 ; protein kinase CK2 gene ; Sp1 ; transcription control
    Abstract: The human genome contains four protein kinase CK2 loci, enclosing three active genes coding for the catalytic subunits alpha and alpha' and the regulatory subunit beta, and a processed alpha subunit pseudogene. Extensive structure and transcriptional control data of the genes are available, except for the CK2 alpha' gene (CSNK2A2). Using in silico and experimental approaches, we find CSNK2A2 to be located on the long arm of chromosome 16 (in contrast to published data), to span 40 kb and to consist of 12 exons, with the translational start in Exon 1 and the stop in Exon 11. Exon/intron boundaries conform to the gt/ag rule, and various potential polyadenylation signals determine transcript species with lengths of 1.7-5.7 kb. The upstream region of the gene displays housekeeping characteristics, lacking a TATA box and possessing several GC boxes as well as a CpG island around Exon 1. According to reporter gene assay results, the promoter activity ranges from -1308 to 197 with the highest activity in region -396 to -129. This region contains binding motifs for various transcription factors, including NF kappa B, Sp and Ets family members. Site-directed mutagenesis indicates that the Ets motifs play, in cooperation with Sp motif clusters, a central role in regulating CK2 alpha' gene transcription. A similar control has been described for the transcription of the CK2 alpha and CK2 beta genes so that the presented data are compatible with the assumption of a coordinate transcriptional regulation of all three active human CK2 genes decisively determined by Ets family members
    Type of Publication: Journal article published
    PubMed ID: 16335532
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  • 5
    ISSN: 1573-4919
    Keywords: canine idiopathic dilated cardiomyopathy ; calcium release channel ; mRNA ; oxidative phosphorylation ; myoglobin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Idiopathic dilated cardiomyopathy is associated with derangement of myocardial sarcoplasmic Ca-homeostasis and energy production. The molecular mechanism for these changes is unknown. Accordingly, we used genetic and experimentally-induced models of canine dilated cardiomyopathy and tested the hypothesis that these metabolic changes resulted from altered gene expression, as indicated by mRNA content. We studied dilated cardiomyopathy occurring naturally (n=9) in Doberman pinschers, and in dogs subjected to rapid ventricular pacing (n=5), in comparison with normal dogs (n=9). We determined content and integrity of mRNA's using Northern and slot blotting, and measured activities of their translated product for the Ca-release channel and Ca-ATPase of sarcoplasmic reticulum, lactate dehydrogenase of glycolysis, citrate synthase of the tricarboxylic acid cycle, and for myoglobin, ATP-synthetase and the adenine nucleotide transporter, which are integral in oxidative phosphorylation. We found that, whereas both mRNA content and enzyme activity for markers of Ca-cycling, glycolysis, and oxidative phosphorylation were downregulated (20–80%) in dilated cardiomyopathy, they were upregulated (10–15%) for tricarboxylic acid cycling and for ribosomal RNA. RNA from cardiomyopathic tissue was up to 50% more degraded than for normal hearts in association with a 150% increase in ribonuclease activity. Downregulation of the Ca-cycle was asymmetric, with the Ca-channel being 65% more affected than the Ca-ATPase. This work supports the general paradigm that transcriptional and translational responses to pathophysiology are major determinants of the metabolic response seen in cardiac failure.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-4919
    Keywords: cardiac muscle ; slow-twitch skeletal muscle ; sarcoplasmic reticulum ; Ca2+ uptake ; CaM kinase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract In both cardiac and slow-twitch skeletal muscle sarcoplasmic reticulum (SR) there are several systems involved in the regulation of Ca2+-ATPase function. These include substrate level regulation, covalent modification via phosphorylation-dephosphorylation of phospholamban by both cAMP-dependent protein kinase (PKA) and Ca2+/calmodulin-dependent protein kinase (CaM kinase) as well as direct CaM kinase phosphorylation of the Ca2+-ATPase. Studies comparing, the effects of PKA and CaM kinase on cardiac Ca2+-ATPase function have yielded differing results; similar studies have not been performed in slow-twitch skeletal muscle. It has been suggested recently, however, that phospholamban is not tightly coupled to the Ca2+-ATPase in SR vesicles from slow-twitch skeletal muscle. Our results indicate that assay conditions strongly influence the extent of CaM kinase-dependent Ca2+-ATPase stimulation seen in both cardiac and slow-twitch skeletal muscle. Addition of calmodulin (0.2 μM) directly to the Ca2+ transport assay medium results in minimal (∼ 112–130% of control) stimulation of Ca2+ uptake activity when the Ca2+ uptake reaction is initiated by the addition of either ATP or Ca2+/EGTA. On the other hand, prephosphorylation of the SR by the endogenous CaM kinase and subsequent transfer of the membranes to the Ca2+ transport assay medium results in stimulation of Ca2+ uptake activity (202% of control). These effects are observable in both cardiac and slow-twitch skeletal muscle SR. PKA stimulates Ca2+ uptake markedly (215% of control) when the Ca2+ uptake reaction is initiated by the addition of prephosphorylated SR membranes or by Ca2+/EGTA but minimally (130% of control) when the Ca2+ uptake reaction is initiated by the addition of ATP. These findings imply that (a) phospholamban is coupled to the Ca2+-ATPase in slow-twitch skeletal muscle SR (as in cardiac SR), and (b) the amount of Ca2+ uptake stimulation seen upon the addition of calmodulin or PKA depends strongly on the assay conditions employed. Our observations help to explain the wide range of effects of calmodulin or PKA addition reported in previous studies. It should be noted that, since CaM kinase is now known to phosphorylate the Ca2+-ATPase in addition to phospholamban, further studies are required to determine the relative contributions of phospholambanversus Ca2+-ATPase phosphorylation in the stimulation of Ca2+-ATPase function by CaM kinase. Also, earlier studies attributing all of the effects of CaM kinase stimulation of Ca2+ uptake and Ca2+-ATPase activity to phospholamban phosphorylation need to be re-examined.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-4919
    Keywords: hypocaloric feeding ; rat ; myocardium ; sarcoplasmic reticulum ; Ca-release channel ; Ca-ATPase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Hypocaloric feeding (HCF) depresses heart function causing cardiac atrophy, bradycardia, and decreased cardiac output. We tested the hypothesis that HCF results in decreased myocardial Ca- and ATP cycling. We reduced protein-calorie intake of adult rats by 20% for 7 days and then allowed them to recover for 3 days. Changes in ionized Ca concentration (nM/s) of 2.5% myocardial homogenates that were attributable to the Ca-ATPase pump and Ca-release channel (CRC), respectively, of the sarcoplasmic reticulum (SR) were depressed 41 and 85% by HCF from 61.6±9.4 and 24.7±3.3, to 36.1±2.8 and 3.6±2.9. Activity of the Ca-pump was restored after 3 days of refeeding, whereas the CRC remained 23% depressed (all p〈0.05). Additionally, the CRC activity was inhibited to a 3-fold greater extent than controls by HCF, but was disinhibited within one day of refeeding. The greater effect on CRC than Ca-pump activity resulted in net Ca-uptake being unaffected by HCF. In addition to depression of Ca-cycling, ATP sythetase and total ATPase activities (IU/g), respectively, were depressed 20 and 15% by HCF from 174±19 and 51.3±3.8 to 140±15 and 43.7±4.7, but were restored to control values within one day of refeeding. We conclude that HCF produces a compensatory, reversible, and asymmetric downregulation and inhibition of Ca-cycling, with the CRC being preferentially affected.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-4919
    Keywords: vanadium compounds ; osteoblast-like cells ; proliferation ; differentiation ; bone development ; growth factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of different vanadium compounds on proliferation and differentiation was examined in osteoblast-like UMR106 cells. Vanadate increased the cell growth in a biphasic manner, the higher doses inhibiting cell progression. Vanadyl stimulated cell proliferation in a dose-responsive manner. Similar to vanadate, pervanadate increased osteoblast-like cell proliferation in a biphasic manner but no inhibition of growth was observed. Vanadyl and pervanadate were stronger stimulators of cell growth than vanadate. Only vanadate was able to regulate the cell differentiation as measured by cell alkaline phosphatase activity. These results suggest that vanadium derivatives behave like growth factors on osteoblast-like cells and are potential pharmacological tools in the control of cell growth.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-4919
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The mitochondrial respiration rate and morphometric indices in endomyocardial biopsy samples were measured in 43 patients with dilated cardiomyopathy selected in accordance to WHO criteria by endomyocardial biopsy studies after excluding of various forms of myocarditis, alcoholic cardiomyopathy and other specific diseases of the heart. A group of 13 patients with unusually high mean myocyte diameter, 30±4 μm, and nuclear size, 57±5 μm, was selected. The remainder of patients (n=30) had significantly lower mean myocyte diameter and nuclear size, 23±3 and 42±6 μm, respectively, (p〈0.01). Creatine-stimulated elevation in mitochondrial respiration rate as measured in saponin-skinned was found in the former group to be much lower (36±4%) as compared with the remainder (90±12%). Also, the former group of patients had higher left ventricular enddiastolic pressure and volume index with concomitantly decreased ejection fraction. The results indicate that marked nuclear and cellular hypertrophy is associated with lower creatine-stimulated mitochondrial respiration rate and more severe cardiac failure. They suggest that disorders in energy supply to myofibrils may be related to disturbances in cellular genetic apparatus.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-4919
    Keywords: aestivation ; protein phosphorylation ; subcellular fractionation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Protein phosphorylation patterns were investigated in whole tissues and subcellular fractions of active and aestivatingOtala lactea (Müller) (Pulmonata, Helicidae). Measurement of overall protein phosphorylation showed that incorporation of32P increased until the second day after injection and remained constant for the remaining 4 days of the time course. Comparison of tissues from aestivating and active snails on day 3 showed a decreased protein phosphorylation in aestivating snails (44% of active). No differences in total and protein-associated radioactivity for foot, mantle or haemolymph were observed. Subcellular fractionation of the hepatopancreas localized the changes to plasma membrane, microsomal, and cytosolic fractions: values for aestivating animals were reduced to 71, 37 and 58% of the corresponding active values. Separation of the individual subcellular fractions on isoelectric focusing columns revealed differences in the phosphate incorporation patterns. Plasma membrane from aestivating animal hepatopancreas had a lower overall level of incorporation and fewer radioactive peaks in the pH 7–10 region than did the plasma membrane fraction from active animals. SDS-PAGE analysis of plasma membrane fractions from active and aestivating snails showed a relative decrease in phosphorylation between 60–80 kDa and 30–40 kDa. IEF analysis of cytosolic proteins from aestivating snail hepatopancreas also showed peaks of radioactivity that were apparently shifted by 0.3 pH units toward higher pI values. Increased phosphate incorporation was observed at a peak that corresponded to the pI value for pyruvate kinase in aestivating snails but definite assignment of peaks was not possible. SDS-PAGE analysis of cytosolic proteins showed an aestivation-related decrease in relative protein phosphorylation between 30–35 kDa and 40–45 kDa. A relative increase in phosphorylation during aestivation was observed for proteins between 16–22 kDa. Overall, the data indicate that snails dramatically alter their protein phosphorylation pattern in hepatopancreas during aestivation. (Mol Cell Biochem143: 7–13, 1995)
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