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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms for regulation of heat shock protein (hsp) 83 expression were examined in Leishmania amazonesis. Transcripts of hsp83 accumulated upon temperature elevation; however, in contrast to non-protozoan eukaryotes (i.e. Drosophila, yeast, avian or human cells), no transcriptional activation was observed. The increase in the hsp83 mRNA level evolved from temperature induced variations in mRNA turn-over: the hsp83 transcript was rapidly degraded at normal temperatures, whereas heat shock led to its stabilization. The quick decay of the mRNA at lower temperatures was dependent on active protein synthesis. A similar pattern of regulation was observed for the transfected chloramphenicol acetyltransferase (CAT) gene, which was flanked by sequences from the hsp83 intergenic region (IR), and cloned into the pX transfection vector (pX-ICI). CAT mRNA was abundant at normal temperatures and further accumulated upon temperature elevation. The altered turn-over rates of CAT mRNA at the different temperatures were observed only in the presence of flanking hsp83 IR sequences. The increase in temperature also affected translational regulation of hsps, and synthesis of hsp83 was more efficient at 35 degrees C than at 26 degrees C. However, the effect of translation was transient, and the steady state level of the protein was hardly altered.
Mol Biochem Parasitol 1994 Mar
PMID:Expression of heat shock protein 83 in Leishmania is regulated post-transcriptionally. 807 27

Primary cultures of oligodendrocytes and astrocytes and purified cultures of Schwann cells were prepared respectively from forebrain and sciatic nerves of newborn rats. The effects of steroid hormones and growth factors on glial cell growth and on the production of myelin-specific proteins and lipids were investigated. Progesterone (P, 100 nM) decreased the proliferation of glial cells of the central nervous system. This inhibitory effect of P was abolished by the simultaneous administration of the antagonist RU486, thus suggesting a receptor-mediated action of the hormone. The expression of myelin-specific proteins, including the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase), and of a myelin-specific lipid, galactocerebroside (Gal C), was also measured during cell differentiation under different hormonal conditions. The expression of MBP in oligodendrocytes was increased by P, and this effect was not blocked by RU486. The combined application of P and insulin promoted a synergistic stimulation of MBP expression. Insulin, by itself, also increased the number of MBP-positive oligodendrocytes in culture. The effects of P and insulin appeared to be selective as dexamethasone, dehydroepiandrosterone, pregnanolone and epidermal growth factor (EGF) had no effect. Only estradiol (E2, 500 nM) increased the number of MBP-immunoreactive cells, but in contrast to P, only a small synergism between E2 and insulin on MBP expression was observed. The expression of CNPase, another myelin-specific protein, was also increased by P and, here again, a synergy between P and insulin could be observed. In contrast, the expression of Gal C, a myelin-specific lipid, was not modified by P or other steroid hormones. Moreover, the increase in Gal C-positive cells observed in response to insulin alone was not further potentiated by P. Glial cells of the peripheral nervous system, namely Schwann cells, are also sensitive to steroid hormones. Schwann cells contain estrogen receptors, and E2 stimulates their proliferation in the presence of forskolin or dibutyryl cyclic AMP (dbcAMP). The mitogenic effect of E2 was abolished by the pure antiestrogen ICI-164,384. Insulin, at micromolar concentration, also stimulated Schwann cell growth when forskolin or dbcAMP were present in the culture medium. The mitogenic effect of insulin was mediated by insulin-like growth factor I (IGF-I) receptors. Indeed, at a physiological nanomolar concentration, IGF-I but not insulin or IGF-II, increased the proliferation of Schwann cells in synergy with forskolin. In addition, Schwann cells express receptors for IGF-I.
J Steroid Biochem Mol Biol 1994 Jan
PMID:Actions of steroid hormones- and growth factors on glial cells of the central and peripheral nervous system. 813

RU 58,668, a new steroidal antiestrogen, has been synthesized. Its in vitro and in vivo pharmacological activities have been compared to those of tamoxifen and ICI 182,780. In vitro, it displayed affinities for human and murine estrogen receptors equivalent to those of 4-hydroxy-tamoxifen, along with moderate affinities for progestin and glucocorticoid receptors. RU 58,668 proved to be a potent antiproliferative agent on MCF-7 cells stimulated by estradiol, or by exogenous or endogenous growth factors (IC50, 0.01 nM). It also inhibited the growth of the insulin-stimulated T47D cell line. In vivo, RU 58,668 displayed a total anti-uterotrophic activity in mice or rats without exhibiting any agonistic effect. Moreover, RU 58,668 was the only antiestrogenic compound tested so far to be able to induce a long term regression of human mammary MCF-7 tumors implanted in nude mice, suggesting its potential use for the treatment of advanced breast cancer.
J Steroid Biochem Mol Biol 1994 Feb
PMID:RU 58,668, a new pure antiestrogen inducing a regression of human mammary carcinoma implanted in nude mice. 814 94

In the absence of serum and estrogen, we show that the growth of the prolactin secreting pituitary tumour cell line, GH3 is stimulated by insulin and insulin-like growth factor-1 (IGF-1) and this response is blocked by the steroidal antiestrogens, ICI 164384 and ICI 182780. From conditioned medium (CM) experiments, growth of low density cells (10k/cm2) is increased by the addition of CM from high density cells (100k/cm2) and this growth effect is also blocked by antiestrogen. Transfection studies with a delta MTV-ERE-LUC reporter plasmid show that in the absence of estrogen and serum, both insulin and IGF-1 induce luciferase expression and this is blocked by the pure antiestrogens. No effect of these treatments was apparent when parallel experiments were conducted with a plasmid construct lacking the vitellogenin estrogen response element. From these and other data discussed in this report, we conclude that for GH3 cells, in the absence of estrogen and serum, the ER is transcriptionally activated by intracellular peptide factor pathways and by this means, acts as the key nuclear factor inducing mitogenesis in response to autocrine and exogenously added growth factors.
J Steroid Biochem Mol Biol 1994 Apr
PMID:The unliganded estrogen receptor (ER) transduces growth factor signals. 818 Jan 9

Epidermal growth factor (EGF) elicits estrogen receptor (ER)-dependent physiological sequelae and estrogen-like biochemical effects on the ER in the mouse uterus. These in vivo observations indicate that EGF may elicit some of its actions by activation of the ER. The effect of peptide growth factors on activation of a consensus estrogen-responsive element was assessed in a strain of Ishikawa human endometrial adenocarcinoma cells with negligible levels of ERs, as determined by Western blot and [3H]estradiol binding, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ERs. EGF and transforming growth factor-alpha induced transcriptional activation of a consensus ERE in an ER-dependent manner in both cell types. Transcriptional activation by the growth factors was inhibited by ICI 164,384, an ER receptor antagonist, and neutralizing antibodies to the EGF receptor. Immunodetection of the ER in BG-1 cells demonstrated that receptor levels were not induced by transforming growth factor-alpha vs. untreated cells. ER deletion mutants containing amino acids 1-339 and 121-599 were transfected into Ishikawa cells. The 1-339 mutant was more active in inducing transcription after EGF treatment than the 121-599 mutant. Estrogen only stimulated transcription in the presence of the 121-599 mutant, while 1-339 was inactive. Interestingly, synergism between a physiological dose of estrogen and peptide growth factors was observed. The presence of cross-talk between EGF receptor and ER signaling pathways suggests that interactions between growth factors and steroid receptors may modulate hormonal activity influencing normal and aberrant function in mammalian cells.
Mol Endocrinol 1993 Aug
PMID:Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. 823 19

1. The effects of chronic administration (28 days s.c. via Alzet osmotic minipumps) of 2-phenylethylamine.HCl (10 mg kg-1 per day) and/or (-)-deprenyl.HCl (1 mg kg-1 per day) on dopamine and noradrenaline receptor subtypes have been measured in rat brain. 3H-CGP 12177 was used to label beta-adrenoceptors; 3H-spiperone and 3H-SCH 23390 were used to label D2-like and D1-like receptors. 2. Total cortical beta-adrenoceptor density was reduced by (-)-deprenyl but not 2-phenylethylamine alone. Combined administration of 2-phenylethylamine and (-)-deprenyl resulted in a significantly larger decrease than (-)-deprenyl alone. Subtype density analysis by competition experiments with ICI 89406 revealed that the (-)-deprenyl effect in cortex was due to a decrease in beta 1-adrenoceptor density. The combination of 2-phenylethylamine and (-)-deprenyl resulted in a significant decrease in both cortical beta 1- and cortical beta 2-adrenoceptors. Cerebellar beta-adrenoceptor density was not altered by the present drug treatments. The Kd values for total beta-adrenoceptor densities and Ki values for beta-adrenoceptor subtype densities were not altered by drug treatment in either cortex or cerebellum. 3. Administration of 2-phenylethylamine and of (-)-deprenyl resulted in a decrease in the density of D1-like 3H-SCH 23390 but not D2-like 3H-spiperone binding to dopamine receptors in the striatum. The effects of combined 2-phenylethylamine and (-)-deprenyl treatment on 3H-SCH 23390 binding were additive. These drug treatments did not alter Kd values for these binding sites. 4. The down-regulation of catecholamine receptors following chronically increased availability of 2-phenylethylamine may be due to the catecholamine releasing or uptake blocking effects of this amine. These effects may also be attributable to a direct neuromodulatory action of 2-phenylethylamine on catecholamine receptors. 5. The parallels between effects of increased 2-phenylethylamine availability and effects of administration of MAO inhibitor antidepressants on catecholamine receptor systems indicate that this substrate for MAO may mediate some of the effects of MAO inhibitor antidepressants.
Cell Mol Neurobiol 1993 Jun
PMID:Down-regulation of beta-adrenergic and dopaminergic receptors induced by 2-phenylethylamine. 824 85

LNCaP cells contain androgen receptors with a mutation in the steroid binding domain (Thr 868 changed to Ala) resulting in a changed hormone specificity. Both the wild-type and mutated androgen receptors were transfected into COS cells. Transcription activation was studied in cells co-transfected with an androgen sensitive reporter (CAT) gene. The wild-type androgen receptor was activated by the agonist R1881, but the antiandrogens did not enhance transcription apart from a partial agonistic effect at high concentrations of cyproterone acetate. The mutated androgen receptor was fully activated by R1881, cyproterone acetate and hydroxyflutamide, but not by ICI 176,334. Receptor transformation to a tight nuclear binding state was studied by preparation of detergent washed nuclei and Western blotting with a specific antibody against the androgen receptor. Nuclei of COS cells transfected with wild-type receptor retained the receptor when the cells had been treated with the agonist R1881, partially retained receptors when treated with antiandrogen cyproterone acetate, but did not retain receptor when treated with hydroxyflutamide or ICI 176,334. The cells transfected with the mutated receptor additionally retained nuclear receptors after treatment with hydroxyflutamide. We conclude that each one of the three antiandrogens tested displayed different characteristics with respect to its effect on transformation and transcription activation.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Effects of antiandrogens on transformation and transcription activation of wild-type and mutated (LNCaP) androgen receptors. 827 6

A substantial proportion of patients with breast cancer are treated with the antioestrogen tamoxifen. As with other endocrine therapies, clinical experience has shown that some tumours in which growth is initially attenuated by tamoxifen treatment become resistant to continued drug treatment and resume growth. The mechanisms underlying the development of tamoxifen resistance have yet to be described but represent an important focus of research with the aim of defining what other therapies might be effective following tamoxifen treatment. Secondly, an understanding of tamoxifen resistance might suggest means to develop more effective agents for primary treatment of the disease. The development of pure antioestrogens, for example ICI 164,384 and ICI 182,780, which differ pharmacologically from tamoxifen in being entirely free of oestrogen partial-agonist activity, together with cell and animal models of tamoxifen resistant human breast cancer, has revealed one mechanism which might be of considerable clinical significance. Pure antioestrogens were shown to inhibit the proliferation of a greater proportion of tumor cells than tamoxifen in vitro, a differential effect that was attributed to the oestrogenic activity of tamoxifen. Subsequently, cell culture studies have shown that breast cancer cell lines selected for resistance to tamoxifen can still remain sensitive to the growth inhibitory action of pure antioestrogens. Similarly, the growth of human breast tumours in nude mice, which is initially attenuated by tamoxifen but then resumes, can be inhibited by pure antioestrogens. Both types of experiment are consistent with the view that tamoxifen resistance in these model systems is due to the oestrogenic action of tamoxifen. Thus, it can be predicted that in some patients whose tumours recur during tamoxifen therapy, a further response to pure antioestrogen treatment might occur. Studies to examine this hypothesis are currently being undertaken with ICI 182,780. One mechanism which might account for the experimental observations is an intrinsic heterogeneity amongst breast tumour cells in their response to tamoxifen, i.e. that there are at least two different populations of cells; one population which responds to tamoxifen as an antioestrogen and one which "reads" tamoxifen as an oestrogen. The growth advantage thus conferred on the latter population would lead to its predominance. If this is what actually happens in a proportion of human tumours, it can be argued that primary treatment of the tumour with a pure antioestrogen, rather than tamoxifen, would be preferred since a more complete and longer-lasting response would be predicted. Recent comparative studies with human breast tumours grown in nude mice support these predictions.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Are breast tumours resistant to tamoxifen also resistant to pure antioestrogens? 827 23

Potential mechanisms for tamoxifen resistance include loss or alteration in estrogen receptor or other transcription factors and altered tamoxifen pharmacology. Using an experimental model, we have previously demonstrated that one form of tamoxifen resistance is related to the acquired ability of tamoxifen to stimulate tumor growth. These tamoxifen-stimulated tumors contain a reduced tamoxifen concentration and an altered metabolite profile suggesting that accumulation of more estrogenic metabolites could explain this phenomenon. However, in vivo treatment of nude mice carrying tamoxifen-stimulated tumors with fixed ring non-isomerizable analogs, or other analogs resistant to conversion to metabolite E (a full estrogen), still resulted in tumor growth stimulation. Growth of these tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182,780, suggesting that this drug should be investigated in patients with tamoxifen resistance. These tamoxifen-stimulated tumors could be further stimulated by estrogen replenishment, and estrogen stimulation was blocked by tamoxifen, indicating that tamoxifen has both agonist and antagonist properties in these tumors. Our data suggest that although tamoxifen-stimulated tumors display a markedly altered metabolite profile, isomerization or metabolism of tamoxifen does not fully explain the development of tamoxifen-stimulated growth. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties over time remains to be defined.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Mechanisms for tamoxifen resistance in breast cancer: possible role of tamoxifen metabolism. 827 45

We studied the down-regulation of beta 2-adrenoceptors in guinea pig lung after chronic exposure to a beta-agonist. Guinea pigs were exposed to either norepinephrine (NE) or vehicle for 7 days. The density and affinity of beta-adrenoceptors were determined by Scatchard analysis of [125I]cyanopindolol binding in a lung membrane preparation and beta 1- and beta 2-adrenoceptor subtypes were studied in the presence of 0.1 microM ICI 118,551, a selective beta 2-adrenoceptor antagonist, or 0.1 microM CGP 20712 A, a selective beta 1-adrenoceptor antagonist, respectively. beta 2-Adrenoceptor mRNA was examined by Northern blot analysis. The tissue distribution of beta 2-adrenoceptors and of beta 2-adrenoceptor mRNA in lung after NE infusion were determined using receptor autoradiography and in situ hybridization, respectively. The functional significance of the decrease in beta 2-adrenoceptor was tested by measuring the relaxation response to a beta 2-agonist in isolated parenchymal strips. NE treatment resulted in decreases of 75 +/- 9%, 84 +/- 4%, and 66 +/- 9% of total beta-, beta 1-, and beta 2-adrenoceptors in the lung, compared with control animals. The administration of NE had only minimal effects on the dissociation constant (Kd) of the receptor for the radioligand. beta 2-Adrenoceptors mRNA was decreased by 46 +/- 13% after NE treatment. There was a correspondence between the distribution of beta 2-adrenoceptors and beta 2-adrenoceptor mRNA localization in both control and NE-treated guinea pigs. NE treatment reduced alveolar beta 2-adrenoceptors by 70 +/- 3% and its mRNA expression by 78 +/- 5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Jan
PMID:Long-term exposure to norepinephrine results in down-regulation and reduced mRNA expression of pulmonary beta-adrenergic receptors in guinea pigs. 829 87


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