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PubMed2001

Cis and trans elements regulating expression of the varicella zoster virus gI gene.

We have identified cis- and trans-acting elements involved in the VZV IE62 protein-activated expression of the varicella zoster virus (VZV) gene which encodes the viral gI glycoprotein. The cis-acting elements include a non-canonical TATA box and a novel 19 base pair sequence located just upstream of the TATA element designated the "activating upstream sequence" or AUS. The AUS is a movable element and its presence results in IE62 activation of a chimeric promoter consisting of the VZV gC TATA box and the gI AUS. We have also determined that the VZV ORF 29 protein modulates the regulatory activity of the IE62 protein at the gI promoter. In combination with the IE62 transactivator, it yields a 10 to 15-fold increase in expression over the levels seen with the IE62 protein alone in T lymphocytes. The upmodulatory activity requires the presence of a 40 base pair sequence, designated the 29RE, which maps between positions -220 and -180 in the gI promoter. In this paper we review these and earlier findings from our laboratories concerning the regulation of the gI promoter.

Cell Line↗

PubMed1993

Autophosphorylation: a salient feature of protein kinases.

Most protein kinases catalyze autophosphorylation, a process which is generally intramolecular and is modulated by regulatory ligands. Either serine/threonine or tyrosine serves as the phosphoacceptor, and several sites on the same kinase subunit are usually autophosphorylated. Autophosphorylation affects the functional properties of most protein kinases. Members of the protein kinase family exhibit diversity in the characteristics and functions of autophosphorylation, but certain common themes are emerging.

Animals↗

PubMedDate not supplied

Autonomic responses and neurohumoral control in the human early antenatal heart.

Previous sporadic findings and the results of recent, more systematic studies now permit us to make an attempt to outline the contribution of the sympathetic and parasympathetic system to the control of the human early antenatal cardiac function. In the developing heart of man, only acetylcholine and catecholamines have so far been proven to act as true autonomic transmitters. Muscarinic-cholinergic responses to acetylcholine and related agents can be detected from the 4th postconception week onwards, i.e. soon after the initiation of the first heartbeats. The same applies to the beta-adrenergic responsiveness to noradrenaline, adrenaline and other adrenergic stimulants in a somewhat later period, commencing at week 5 after conception. The maximum cardiac response to all these agonists becomes stronger as development continues. Evidence is accumulating to suggest that prostaglandins and triiodothyronine might modulate the regulatory function of autonomic transmitters in the human early antenatal heart. Morphological and functional establishment of the autonomic innervation occurs in the human heart well after the appearance of the reactivity to autonomic transmitters. Under 'in vitro' conditions, muscarinic-cholinergic neuro-effector transmission can be demonstrated in 10-12 week-old hearts, and cardiac beta-adrenergic transmission can first be detected in weeks 13-14. From these observations and from the appearance of the 'in utero' fetal tachycardiac response to atropine in weeks 15-17 and the bradycardiac response to beta-blockers in weeks 23-28, it seems that the parasympathetic-cholinergic control of the developing human heart becomes functional and can play a role in the overall regulation of the antenatal cardiac function earlier than the sympathetic-adrenergic neural control.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1987

The responsiveness to (1-24) ACTH of Mongolian gerbil adrenals superfused in vitro as a function of basal secretion.

Wide variations have been found in the responsiveness to (1-24)ACTH of Mongolian gerbil adrenal glands superfused in vitro. These variations were not correlated to corticosteroid plasma levels or to adrenal weights. In contrast, (1-24)ACTH-stimulated secretion greatly depended on basal in vitro secretion (quarters: r = 0.97, p less than 0.01; slices: r = 0.90, p less than 0.001) indicating that the fine adjustment of basal corticosteroidogenesis forms an important part of the regulatory mechanisms modulating (1-24)ACTH-stimulated corticosteroid secretion in vitro.

Adrenal Cortex Hormones↗

PubMed1982

Effect of purine nucleotides and other compounds on the uptake of histamine and histidine.

The uptake of 14C-ring labelled histamine and histidine was studied in human and guinea-pig leucocytes, and in rat peritoneal mast cells. Histamine uptake by sensitized human leucocytes was partly released by antigen or anti-IgE challenge, suggesting that histamine is taken up by the same cells that synthesize and secrete that amine, i.e. basophils. Histamine antagonists, particularly of the H2-subclass, had an inhibitory effect, but histamine agonists had a relatively small and inconsistent effect. Adrenoceptor stimulants and phosphodiesterase inhibitors produced small effects, but dibutyryl cAMP at a concentration of 4-10 mM consistently increased histamine uptake by more than 100% during a 30 min incubation. By contrast, ATP exerted an inhibitory effect, starting at a concentration of 0.2 mM and reaching a maximum (90% inhibition) at 10 mM. Histidine uptake was inhibited by ATP and slightly stimulated by cAMP. Propranolol caused stimulation of histamine uptake and inhibition of histidine uptake at micromolar concentrations. These results suggest that the uptake of histamine is not due to simple diffusion. Although it does not contribute significantly to total cell histamine content or to the removal mechanism of extracellular histamine, it may contribute to the auto-regulatory processes modulating histamine release, synthesis and metabolism. It may also have a significant effect on the extracellular level of histamine, under the influence of drugs or in pathological states.

Adenosine↗

PubMed2000

Early expression of herpes simplex virus (HSV) proteins and reactivation of latent infection.

During the last decade, new data accumulated describing the early events during herpes simplex virus 1 (HSV-1) replication occurring before capsid formation and virion envelopment. The HSV virion carries its own specific transcription initiation factor (alpha-TIF), which functions together with other components of the cellular transcriptase complex to mediate virus-specific immediate early (IE) transcription. The virus-coded IE proteins are the transactivator and regulatory elements modulating early transcription and subsequent translation of nonstructural virus-coded proteins needed mainly for viral DNA synthesis and for the supply of corresponding nucleoside components. They also cooperate at the late transcription and translation of the virion (capsid, tegument and envelope) proteins. In addition, the transactivator IE proteins down-regulate their own transcription, while others facilitate viral mRNA processing or interfere with the presentation of newly synthesized virus antigens. Establishment of latency is closely related to the transcription of a separate category of transcripts, termed latency-associated (LAT). Formation of LATs occurs mainly in nondividing neurons which are metabolically less active and express lower levels of cellular transcription factors (nonpermissive cells). Expression of the stable non-spliced (2 kb), and especially of stable spliced (1.5 and 1.45 kb) LATs is a prerequisite for HSV reactivation. Different HSV genomes (from various HSV strains) do not undergo IE transcription at the same rate. Restricted IE transcription and the absence of viral DNA synthesis favors LAT formation and persistence of the silenced genome. Uneven levels of LAT expression and differences in the metabolic state of carrier neurons influence the reactivation competence. Under artificial or natural activation conditions, sufficient amounts of IE transactivator proteins and proteins promoting nucleoside metabolism are synthesized even in the absence of the viral alpha-TIF facilitating reactivation.

Animals↗

PubMed2004

[Specific immunotherapy. Hyposensitization with allergens].

Successful allergen-specific immunotherapy (SIT) induces complex immunologic chan-ges resulting in reduced allergic inflammatory reactions. SIT has long-term effects in mild forms of inhalant allergies and is effective even when standard pharmacotherapy fails. Moreover, the risk to develop additional allergic sensitizations and the development of asthma is significantly reduced in children with allergic rhinitis. SIT is the treatment of choice in patients with systemic reactions to hymenoptera venoms. Although the exact effector mechanisms of SIT still have to be clarified, the most probable effect is a modulation of regulatory T cells associated with a switch of allergen-specific B-cells towards IgG4 production. The critical point to insure efficacy and safety is the selection of patients and allergens, task best performed by a specialist trained in allergology. Further details are available in the position papers of the German allergy societies - DGAI(Deutsche Gesellschaft fiir Allergologie und Klinische Immunologie) and ADA (Arzte-verband Deutscher Allergologen) - which can be found at www.dgaki.de.

Adolescent↗

PubMed2000

Mutations in the Bacillus subtilis purine repressor that perturb PRPP effector function in vitro and in vivo.

The Bacillus subtilis pur operon repressor (PurR) has a PRPP (5-phosphoribosyl 1-pyrophosphate) binding motif at residues 199-211. Two PurR PRPP binding region mutations (D203A and D204A) were constructed, and the effects on binding of repressor to the pur operon control site in vitro and on regulation of pur operon expression in vivo were investigated. PRPP significantly inhibited the binding of wild-type but not mutant PurR to pur operon control site DNA. In strains with the D203A and D204A mutations, pur operon expression in vivo was super-repressed by addition of adenine to the growth medium. These results support the role of PRPP in modulating the regulatory function of PurR in vivo. YabJ, the product of the distal gene in the bicistronic purR operon, is also required for PurR function in vivo.

Bacillus subtilis↗

PubMed1987

Effect of estrogen on dehydroepiandrosterone formation by baboon fetal adrenal cells in vitro.

The present study determined if estrogen modulates the responsivity of the adrenal gland of the baboon fetus to tropic hormones such as adrenocorticotropic hormone and prolactin. Adrenal glands were obtained from seven baboon fetuses at midgestation (days 100 to 105). Adrenal cells were dispersed in medium 199 with 0.2% collagenase for 10 minutes at 37 degrees C. Approximately 10(5) cells/4.0 ml of medium 199 were incubated for 24 hours at 37 degrees C with 10 nmol of adrenocorticotropic hormone or 10 nmol of ovine prolactin in the presence or absence of 10(-5) or 10(-6) mol/L of estradiol. The major steroid formed and secreted into the medium was dehydroepiandrosterone. Mean +/- standard error basal formation of dehydroepiandrosterone was 176 +/- 64 ng/10(5) cells/24 hours. Dehydroepiandrosterone formation was increased (p less than 0.05) 3.5-fold and five-fold by adrenocorticotropic hormone and prolactin, respectively. Estradiol at 10(-5) mol/L prevented the response in dehydroepiandrosterone obtained with adrenocorticotropic hormone alone. Estradiol alone had no effect on dehydroepiandrosterone. The results suggest that estrogen modulates the regulatory effects of adrenocorticotropic hormone on dehydroepiandrosterone formation by the adrenal gland of the baboon fetus.

Adrenal Glands↗

PubMed1995

Lipoxygenase activity on the plasmalemma of sunflower protoplasts and its modulation.

A lipoxygenase (EC 1.13.11.12) activity on the plasmalemma of sunflower (Helianthus annuus L.) protoplasts and its possible modulation by regulatory molecules were investigated. The activity was followed as both linolenic acid-dependent conjugated diene formation and oxygen uptake. Protoplasts exhibited a lipoxygenase activity inhibited by propyl gallate, salicylhydroxamic acid and butylated hydroxytoluene, and stimulated by the addition of CaCl2, H2O2 and ATP. The stimulation by CaCl2 and H2O2 was evident up to 1.5 mM and 5 nM, respectively. Higher concentrations of H2O2 caused a lower extent of stimulation and then became inhibitory. The stimulatory effect of CaCl2 was prevented by chelators (EGTA or EDTA), a Ca2+ channel blocker (gadolinium oxide) or a Ca2+ ionophore (A23187). Negligible lipoxygenase was released from protoplasts after 6 h incubation in 3.6 mM MES-Tris (pH 5.6), 0.5 M glycine betaine and 1 mM CaCl2, whereas mechanical disruption of cell integrity, liberating soluble lipoxygenase, strongly increased such an activity. However, microsomal membranes obtained from hypocotyls still retained a part of this activity which was also recovered in a highly purified plasma membrane preparation.

Cell Membrane↗

PubMed1993

Stress-induced changes of extracellular 5-hydroxyindoleacetic acid concentrations followed in the nucleus raphe dorsalis and the frontal cortex of the rat.

In the present paper, the effect of different stressors on extracellular 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the frontal cortex and the N. raphe dorsalis (NRD) of the rat were studied. The following stressful procedures were used: Immobilization, 10 min, cold, 20 min, and forced exercise in a rotating wheel, 2h. These procedures were compared with a handling procedure, 10 min. The extracellular 5-HIAA concentration was followed by in vivo voltammetry with carbon multifibre electrodes in the awake animal. Handling had no significant effect on extracellular 5-HIAA concentrations neither in the frontal cortex nor the NRD, whereas immobilization and cold evoked significant increases in both brain areas. During and after forced exercise a significant increase was measurable only in the frontal cortex, while extracellular 5-HIAA concentrations were unchanged in the NRD. Since it is very likely that the modulation of the activity of the central serotoninergic system under stressful conditions is closely connected with changes in behaviour and temperature regulation, we compared our findings on extracellular 5-HIAA levels during stress with the effect of the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), a substance known to reduce body temperature. The i.p. injection of a low dose decrease significantly both, the extracellular 5-HIAA concentration in the NRD and body temperature. Our results suggest that the serotoninergic activation in the frontal cortex may prove to be a general response to stress which could function perhaps as a part of the central coping mechanism, whereas serotonin (5-HT) in the NRD may modulate specific regulatory responses such as body temperature.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Ligand-modulated binding of a gene regulatory protein to DNA. Quantitative analysis of cyclic-AMP induced binding of CRP from Escherichia coli to non-specific and specific DNA targets.

This paper describes a generally applicable method for quantitative investigation of ligand-dependent binding of a regulatory protein to its target DNA at equilibrium. It is used here to analyse the coupled binding equilibria of cAMP receptor protein from Escherichia coli K12 (CRP) with DNA and the physiological effector cAMP. In principle, the DNA binding parameters of CRP dimers with either one or two ligands bound are determinable in such an approach. The change of protein fluorescence was used to measure CRP binding to its recognition sequence in the lac control region and to non-specific DNA. Furthermore, the binding of cAMP to preformed CRP-DNA complexes was independently studied by equilibrium dialysis. The data were analysed using a simple interactive model for two intrinsically identical sites and site-site interactions. The intrinsic binding constant K and the co-operativity factor alpha for binding of cAMP to free CRP depend only slightly on salt concentration between 0.01 M and 0.2 M. In contrast, the affinity of cAMP for CRP pre-bound to non-specific DNA increases with the salt concentration and the co-operativity changes from positive to negative. This results from cation rebinding to the DNA lattice upon forming the cAMP-CRP-DNA complex from cAMP and the pre-formed CRP-DNA complex. The CRP-cAMP1 complex shows almost the same affinity for specific and non-specific DNA as the CRP-cAMP2 complex, and both displace the same number of cations. It is concluded that the allosteric activation of CRP is induced upon binding of the first cAMP. These results are used to estimate the occupation of the CRP site in the lac control region in relation to the cAMP concentration in vivo. Under physiological conditions the lac promoter is activated by the CRP dimer complexed with only one cAMP. Furthermore, a model for the differential activation of various genes expressed under catabolite repression is presented and discussed.

Bacterial Proteins↗

PubMed1994

Urokinase-type plasminogen activator and its receptor: new targets for anti-metastatic therapy?

Urokinase-type plasminogen activator (uPA) and its receptor are instrumental in cell invasion and metastasis; their high levels of expression in human tumours correlates with a high risk of recurrence. uPA has a pleiotropic effect on cell migration and spreading in vivo and in vitro through the activation of plasminogen or other protein factors at the cell surface or in the extracellular matrix. Three specific inhibitors, with different tissue-specificities and regulatory properties, modulate cell-surface exposure of uPA activity. Overall, uPA is at the centre of a complex system affecting cell movement and invasiveness, and inhibition of uPA is now a goal of anti-metastatic therapy. The role of uPA and its inhibition are discussed in this review by Francesca Fazioli and Francesco Blasi.

Amino Acid Sequence↗

PubMed1985

Estradiol induced alterations of the immune system--I. Enhancement of IgM production.

Estrogens have been postulated as natural modulators of the immune system. In this study we have evaluated the effect of estradiol on in vivo immunoglobulin production in male rats. Administration of either a 75 microgram/kg or 750 microgram/kg dose of estradiol resulted in a dose-related increase of anti-sheep red blood cell antibody titers during a primary antibody response. These same animals when dosed with estradiol during a secondary antibody response showed an earlier appearance of the peak antibody titer in estradiol-treated rats as compared to controls. Rats dosed with estradiol only during the secondary antibody response period also showed a dose-related increase in Ab titer over control values but no shift in the time of appearance of the peak titer. Treatment of sera with 2-mercaptoethanol to evaluate IgG titers showed that 2-mercaptoethanol treatment both reduced the titer to control values and eliminated the estradiol-induced shift in the appearance of the peak antibody titer in rats given estradiol during the primary and secondary antibody response periods. Sera from animals dosed with estradiol during the secondary antibody response period only also showed titers reduced to control levels after 2-mercaptoethanol treatment of the sera. Estradiol-treated rats also had an increase in antibody titers to polysaccharide from Type III pneumococci, a T-cell independent antigen. While total antibody responses were increased following estradiol, there were no differences in the number of antibody-producing cells between control and estradiol-treated animals. The results of these studies suggest that estradiol exerts a direct effect on B cells resulting in increased synthesis of IgM antibodies. We cannot rule out, however, some modulation through regulatory T-cells.

Animals↗

PubMed1994

Hypothalamic cholinergic systems in mercuric chloride-induced hyperglycemia.

The roles of hypothalamic neuron mechanisms in regulation of blood glucose were studied in rats. Microinjection of HgCl2 and neostigmine into the third ventricle under anesthesia caused marked hyperglycemia. To characterize the effective neurons in the hypothalamus, tissue contents of neurotransmitters and extracellular levels of metabolites in the ventromedial part of the hypothalamus were measured by microwave irradiation and in vivo brain microdialysis. HgCl2 increased both the content and the extracellular levels of choline. Neostigmine increased the acetylcholine content. In both instances, norepinephrine (NE) and dopamine (DA) content were decreased. Extracellular levels of DA metabolites were increased. On the other hand, serotonin content and extracellular serotonin metabolite level remained constant. In medulloadrenalectomized and atropine-coadministered rats, no marked hyperglycemia was induced by HgCl2 or neostigmine. These results show that the muscarinic cholinergic system participates in the HgCl2-induced central hyperglycemic effect through the function of the adrenal medulla. NE neurons may also be related to hypothalamic glycoregulation, and DA neurons might modulate the regulatory mechanisms.

Animals↗

PubMed1996

Cell-type-specific modulation of PDGF-B regulatory elements via viral enhancer competition: a caveat for the use of reference plasmids in transient transfection assays.

The human platelet-derived growth factor-B (PDGF-B) gene has been shown to display a wide range of levels of mRNA transcription in a variety of cell types. Functional analyses of PDGF-B gene expression have begun to reveal intricate, cell-type-specific regulatory mechanisms involving multiple control elements. We have previously isolated and characterised several elements involved in the control of human PDGF-B gene expression in the JEG-3 choriocarcinoma cell line and in the breast cancer-derived cell line, ZR-75. Assessment of the positive or negative regulatory contributions of these elements was carried out using transient transfection assays. Such studies routinely require the inclusion of a reference plasmid in order to determine transfection efficiency. Here we show that competition for regulatory factors occurs in transfected cells between viral enhancers and elements regulating PDGF-B gene transcription. A frequently used reference plasmid which utilises the SV40 promoter and enhancer region to drive expression of a beta-galactosidase reporter gene was found to severely repress the activity of a co-transfected reporter construct containing the PDGF-B promoter and its intronic enhancer in JEG-3 cells. This competition was localised to the enhancer region of the SV40 regulatory sequences and surprisingly, the effect was reversed in ZR-75 cells; where increasing the amount of reference plasmid strongly stimulated the activity of the PDGF-B construct. These results imply that the same intronic region which functions equally well as an enhancer in two distinct cell-types, may operate in response to different transcription factor complements. Furthermore, this data demonstrates that the choice of reference plasmid and its quantitative use can be a crucial factor when examining putative regulatory elements by transient transfection methods.

Chloramphenicol O-Acetyltransferase↗

PubMedDate not supplied

Endogenous ethanol--its metabolic, behavioral and biomedical significance.

Ethanol is constantly formed endogenously from acetaldehyde, and level of the former can be measured in both human beings and animals. Acetaldehyde can be generated in situ from the metabolism of pyruvate, threonine, deoxyribose-5-phosphate, phosphoethanolamine, alanine and presumably from other substrates. The levels of blood and tissue endogenous ethanol change as a function of various physiologic and experimental conditions such as starvation, aging, stress, cooling, adrenalectomy, etc. and are regulated by many exogenous compounds such as antimetabolites, derivatives of amino acids, lithium salts, disulfiram, cyanamide, etc. Under free choice alcohol selection situations, the levels of endogenous ethanol in rat blood and alcohol preference by the animals are negatively correlated. Similar negative correlations have been found between the levels of blood endogenous ethanol and the frequency of delirium in alcoholic patients undergoing alcohol withdrawal. Endogenous ethanol and acetaldehyde can therefore be regarded as compounds which fulfil substrate, regulatory and modulator functions.

Alcoholism↗

PubMed1991

Complex structure and regulation of the ABP/SHBG gene.

Extracellular androgen-binding proteins (ABPs) are thought to modulate the regulatory functions of androgens and the trans-acting nuclear androgen receptor. Testicular ABP and plasma sex hormone-binding globulin (SHBG), which is produced in the liver, are encoded by the same gene. We report here that the ABP/SHBG gene is also expressed in fetal rat liver and adult brain. Immunoreactive ABP was localized in the brain and fetal liver and mRNAs were identified in both tissues by northern blot hybridization. Analysis of brain and fetal liver cDNA clones revealed alternatively processed RNAs with sequence characteristics suggesting the encoded proteins could act as competitors of ABP/SHBG binding to cell surface receptors. One cDNA represented a fused transcript of the ABP/SHBG gene and the histidine decarboxylase gene that was apparently formed by a trans-splicing process. Gene sequencing experiments indicate that tissue-specific ABP/SHBG gene promoter-enhancer elements are utilized in testis, brain and fetal liver. These data demonstrate that the structure, RNA transcript processing and likely regulation of the ABP/SHBG gene are very complex.

Androgen-Binding Protein↗