Abstract:
:Two newly identified, overlapping (1 bp) glucocorticoid response elements (GREs) at -759 and -773 bp in the promoter of the rat phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) gene are primarily responsible for its glucocorticoid sensitivity, rather than the originally identified -533-bp GRE. A dose-dependent increase in PNMT promoter activity was observed in RS1 cells transfected with a wild-type PNMT promoter-luciferase reporter gene construct and treated with dexamethasone (maximum activation at 0.1 microM). The type II glucocorticoid receptor antagonist RU38486 (10 microM) fully inhibited dexamethasone (1 microM) activation of the PNMT promoter, consistent with classical glucocorticoid receptors mediating corticosteroid-stimulated transcriptional activity. Relative IC(50) values from gel mobility shift competition assays showed that the -759-bp GRE has a 2-fold greater affinity for the glucocorticoid receptor than the -773-bp GRE. Site-directed mutation of the -533-, -759-, and -773-bp GREs alone or in tandem demonstrated that the -759-bp GRE was also functionally more important, but both the -759- and -773-bp GREs are required for maximum glucocorticoid responses. Moreover, the -533-bp GRE, rather than increasing glucocorticoid sensitivity of the promoter, may limit corticosteroid responsiveness mediated via the -759- and -773-bp GREs. Finally, the glucocorticoid receptor bound to the -759- and -773-bp GREs interacts cooperatively with Egr-1 and/or AP-2 to stimulate PNMT promoter activity in RS1 cells treated with dexamethasone. In contrast, glucocorticoid receptors bound to the -533-bp GRE only seem to participate in synergistic activation of the PNMT promoter through interaction with activator protein 2.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Tai TC,Claycomb R,Her S,Bloom AK,Wong DLdoi
10.1124/mol.61.6.1385keywords:
subject
Has Abstractpub_date
2002-06-01 00:00:00pages
1385-92issue
6eissn
0026-895Xissn
1521-0111journal_volume
61pub_type
杂志文章abstract::Metallothioneins (MTs) are low molecular weight, thiol-rich, metal-binding proteins. Auranofin (AF) is a gold compound active in the treatment of rheumatoid arthritis. The effects of AF on regulation of MT gene expression in Chinese hamster ovary cells were studied. AF-resistant cells accumulated substantial amounts o...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-01-01 00:00:00
abstract::Binding equilibria of 12 nonsteroidal, anti-inflammatory substances, salicylic acid, diflunisal, phenylbutazone, azapropazone, fenbufen, biphenylacetic acid, naproxen, flurbiprofen, ibuprofin, diclofenac, indomethacin, and benoxaprofen, to defatted human serum albumin has been investigated at 37 degrees, pH 7.4, in a ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract::Type II DNA topoisomerases are targets of acridine drugs. Nine mutations conferring resistance to acridines were obtained by forced molecular evolution, using methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA), methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.032953
更新日期:2007-04-01 00:00:00
abstract::Compound BM5 [N-methyl-N(1-methyl-4-pyrrolidino-2-butynyl) acetamide] has previously been described as an agonist at postsynaptic muscarinic receptors and as an antagonist at presynaptic receptors. In the current work, we studied the ability of this compound to selectively stimulate phosphoinositide (PI) turnover in C...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-09-01 00:00:00
abstract::The P2Y(1) receptor is responsible for the initiation of platelet aggregation in response to ADP and plays a key role in thrombosis. Although this receptor is expressed early in the platelet lineage, the regulation of its expression during megakaryocyte differentiation is unknown. In the mouse megakaryocytic cell line...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.5.1112
更新日期:2001-11-01 00:00:00
abstract::We studied the ability of norepinephrine to stimulate [3H]inositol trisphosphate production and calcium mobilization in rat-1 fibroblasts stably expressing the cloned alpha 1-adrenergic subtypes and their sensitivity to phorbol-12-myristate-13-acetate (PMA). It was observed that the three subtypes were able to activat...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-07-01 00:00:00
abstract::TNP-ATP has become widely recognized as a potent and selective P2X receptor antagonist, and is currently being used to discriminate between subtypes of P2X receptors in a variety of tissues. We have investigated the ability of TNP-ATP to inhibit alpha,beta-methylene ATP (alpha,beta-meATP)-evoked responses in 1321N1 hu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.6.1502
更新日期:2000-12-01 00:00:00
abstract::Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.102
更新日期:2002-07-01 00:00:00
abstract::Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phospho...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.041160
更新日期:2008-03-01 00:00:00
abstract::Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.078402
更新日期:2012-09-01 00:00:00
abstract::Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through beta(2)-adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both G(s) and G(i) proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, bu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.5.1313
更新日期:2004-05-01 00:00:00
abstract::Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K+ channels. Here, we homology-modeled voltage- and Ca2+-gated K+ channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.017970
更新日期:2006-04-01 00:00:00
abstract::G-protein-coupled receptor activation is generally analyzed under equilibrium conditions. However, real-life receptor functions are often dependent on very short, transient stimuli that may not allow the achievement of a steady state. This is particularly true for synaptic receptors such as the α(2A)-adrenergic recept...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.077693
更新日期:2012-06-01 00:00:00
abstract::Adenosine receptors of the A1 and A2 subtypes were characterized in membranes from DDT1 MF-2 smooth muscle cells. These cells possess a high density of A1 adenosine receptors (Bmax = 0.8-0.9 pmol/mg of protein), as measured by both agonist and antagonist radioligands. Agonists compete for [125I]N6-[2-(4-amino-3-iodoph...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-02-01 00:00:00
abstract::Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.029504
更新日期:2007-04-01 00:00:00
abstract::To screen for residues of hKv1.3 important for current block by the phenylalkylamine verapamil, the inactivated-state-reduced H399T mutant was used as a background for mutagenesis studies. This approach was applied mainly to abolish the accumulation in the inactivated blocked state, recovery from which in the wild typ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.012401
更新日期:2005-10-01 00:00:00
abstract::The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to acti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2001-07-01 00:00:00
abstract::The anti-arrhythmic quinidine has been reported to be a competitive inhibitor of the catalytic activities of human liver P-450DB, including sparteine delta 2-oxidation and bufuralol 1'-hydroxylation, and we confirmed the observation that submicromolar concentrations are strongly inhibitory. Human liver microsomes oxid...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::The irreversible proteolytic nature of protease-activated receptor-2 (PAR2) activation suggests that mechanism(s) responsible for termination of receptor signaling are critical determinants of the magnitude and duration of PAR2-elicited cellular responses. Rapid desensitization of activated G-protein-coupled receptors...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.006072
更新日期:2005-01-01 00:00:00
abstract::Sulfation is an important pathway in the biotransformation of many drugs, xenobiotic compounds, neurotransmitters, and hormones. The sulfate donor for these reactions is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). We set out to determine whether PAPS might serve as a photoaffinity ligand for sulfotransferase enzymes...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-01-01 00:00:00
abstract::The action of tetrahydroaminoacridine (THA), a centrally active cholinesterase inhibitor that may provide symptomatic benefit in Alzheimer's disease, was studied on responses to the excitatory amino acid N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons, using whole-cell voltage-clamp and single-channel reco...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-05-01 00:00:00
abstract::Dilute formalin injected into the rat hindpaw as a nociceptive stimulus increases neurokinin-1 receptor (NK-1R) mRNA levels in the dorsal horn of the spinal cord. Increased NK-1R mRNA levels could result from increased mRNA stability or an increased rate of NK-1R mRNA transcription. In this study, RNA samples prepared...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-11-01 00:00:00
abstract::Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect and mammalian neurons, although recent studies have raised the possibility that these compounds ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::The diphosphoinositol polyphosphates ("inositol pyrophosphates") are a specialized subgroup of the inositol phosphate signaling family. This review proposes that many of the current data concerning the metabolic turnover and biological effects of the diphosphoinositol polyphosphates are linked by a common theme: these...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.109.055897
更新日期:2009-08-01 00:00:00
abstract::Hepatocyte nuclear factor 4alpha (HNF4alpha) is a key transcription factor for the constitutive expression of cytochromes P450 (P450s) in the liver. However, human hepatoma HepG2 cells show a high level of HNF4alpha but express only marginal P450 levels. We found that the HNF4alpha-mediated P450 transcription in HepG2...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.025403
更新日期:2006-11-01 00:00:00
abstract::Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.1.143
更新日期:2003-07-01 00:00:00
abstract::Microinjection, but not extracellular application, of cytidine-5'-diphosphate-D-glucose (CDPG) has been shown to elicit Ca(2+)-dependent currents in Xenopus laevis oocytes. These responses were comparable to those of inositol-1,4,5-trisphosphate (InsP3) in being both rapid and dose dependent. For example, maximal ampl...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-02-01 00:00:00
abstract::Airway smooth muscle (ASM) cells can act as effector cells in the initiation and/or perpetuation of airway inflammation in asthma by producing various inflammatory chemokines or cytokines. Previous studies from our laboratory and others showed that the combination of tumor necrosis factor-alpha (TNFalpha) and interfer...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.030171
更新日期:2007-02-01 00:00:00
abstract::We examined the effects on allosteric modulation and ligand binding of the mutation of amino acid residues of the human A(3) adenosine receptor (A(3)AR) that are hypothesized to be near one of three loci: the putative sodium binding site, the putative ligand binding site, and the DRY motif in transmembrane helical dom...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.5.1021
更新日期:2003-05-01 00:00:00
abstract::Multidrug resistance protein 1 (MRP1) is a member of the "C" branch of the ATP-binding cassette transporter superfamily. The NH(2)-proximal nucleotide-binding domain (NBD1) of MRP1 differs functionally from its COOH-proximal domain (NBD2). NBD1 displays intrinsic high-affinity ATP binding and little ATPase activity. I...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.007708
更新日期:2005-06-01 00:00:00