Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.99.3 (PRE)
1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human progesterone receptor (PR) is dependent upon hormone and a nuclear accessory factor(s) for maximal binding to progesterone response elements (PRES) in vitro. Recombinant full-length PR, expressed in a baculovirus system and purified to apparent homogeneity, was used as a substrate to isolate and identify the accessory factor(s). The major PRE binding enhancement activity present in nuclear extracts was shown to be associated with the high mobility group chromatin protein HMG-1. Moreover, HMG-1 was equally effective in enhancing the DNA binding of both the A and B isoforms of PR. Enhancement of PRE binding was highly selective for HMG-1 as a single purified protein and was not mimicked by a general protein stabilization effect. In gel mobility shift assays, it appeared that HMG-1 enhanced PRE binding without stably participating as a component of the final DNA-PR complex, suggesting that HMG-1 acts indirectly by modifying the PR protein or the target DNA. HMG-1 is a sequence-independent DNA binding protein that recognizes distorted DNA structures and is also able to promote further distortions by bending DNA. Enhancement of PRE binding was found to be intrinsic to the conserved DNA binding domain of HMG-1 suggesting that HMG-1 acts by promoting a structural alteration in the target PRE-DNA.
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PMID:Nuclear accessory factors enhance the binding of progesterone receptor to specific target DNA. 813 95

The effect of steroid hormones on multiplication of the human polyomavirus BK (BKV) was studied. Physiological concentrations of the synthetic glucocorticoid dexamethasone, progesterone R5020, or estrogen 17 beta-estradiol enhanced the permissivity of the host cell for BKV, resulting in an up to 11-fold (dexamethasone), 5-fold (progesterone), or 3-fold (17 beta-estradiol) higher virus yield. The increase in virus yield in dexamethasone-stimulated cells correlated with enhanced steady-state levels of viral transcripts. The late leader sequence of the BKV control region contains a hormone response unit composed of a nonconsensus glucocorticoid and/or progesterone response element (GRE/PRE) and a fully consensus estrogen response element (ERE). DNA-protein binding studies showed that the glucocorticoid receptor and the progesterone receptor bound to this BKV GRE/PRE-like sequence, while the estrogen receptor could bind to the BKV ERE motif. By transient transfection assays, we were able to show that these sequences can mediate steroid hormone-induced gene expression. However, no cooperative transactivation effect between the BKV GRE/PRE-like motif and BKV ERE motif was observed. This BKV hormone response unit may play an important role in vivo by enhancing a productive BKV infection, and perhaps also by reactivating a latent infection, during physiological or pathological conditions accompanied by increased steroid hormone levels.
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PMID:A steroid hormone response unit in the late leader of the noncoding control region of the human polyomavirus BK confers enhanced host cell permissivity. 813 26

Oligonucleotides provide novel reagents for inhibition of gene expression because of their high affinity binding to specific nucleotide sequences. We describe a 38 base, single-stranded DNA that forms a triple helix or 'triplex' on progesterone response elements of a target gene. This triplex-forming oligonucleotide binds with a Kd = 100 nM at 37 degrees C and physiological pH, and blocks binding of progesterone receptors to the target. Furthermore, it completely inhibited progesterone receptor-dependent transcription in vitro. To approach in vivo conditions, triplex-forming oligonucleotides were tested in cell transfection studies. The derivation of the oligonucleotides with cholesterol enhanced their cellular uptake and nuclear concentration by at least four-fold. The cholesterol-derivatized triplex-forming oligonucleotide specifically inhibited transcription of the PRE-containing reporter gene in cells when applied to the medium at micromolar concentrations. This is the first demonstration of steroid-responsive gene inhibition by triplex formation and joins the growing body of evidence indicating that oligonucleotides have therapeutic potential.
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PMID:In vivo transcription of a progesterone-responsive gene is specifically inhibited by a triplex-forming oligonucleotide. 833 87

Circular permutation analysis was used to determine the degree of DNA bending induced by binding of the glucocorticoid receptor (GR) DNA binding domain (DBD), the human progesterone receptor (PR) DBD, PR-A:A and PR-B:B homodimers, and PR-A:B heterodimers to the glucocorticoid response element/progesterone response element (GRE/PRE). The bending angles induced by the GR DBD and the PR DBD were approximately 28 degrees and 25 degrees, respectively. The PR-B:B and PR-A:A homodimers and the PR-A:B heterodimers all induced similar DNA bending angles of 72-77 degrees. The substantially greater DNA bend induced by full-length PR compared to the PR DBD indicates that sequences outside the classic zinc finger DNA binding domain may play an important role in the interaction of PR with the GRE/PRE. Because PR-A:A and PR-B:B homodimers and the PR-A:B heterodimers induce similar DNA bends, the different abilities of the PR-A and PR-B isoforms to activate transcription are not due to differences in their abilities to distort DNA structure.
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PMID:DNA bending is induced by binding of the glucocorticoid receptor DNA binding domain and progesterone receptors to their response element. 918 56

Previous reports have shown that progestins stimulate the proliferation of the human breast cancer cell line T47D in culture. Under different conditions other reports have shown progestin stimulation, inhibition or no effect on growth. It has also been shown that c-myc expression is stimulated at early times by progestins. We are currently testing the hypothesis that the mechanism of growth enhancement by progestins involves the stimulation of expression of c-myc. This hypothesis predicts a progesterone regulatory region in or near the c-myc gene. We have identified a region, from -2327 to -1833, which serves this function. This region includes a 15 bp sequence with homology to the PRE (progesterone response element) consensus sequence. Human progesterone receptor (PR) binds to this sequence in a specific, ligand-enhanced manner in electrophoretic mobility shift assays (EMSA). A 3507 bp HindIII-XbaI fragment of the 5' flanking region of the c-myc gene, -2327 to +1180, containing the progestin regulatory region and the c-myc promoter, confers progestin responsiveness to the CAT (chloramphenicol acetyl transferase) reporter gene in progesterone receptor (PR)-rich T47D human breast cancer cells, but not in PR-negative MDA-MB-231 cells. Removal of the progestin regulatory region abrogates progestin responsiveness. These data demonstrate that the sequence from -2327 to -1833 of the human c-myc gene includes a positive progestin regulatory region.
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PMID:A sequence in the 5' flanking region confers progestin responsiveness on the human c-myc gene. 940 78

The integrin alpha 6 subunit associates with either the beta 1 or beta 4 subunit to form receptors for laminin, a major component of the basement membrane. Here, we characterized basal promoter of the human integrin alpha 6 subunit gene. The transcription start site, mapped by primer extension analysis, was 208 bp upstream of the translation start site. The promoter region lacked canonical TATA and GC boxes, but did contain a TATA-like sequence (GATAAA) 23 bp upstream of the major transcription start site. Consensus binding sites for Sp1 and the NF-kappa B complex were also present in the promoter region. A putative glucocorticoid/progesterone receptor responsive element (GRE/PRE), together with the Ap1 and c-myc binding sites located around 350-360 bp upstream of the transcription start site, represented positive regulatory sequences. Our current study showed a molecular model by which progesterone promotes tumor cell invasion through the basement membrane by up-regulating the laminin receptor.
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PMID:Identification of regulatory elements of human alpha 6 integrin subunit gene. 942 59

The steroid 5alpha-reductase (5alpha-R) plays an important physiological role in the conversion of steroid hormones such as androgen and progesterone to their 5alpha-reduced derivatives. 5alpha-R type II (5alpha-R2), one of two 5alpha-R isoforms, is thought to be a key enzyme in the generation of neuroactive steroids in the brain, particularly allopregnanolone (AP), via the production of its precursor dihydroprogesterone from progesterone. In the present study, we investigated possible regulatory mechanisms of 5alpha-R2 gene expression by steroid hormones in the female mouse brain. We first cloned mouse 5alpha-R2 (m5alpha-R2) cDNA by degenerate PCR, and found that progesterone induced 5alpha-R2 gene expression to levels detectable by in situ hybridization in female mouse brains. Functional analysis of the m5alpha-R2 gene promoter by a transient expression assay with human progesterone receptor (PR) and androgen receptor (AR) expression vectors identified a progesterone and androgen regulatory element (m5alpha-R2 PRE/ARE). Results of an electrophoretic mobility shift assay revealed that both PR and AR homodimers bound directly to m5alpha-R2 PRE/ARE sequence. These findings suggest that the gene expression of m5alpha-R2 is transcriptionally regulated by progesterone in female brains.
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PMID:Transcriptional regulation of the mouse steroid 5alpha-reductase type II gene by progesterone in brain. 1188 37

Previous studies have shown that progestin activates the transcription of IGFBP-1 (insulin-like growth factor binding protein-1). Four regions in the IGFBP-1 promotor have been identified to enhance the transcription. Two of the regions, located at -73 to -65 bp and -319 to -311 bp formed identical DNA-protein complexes with the nuclear extracts of endometrial stromal/decidual cells. To identify the binding protein(s) in endometrial cells that interact with these two regions, we have used the TGTCAATTA repeats (-319 to -11 bp of the IGFBP-1 promoter) to screen the human decidual cDNA library by yeast one-hybrid system. We found that Hox A10, HoxA11, HoxB2, HoxB4, and HoxD11 interacted with the TGTCAATTA repeats in yeast cells. Among these hox genes, the full-length coding region of HoxA10, HoxA11, and HoxB4 were used for functional analysis in three types of endometrial cells, undifferentiated endometrial stromal cells, decidual cells (differentiated stromal cells) and endometrial adenocarcinoma cell line (HEC1-B). All these endometrial cells produce IGFBP-1. Transient transfection assay showed that HoxA10 expression vector increased the promoter activity (the IGFBP-1 proximal promoter containing TGC/TCAATTA and two functional PRE sites) in endometrial stromal cells and in HEC-1B cells, but not in decidual cells. HoxB4 enhanced the promoter activity only in decidual cells, while HoxA11 had no apparent effect in all three types of cells. To evaluate whether Hox proteins would interact with progesterone receptor (hPR), cells were transfected with the promoter construct, Hox and hPR expression vectors. hPR alone activated the IGFBP-1 promoter activity, but expression of Hox gene suppressed the activation. Hox proteins also suppressed the hPR enhanced promoter activities of MMTV (containing consensus-PRE sites) and glycodelin (GdA, containing Sp1 site which mediates the hPR function). These data showed that Hox genes selectively activate the transcription of the IGFBP-1 and GdA genes in different types of endometrial cells. Hox genes, however, suppress the hPR enhanced activities. In addition, we found that HoxB4 expression was induced by estrogen and progestin. Other investigators have shown that HoxA10 and 11 were stimulated by progestin. These findings show that Hox proteins are molecular mediators of the steroid hormones during endometrial cell development.
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PMID:Hox proteins activate the IGFBP-1 promoter and suppress the function of hPR in human endometrial cells. 1248 92

Inflammation is associated in some tissues with diminished responsiveness to steroid hormone action. We hypothesized that proinflammatory cytokines alter steroid hormone sensitivity, in part, by reducing levels of key nuclear receptor coactivators. Treatment of cultured human uterine smooth muscle cells (UtSMC) with TNF-alpha significantly reduced mRNA for the coactivators, SRC-1 (42%, P<0.01) and 2 (47%, P<0.03), and diminished the respective protein levels, but did not significantly alter the mRNAs encoding SRC-3, CBP and the corepressors, NCoR and SMRT; or progesterone receptor protein levels. To assess TNF-alpha effects on steroid hormone-mediated transcriptional activity, UtSMC were transfected with progesterone receptor B (PR-B) and a model PRE2-luciferase reporter construct. Transfected UtSMC were treated with progesterone alone or in the presence of TNF-alpha, and assayed for luciferase activity. TNF-alpha (10 ng/ml) diminished progesterone-stimulated PR-B-mediated transactivation by approximately 60% (P<0.02). The TNF-alpha-dependent decrease in PRE-luciferase activity was fully prevented by cotransfection with SRC-2, and partially prevented with exogenous SRC-1. In conclusion, TNF-alpha impairs progesterone-stimulated PR-B-mediated transactivation, and these effects appear to be due, in part, to reduced expression of SRC-1 and -2, which is a novel mechanism by which inflammation can functionally block steroid hormone action.
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PMID:Tumor necrosis factor-alpha suppresses the expression of steroid receptor coactivator-1 and -2: a possible mechanism contributing to changes in steroid hormone responsiveness. 1523 21

The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.
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PMID:In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. 1854 May 73


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