Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of ligand-induced (homologous) down-regulation of the glucocorticoid receptor (GR) has been studied. Dexamethasone caused a down-regulation of the levels of GR mRNA and protein both in hepatoma tissue culture cells and rat liver in vivo. The decrease in the level of rat liver GR mRNA was due to a reduced transcription rate of the GR gene, as assessed by nuclear run-on transcription experiments. The half-life of GR mRNA in hepatoma tissue culture cells was determined to be approximately 4.5 h and was unaffected by dexamethasone. In addition to the transcriptional regulation of GR gene expression, a dexamethasone-dependent posttranslational modification in the rate of GR protein turnover was observed. In the absence of dexamethasone, GR protein half life was approximately 25 h whereas it decreased to approximately 11 h in the presence of hormone. Down-regulation of GR protein occurred with a 6- to 24-h delay as compared to the decline in GR mRNA. This is most likely due to the differences in half-lives of GR mRNA and protein, respectively. Our results suggest that auto-regulation of GR by its cognate ligand is complex and occurs at both transcriptional and posttranslational levels.
Mol Endocrinol 1988 Dec
PMID:Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. 321 65

The in vitro acetylation of HMG proteins was studied using liver slices of young (18-week) and old (138-week) male rats. Acetylation of total HMG proteins is lower in old age. The incorporation of (14C) acetate into individual HMG proteins varies remarkably with advancing age. Whereas acetylation of high mol. wt. proteins (HMG 1 and 2) is higher, that of low mol. wt. proteins (HMG 14 and 17) is lower in the liver of young rats as compared to the old ones. Spermine stimulates the acetylation of HMG 1 and 14 in young and HMG 1, 2 and 14 in old age. It inhibits the acetylation of HMG 17 in both ages. Dexamethasone decreases the level of incorporation of (14C) into HMG 1 and 17 in young and HMG 14 and 17 in old rats. On the other hand, it stimulates the acetylation of HMG 14 by two-fold in young and that of HMG 1 and 2 by more than three-fold in old rats. Such alteration in the acetylation of HMG proteins may account for age-related changes in the structure and function of chromatin.
Mol Biol Rep
PMID:In vitro acetylation of the liver HMG non-histone proteins and its modulation by spermine and dexamethasone during aging of rats. 327 47

Three phenotypically distinct isolates from lymphosarcoma P1798 have been compared with respect to properties of the glucocorticoid receptor. Wild type P1798 cells express functional receptors and glucocorticoid treatment of such cells causes cytolysis in vivo. Wild type cells do not undergo cytolysis in culture. Rather, such cells exhibit reversible inhibition of proliferation in the presence of dexamethasone. Two variant populations were selected from this background. One was selected for the ability to form tumors in mice receiving pharmacological doses of glucocorticoids. Cells from such tumors are resistant to the cytolytic effects of glucocorticoids in vivo, but are sensitive to the antiproliferative effects of the hormone in culture. Variants were also selected based upon their ability to proliferate in the presence of dexamethasone in culture. These variants were resistant to glucocorticoid-mediated cytolysis in vivo. Wild type P1798 cells express approximately 20,000 high affinity dexamethasone-binding sites per cell. Dexamethasone-mesylate labeling and immunoblotting experiments indicate that hormone binding is due to a polypeptide of Mr 90-100 K. This polypeptide is encoded in an mRNA species that resolved as a single entity of approximately 7000 nucleotides. Variants selected for resistance to cytolysis in vivo are indistinguishable in any of these respects from wild type cells. The receptors are fully functional, as evidenced by their ability to precipitate growth arrest of dexamethasone-treated cultures. Variants selected for resistance in culture harbor a receptor mutation. They express fewer than 500 dexamethasone-binding sites per cell. Such variants contain neither detectable dexamethasone-mesylate-binding protein nor any protein that is recognized by a receptor antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1988 Mar
PMID:Biochemical and molecular characterization of the glucocorticoid receptor of lymphosarcoma P1798 variants. 339 56

The effect of dexamethasone on enkephalin-containing (EC) peptide levels and preproenkephalin mRNA levels was determined in adrenal medullary explants (glands) from sham and hypophysectomized (hypox) rats. Culture for 4 days in serum-free medium without dexamethasone resulted in a 13- and 4-fold increase in EC peptide levels in sham and hypox glands, respectively. The addition of dexamethasone (10(-5) M) produced a 20- to 26-fold increase in EC peptides in sham and hypox glands. In serum free medium, hypox glands showed a concentration dependent increase in EC peptides with the ED50 for dexamethasone equal to 5.7 x 10(-7) M. Since the glucocorticoid antagonist RU486 partially blocked the rise in EC peptides in sham glands, it appears that the increase in EC peptides in sham glands in the absence of dexamethasone is a result of a higher concentration of endogenous corticosterone in sham compared to hypox glands. Dexamethasone resulted in a 6-fold increase in preproenkephalin mRNA in hypox glands cultured for 2 days. This increase was approximately proportional to the increase in EC peptides seen at 4 days. In serum free medium progesterone, testosterone, and deoxycorticosterone failed to increase EC peptides in hypox glands. These results indicate that glucocorticoid treatment is required for maximal proenkephalin gene expression and EC peptide biosynthesis in cultured glands.
Mol Endocrinol 1988 Jul
PMID:Glucocorticoid regulation of enkephalins in cultured rat adrenal medulla. 341 28

Phosphorylation of high mobility group (HMG) proteins and its modulation by dexamethasone were examined in vitro by incubating liver slices of young (15-) and old (138-week) male rats with (32P) orthophosphate. HMG proteins were extracted and analyzed by acid-urea polyacrylamide gel electrophoresis. Phosphorylation of HMG proteins, particularly of HMG2, 14 and 17 decreases drastically in old rats. Dexamethasone stimulates the phosphorylation of total HMG proteins in both ages. Individual HMG proteins vary in the extent of 32P incorporation. Such differential phosphorylation of HMG proteins and its modulation by dexamethasone may affect chromatin organization and gene expression during aging.
Mol Biol Rep 1987
PMID:Dexamethasone-induced phosphorylation of high mobility group nonhistone proteins of aging rats. 343 43

Human KB carcinoma cells resistant to high levels of colchicine, vinblastine, vincristine, adriamycin, and actinomycin D exhibit reduced accumulation of these structurally unrelated chemotherapeutic agents (Akiyama, S.-I., Fojo, A., Hanover, J. A., Pastan, I., and Gottesman, M. M. (1985) Somatic Cell Mol. Genet. 11, 117-126; Fojo, A., Akiyama, S.-I., Gottesman, M. M., and Pastan, I. (1985) Cancer Res. 45, 3002-3007). To examine the mechanism of reduced drug accumulation in these cells, we measured [3H]vinblastine ([3H]VBL) binding to membrane vesicles made from drug-sensitive (KB-3-1), drug-resistant (KB-C4), and revertant (KB-R1) cells. Membrane vesicles from KB-C4 cells bound up to 8-fold more [3H]VBL than vesicles from the parental KB-3-1 or revertant KB-R1 cell lines. No difference in binding of [3H]dexamethasone, to which the cells are equally sensitive, was observed. The difference in [3H]VBL binding by vesicles from resistant and sensitive cells was eliminated by the addition of 10 micrograms/ml verapamil, which is known to reverse the multidrug-resistance phenotype. Drug binding by KB-C4 vesicles was osmotically insensitive, temperature-dependent, and trypsin-sensitive. Binding of [3H]VBL by KB-C4 vesicles was inhibited by vinblastine, vincristine, and daunomycin (in decreasing order). Dexamethasone at 100 microM, colchicine at 100 microM, and actinomycin D at 100 microM did not significantly inhibit [3H]VBL accumulation. No significant differences in tubulin content were detected among vesicles from sensitive and resistant cells. These data demonstrate that membrane vesicles from multiply drug-resistant cells bind increased amounts of vinblastine.
 ...
PMID:Increased vinblastine binding to membrane vesicles from multidrug-resistant KB cells. 371 Nov 17

We examined the uptake of 3-O-methyl-D-glucose, a nonmetabolizable hexose, by isolated rat hepatocytes. The uptake of 3-O-methyl-D-glucose was linear for 1 min at 22 degrees, and Lineweaver-Burk analysis demonstrated an apparent Km of approximately 6 mM. Cytochalasin B (40 microM) and phloridzin (2 mM) inhibited 3-O-methyl-D-glucose uptake by 88% and 63%, respectively. D-Glucose (20 mM) inhibited the initial rate of 3-O-methyl-D-glucose uptake by 55% (p less than 0.001), whereas L-glucose was without any significant effect. The uptake of 3-O-methyl-D-glucose remained unchanged in the presence of Na+ (0-150 mM) in the incubation medium. After 30 min dexamethasone inhibited glucose uptake (the maximal effect being achieved in a time- and concentration-dependent manner) at 2 microM and 0.5 microM concentrations by 50% and 25%, respectively. Dexamethasone produced a decrease in the Vmax but did not change the Km. Insulin, glucagon, gastric inhibitory polypeptides, and pancreozymin had no effect on 3-O-methyl-D-glucose uptake in isolated hepatocytes. These findings are consistent with the conclusion that 3-O-methyl-D-glucose uptake in isolated rat hepatocytes occurs via a stereospecific, carrier-mediated, facilitated diffusion process. Dexamethasone decreases this process of facilitated diffusion in the isolated hepatocyte.
Mol Pharmacol 1983 Jan
PMID:3-O-methyl-D-glucose uptake in isolated rat hepatocytes. Effects of dexamethasone. 686 98

Fifty-four independent dexamethasone-resistant clones were isolated from the clonal, glucocorticoid-sensitive human leukemic T-cell line CEM-C7. Resistance to 1 microM dexamethasone was acquired spontaneously at a rate of 2.6 X 10(-5) per cell per generation as determined by fluctuation analysis. After mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the phenotypic expression time for dexamethasone resistance was determined to be 3 days. Spontaneous acquisition of resistance to 0.1 mM 6-thioguanine appeared to occur at a much slower rate, 1.6 X 10(-6) per cell per generation. However, the expression time after MNNG mutagenesis for this resistant phenotype was greater than 11 days, suggesting that the different rates of acquisition for the two phenotypes measured by fluctuation analysis were the results of the disparate expression times. The mutagens ICR 191 and MNNG were effective in increasing the dexamethasone-resistant fraction of cells in mutagenized cultures; ICR 191 produced a 35.6-fold increase, and MNNG produced an 8.5-fold increase. All the spontaneous dexamethasone-resistant clones contained glucocorticoid receptors, usually less than half of the amount found in the parental clone. They are therefore strikingly different from dexamethasone-resistant clones derived from the mouse cell lines S49 and W7. Dexamethasone-resistant clones isolated after mutagenesis of CEM-C7 contained, on the average, lower concentrations of receptor than did those isolated spontaneously, and one clone contained no detectable receptor. These results are consistent with a mutational origin for dexamethasone resistance in these human cells at a haploid or functionally hemizygous locus. They also suggest that this is a useful system for mutation assay.
Mol Cell Biol 1981 Jun
PMID:Isolation and characterization of dexamethasone-resistant mutants from human lymphoid cell line CEM-C7. 696 6

Application of dexamethasone was found to induce an enhanced expression level of mRNA encoding the growth associated protein (GAP-43) after peripheral nerve injury. Following hypoglossal nerve axotomy, a dexamethasone releasing pellet (1.5 mg released in 3 weeks) was placed near the transected nerve. GAP-43 mRNA was detected in the hypoglossal nucleus by non-radioactive in situ hybridization histochemistry using an alkaline phosphatase-labeled oligonucleotide probe. A significant elevation of GAP-43 mRNA level was observed 2 weeks after the transection in dexamethasone treated animals. This induction was not observed in the dorsal motor nucleus of vagus which expresses moderately high levels of GAP-43 mRNA even without nerve injury. Although dexamethasone did not alter the maximum level of GAP-43 mRNA in the hypoglossal nucleus after nerve injury, it prolonged the period in which the mRNA expression remained elevated. This may be due to post-transcriptional effect by the glucocorticoid. Dexamethasone treatment also caused a slight facilitation of reprojection. This may be due to the enhancement of GAP-43 mRNA level by the glucocorticoid.
Brain Res Mol Brain Res 1995 Sep
PMID:Dexamethasone enhances level of GAP-43 mRNA after nerve injury and facilitates re-projection of the hypoglossal nerve. 750 Aug 42

Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). In the present study we have examined these three initial steps in insulin action during the differentiation of 3T3-F442A adipocytes and after treatment with dexamethasone or insulin. The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. The mRNA expression of these two proteins showed a similar 8-fold increase during differentiation. In addition there was a 3.5-fold increase in PI 3-kinase protein [85 kilodalton (kDa) subunit] and a 16-fold increase in IRS-1-associated PI 3-kinase activity between day 0 and day 8 of differentiation. Dexamethasone (1 microM) treatment of differentiated cells induced a further 48% (P < 0.05) increase in insulin receptor level, but the autophosphorylation of the receptor was decreased by 31 +/- 1% (P < 0.02). At the same time there was a decrease by 56 +/- 4% (P < 0.005) in IRS-1 protein and by 31 +/- 1% (P < 0.001) in IRS-1 phosphorylation. The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. By contrast, dexamethasone induced a 69% increase in the level of PI 3-kinase as determined by immunoblotting. The combined effect of decreased IRS-1 phosphorylation and increased PI 3-kinase protein was a minimal change (15% decrease) in the association/activation between IRS-1 and PI 3-kinase. Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. There was an even more marked decrease in the phosphorylation level of these proteins. Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Endocrinol 1994 May
PMID:Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and dexamethasone. 752 Jan 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>