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 structure of the 42-kilobase (kb) long chicken progesterone receptor (cPR) gene and of all six transcripts that are detectable on Northern blots was determined. The first of 8 exons encodes the N-terminal region A/B which is highly divergent among different species and contains a constitutive transcription activation function. The DNA (DBD)- and hormone-binding domains (HBD) are assembled from 2 and 5 exons, respectively, with the individual "zinc fingers" of the DBD encoded by separate exons. In addition to the previously described 4.5-kb cPR mRNA species, alternative polyadenylation, splicing variation, and "5'-truncation" lead to the generation of 5 further mRNAs. Most importantly, this 5'-truncation produces, by an as yet unidentified mechanism, an abundant transcript which encodes form A but not form B of cPR. Lack of splicing at the exon 2 splice-donor and polyadenylation due to a signal site in the second intron generates a previously undetected 3.4-kb mRNA species. The corresponding cDNA was sequenced in its entirety and shown to encode only region A/B and the N-terminal "finger" of the DBD. Alternative polyadenylation upstream of the signal site for the 4.5-kb mRNA is responsible for the appearance of a 3.3-kb mRNA. The longest cPR mRNA (8.2 kb) originates from a transcription termination point more than 3 kb downstream of the 4.5-kb mRNA 3'-end. Finally, the primary sequence of more than 2 kb upstream sequences of the cPR gene, containing several consensus hexamer progestin/glucocorticoid receptor-binding sites (PRE/GRE and putative Sp1 binding motifs, is discussed.
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PMID:Characterization of multiple mRNAs originating from the chicken progesterone receptor gene. Evidence for a specific transcript encoding form A. 230 88

We analyzed IGFBP-1 gene promoter activity by transient transfection during the progressive decidualization of human endometrial stromal cells. A time study over a 13-day culture period showed that the promoter activity increased exponentially to > 10(4) fold in cells treated with MPA and RLX correlating with the secretion rate and steady-state mRNA levels of the endogenous gene. Deletion analysis showed that two regions in the IGFBP-1 gene promoter are responsible for the activation of the IGFBP-1 gene. The basal promoter region between -1 and -300 bp contains multiple sections of functional elements homologous either to CRE, PRE, or CCAAT. The major difference of IGFBP-1 gene activation in endometrium and the hepatic system lies in the distal promoter region, between -2.6 and -3.4 kb, which mediates 95% of the total promoter activity derived from -3.3 kb to +68 bp. Functional and binding analysis in the distal promoter region showed that multiple Sp1 elements interacting with a novel Sp3 transcription factor activates the hIGFBP-1 gene promoter.
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PMID:Differentiation-dependent and cell-specific regulation of the hIGFBP-1 gene in human endometrium. 932 21

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 high mobility group (HMG) I proteins are small, non-histone chromosomal proteins that promote gene activation during development and within rapidly dividing cells. They do so by facilitating enhanceosome formation on inducible genes, via both protein/DNA and protein/protein interactions. The HMG I-C gene is tightly regulated, normally being expressed exclusively during embryonic development. However, HMG I-C expression is also observed frequently in a number of tumor types, and this expression has been shown to contribute to the malignant transformation process. With the aim of dissecting pathways that lead to aberrant expression of HMG I-C in tumor cells, we have analyzed HMG I-C gene regulation in the human hepatoma cell line PLC/PRF/5. One of the two HMG I-C transcripts detected in this cell line originates from a novel downstream initiation site at nucleotide -161 relative to the first methionine. Transcription from the downstream initiation site is mediated by a PRE located between nt -222 and -217. We show here that the Sp1 and Sp3 transcription factors interact with the PRE and transactivate the HMG I-C promoter in a cooperative fashion. This study provides the first characterization of this downstream HMG I-C promoter.
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PMID:A novel downstream positive regulatory element mediating transcription of the human high mobility group (HMG) I-C gene. 1047 23

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

Previous studies have shown that progestin induces the production of fibronectin (FN) and its mRNA content in human endometrial stromal cells. The mechanism of the upregulation was unclear. In the present study, we provide evidence that hPR regulates the FN promoter activity mainly through the CRE/AP1 site located in the proximal region of the promoter in human decidual fibroblasts. Various lengths of the proximal region of the FN promoter were linked to the reporter vector to construct promoter-reporter plasmids and were then transfected into human decidual fibroblasts. Deletion and mutation analysis showed that CRE/AP1 and Sp1 sites in the proximal region mediated the basal promoter activity. To evaluate progestin-mediated transcriptional activation, decidual fibroblasts were transfected with p300 (FN promoter-reporter construct) and hPR expression vector. Cells treated with medroxyprogesterone acetate (MPA) increased the promoter activity ranging from 2.5- to 9-fold determined in 10 decidual specimens. hPRA enhanced activation was stronger than that of hPRB. Structural analysis of hPR showed that DNA and ligand binding domains are essential for the activation, and missing the TAF1 domain weakens the activation. The proximal promoter region of the FN gene lacks a canonical PRE site. Mutation at the CRE/AP1 site eliminated the upregulation by progestin. To evaluate the interaction of hPR with the CRE/AP1 site, the CRE/AP1 site was mutated to the consensus AP1 cis-element (TGACGTCA, -172 to -165 bp, mutated to TGAC_TCA) which eliminated the CREB binding. FN promoter activity derived from p300AP1 mutant was found to be higher than that of p300. These results showed that hPR interacts with the AP1 binding proteins, but not with CREB. Progestin treatment or overexpression hPR did not alter appreciably the content of c-jun or c-fos in decidual fibroblasts nuclear extracts. Antibody to hPR (hPRa3), which precipitated hPR also coprecipitated c-jun and c-fos, whereas CREB was not precipitated by hPRa3. The observation implies that hPRs are brought to the FN promoter region by AP1 proteins to enhance the transcription. In summary, this study provides molecular evidence that the CRE/AP1 site and c-jun/c-fos in decidual fibroblasts mediate the hPR-enhanced activation of FN transcription.
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PMID:Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts. 1461 84

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated tumor. Response to progestin-based therapy correlates positively with progesterone receptor (PR) expression. However, many endometrial tumors have low levels or loss of PR, limiting the clinical application of progestin. We evaluated the ability of epigenetic modulators to restore functional PR expression in Type I endometrial cancer cells with low basal PR. Treatment with the histone deacetylase inhibitor (HDACi) LBH589 induced a profound upregulation of PR mRNA. LBH589 restored PR protein expression at 24 hours and sustained expression for 72 hours, even in the presence of progesterone. LBH589 promoted a dose-dependent increase in PR protein levels, with an obvious increase with 10 nM LBH589. To investigate if the restored PR is functional as a transcription factor, we examined PR nuclear localization and expression of PRE- or Sp1-containing target genes. After treatment with LBH589 in the absence or presence of progesterone, PR nuclear expression was increased as demonstrated by Western blotting of nuclear fractions and immunostaining. Next, restored PR upregulated FoxO1, p21, and p27 and downregulated cyclin D1 in a ligand-dependent manner. Finally, LBH589 treatment induced cell cycle arrest in G1 that was further augmented by progesterone. Regulation of PR target genes was also achieved with other HDAC inhibitors, indicating that agents in this class work similarly with respect to PR. Our findings reveal that epigenetic modulators can restore endogenous functional PR expression in endometrial cancer cells and suggest that strategies to re-establish PR expression will resensitize endometrial tumors to progestin therapy.
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PMID:Epigenetic modification restores functional PR expression in endometrial cancer cells. 2388 56