Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Response Elements”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2005

Intergenic transcription through a polycomb group response element counteracts silencing.

Polycomb group response elements (PREs) mediate the mitotic inheritance of gene expression programs and thus maintain determined cell fates. By default, PREs silence associated genes via the targeting of Polycomb group (PcG) complexes. Upon an activating signal, however, PREs recruit counteracting trithorax group (trxG) proteins, which in turn maintain target genes in a transcriptionally active state. Using a transgenic reporter system, we show that the switch from the silenced to the activated state of a PRE requires noncoding transcription. Continuous transcription through the PRE induced by an actin promoter prevents the establishment of PcG-mediated silencing. The maintenance of epigenetic activation requires transcription through the PRE to proceed at least until embryogenesis is completed. At the homeotic bithorax complex of Drosophila, intergenic PRE transcripts can be detected not only during embryogenesis, but also at late larval stages, suggesting that transcription through endogenous PREs is required continuously as an anti-silencing mechanism to prevent the access of repressive PcG complexes to the chromatin. Furthermore, all other PREs outside the homeotic complex we tested were found to be transcribed in the same tissue as the mRNA of the corresponding target gene, suggesting that anti-silencing by transcription is a fundamental aspect of the cellular memory system.

Animals↗
PubMed1996

Regulation of BiP gene expression by cyclopentenone prostaglandins through unfolded protein response element.

Delta12-Prostaglandin (PG) J2, a cyclopentenone prostaglandin, plays a role in various stress responses. BiP, a stress-inducible chaperone protein, is implicated in protein folding and translocation in endoplasmic reticulum and induced in the condition of accumulation of unfolded proteins. Here, we examined the effect of Delta12-PGJ2 on the expression of the BiP gene. Delta12-PGJ2 markedly stimulated the expression of the BiP gene in a time- and concentration-dependent manner in HeLa cells. This stimulation was specific for cyclopentenone PGs among various PGs. Cycloheximide pretreatment completely inhibited the Delta12-PGJ2-induced expression of the BiP gene, suggesting that the effects on nascent protein synthesis are involved in the signaling mechanism. Delta12-PGJ2 markedly stimulated the promoter activity of the 5'-flanking region of the BiP gene through the unfolded protein response element. Furthermore, Delta12-PGJ2 stimulated the enhancer activity of the 3'-half of the unfolded protein response element, and this stimulation required three nucleotides within this region. Gel mobility shift assay demonstrated that this region was occupied with two specific nuclear protein factors with different mobilities in the control cells, and Delta12-PGJ2 induced the dissociation of the protein-DNA complex with lower mobility. These findings indicate that Delta12-PGJ2 stimulates the expression of BiP gene through the 3'-half of the unfolded protein response element.

Base Sequence↗
PubMed2001

Conformation and rigidity of DNA microcircles containing waf1 response element for p53 regulatory protein.

The tumor-suppressor activity of p53 is closely related to its DNA-binding properties. It binds a number of DNA response-elements and it is likely that these share a common structural feature. Here, we present a new, general method to determine the absolute twist of flexible DNA promoter sequences based on direct imaging of the topology of microcircles containing the sequences. We have used magnetically driven dynamic force microscopy ("MacMode" AFM) to observe, in solution, the conformation of 168 base-pair DNA microcircles, each containing four equally spaced copies of the waf1/cip1/p21 p53 response-element. Analysis of the images showed that the microcircles are markedly puckered with a small excess of negatively writhed molecules. The average measured values of writhe are 0.109+/-0.013 (for 60 positively writhed molecules) and -0.098+/-0.011 (for 65 negatively writhed molecules). These values lead directly to a difference in linking number for the positively and negatively writhed molecules prior to ligation, from which we derive a twist mismatch of 178 degrees (overtwist). This is 44.5 degrees for each 42-mer precursor containing a single waf1/cip1/p21 p53 response-element, in good agreement with the range of values deduced by indirect biochemical techniques. The two values of writhe may also be used to determine the ratio of the bending (B) to twisting (C) rigidity, yielding B/C=0.23. This is about one-third of the value for long, random-sequence DNA, suggesting that the waf1/cip1/p21 p53 response-element is extremely flexible, a result that is also consistent with indirect biochemical experiments. These results support the idea, proposed by us earlier, that torsional stress may play a role in the regulation of p53 binding through modulation of twist at the binding site.

Aluminum Silicates↗
PubMed1999

One mechanism for cell type-specific regulation of the bax promoter by the tumor suppressor p53 is dictated by the p53 response element.

Key to the function of the tumor suppressor p53 is its ability to activate the transcription of its target genes, including those that encode the cyclin-dependent kinase inhibitor p21 and the proapoptotic Bax protein. In contrast to Saos-2 cells in which p53 activated both the p21 and bax promoters, in MDA-MB-453 cells p53 activated the p21 promoter, but failed to activate the bax promoter. Neither phosphorylation of p53 on serines 315 or 392 nor an intact C terminus was required for p53-dependent activation of the bax promoter, demonstrating that this differential regulation of bax could not be explained solely by modifications of these residues. Further, this effect was not due to either p73 or other identified cellular factors competing with p53 for binding to its response element in the bax promoter. p53 expressed in MDA-MB-453 cells also failed to activate transcription through the p53 response element of the bax promoter in isolation, demonstrating that the defect is at the level of the interaction between p53 and its response element. In contrast to other p53 target genes, like p21, in which p53-dependent transcriptional activation is mediated by a response element containing two consensus p53 half-sites, activation by p53 of the bax element was mediated by a cooperative interaction of three adjacent half-sites. In addition, the interaction of p53 with its response element from the bax promoter, as compared with its interaction with its element from the p21 promoter, involves a conformationally distinct form of the protein. Together, these data suggest a potential mechanism for the differential regulation of p53-dependent transactivation of the bax and p21 genes.

Base Sequence↗
PubMedDate not supplied

A G/A polymorphism in the androgen response element 1 of prostate-specific antigen gene correlates with the response to androgen deprivation therapy in Japanese population.

Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. The purpose of this study was to investigate the allelic differences in the PSA promoter activity in vitro and the relation to several clinical factors of prostate cancer patients in the Japanese population. No significant differences of promoter activity in luciferase assay and binding activity of androgen receptor were noted between the two alleles in vitro. The PSA -158 G/A polymorphism was determined by PCR amplification and restriction digestion assays in 101 organ-confined prostate cancer (PC) patients who underwent radical prostatectomy and 52 controls with benign prostatic hyperplasia. The results revealed that homozygosity for the A allele in Japanese is less common (only 8.5%) than in ethnic populations. There were no significant differences in serum PSA value at the time of diagnosis, differentiation of cancer, pathological stage, cancer volume or ratio of serum PSA/ cancer volume. However, cancer volume after neoadjuvant endocrine therapy was significantly smaller in GG genotype than in AA + AG genotypes. Our data indicate that the PSA -158 G/A polymorphism has no effect on the PSA promoter activity in vitro and no association with the serum PSA level in Japanese men, however suggest that the patients with GG genotype of ARE1 may be more sensitive to androgen ablation therapy. Taken together, the ARE1 polymorphism in the PSA gene promoter may be one of the biomarkers for response to androgen deprivation therapy.

Aged↗
PubMed2004

Differential effect of small ubiquitin-like modifier (SUMO)-ylation of the androgen receptor in the control of cooperativity on selective versus canonical response elements.

The androgen receptor (AR) can be small ubiquitin-like modifier (SUMO)-ylated in its amino-terminal domain at lysines 385 and 511. This SUMO-ylation is responsive to several agonists, but is not induced by the pure antagonist hydroxyflutamide. We show that the main site of interaction of Ubc9, the SUMO-1 conjugating enzyme, resides in transcription activation unit 5. Overexpression of SUMO-1 represses the AR-mediated transcription, and this effect is abolished after mutating both SUMO-1 acceptor sites. On the other hand, the mutation of lysine 385 clearly affects the cooperativity of the receptor on multiple hormone response elements. Lysine 511 is not implicated in this function. Surprisingly, these effects on cooperativity clearly depend on the nature of the response elements. When selective androgen response elements, which are organized as direct repeats of 5'-TGTTCT-3'-like sequences, were tested, the lysine 385 mutation did not increase the androgen response. Point mutations changing the direct-repeat elements into inverted-repeat elements restored the effects of the lysine 385 mutation on cooperativity. In conclusion, SUMO-ylation of the AR might have a differential function in the control of cooperativity, depending on the conformation of the AR dimer bound to DNA.

Amino Acid Motifs↗
PubMed2002

Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.

Hormone-activated ERs (ERalpha and ERbeta) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the regulatory regions of target genes. Once considered to function solely as receptor tethers, there is an increasing amount of recent evidence to suggest that the sequence of the ERE can influence receptor activity. In this study, we have performed a systematic analysis of the role of different EREs in ER pharmacology. Specifically, by measuring ER activity on the vitellogenin A2, complement 3 gene, pS2, and lactoferrin EREs, we demonstrate that the activities of E2 and xenoestrogen ligands through ERalpha and ERbeta are significantly influenced by the nature of the response element. Using a series of ERalpha and ERbeta interacting peptides that contain the coactivator-binding motif LXXLL, we show that the type of ERE with which the receptor associates regulates the structure of the coactivator pocket on ER. Furthermore, using a novel ELISA developed to measure ER-coactivator interactions revealed that these different conformational states of ERalpha and ERbeta are functionally relevant, as they dictate receptor coactivator binding preference. Together, these results indicate that the DNA response element is a key regulator of receptor structure and biological activity and suggest the ERE sequence influences the recruitment of coactivators to the ER at target gene promoters. We propose that DNA-induced alteration of protein structure and coregulator recruitment may serve as a universal regulatory component for differential gene expression by other nuclear hormone receptors and unrelated transcription factors.

Allosteric Regulation↗
PubMed2001

Nuclear-receptor interactions on DNA-response elements.

Nuclear receptors regulate transcription by binding to DNA-response elements using their conserved DNA-binding domains. These response elements contain conserved hexameric sequences that can be arranged in various bipartite configurations, including inverted and direct repeats. A series of structural studies on receptor--DNA binding complexes illustrate the strategies used by receptors to recognize the symmetry of their binding site as well as its sequence. These structures also indicate how cooperation between receptors enhances their joint affinity and selectivity for correctly configured sites.

Binding Sites↗
PubMed2000

Characterization of the responsive elements to hormones in the rat aldolase B gene.

Transcription of the aldolase B gene, AldB, in the liver is regulated by hormones such as insulin and glucagon. To characterize the elements that are responsive to these hormones in the upstream region of AldB, plasmids carrying various length of the upstream region of this gene were constructed and transfected to primary cultured rat hepatocytes. The promoter activities were gradually increased by progressive deletion of the 5'-upstream region, and high activities were observed for constructs carrying the sequence between -408 and -85 bp, suggesting the presence of suppressive element(s) in the upstream region of -409 bp. The transcription activities of the mutants containing the sequences between -228 and -85 bp were enhanced by insulin, and glucagon suppressed the transcription activities of those containing the sequence between -764 and -85 bp. Two sequence elements similar to the cAMP-responsive element (CRE), one from -89 to -82 bp and another from +13 to +20 bp, were found in the upstream sequence of the gene. The latter element is not functional because its deletion did not affect either the transcription efficiency or glucagon response. However, the deletion of the former element diminished both functions. A gel retardation assay showed that the nuclear factor binds to the former element, which was competitive with authentic CRE oligonucleotide but not with the mutant CRE one. These results suggest that the CRE-like element in the promoter region is prerequisite for both fundamental transcription efficiency of the gene and suppression by glucagon in hepatocytes.

5' Untranslated Regions↗
PubMed1989

Comparative analysis of the HTLV-I Rex and HIV-1 Rev trans-regulatory proteins and their RNA response elements.

The Rex proteins of types I and II human T-cell leukemia viruses (HTLV-I, HTLV-II) are required for expression of the viral structural gene products, gag and env and, thus, are essential for the replication of these pathogenic retroviruses. The action of Rex is sequence specific, requiring the presence of a cis-acting Rex response element located in the 3' long terminal repeat. This element corresponds to a predicted RNA secondary structure and functions in an orientation-dependent but position-independent manner. Rex acts through this response element to stimulate the nuclear export of the unspliced or singly spliced viral mRNA species encoding the virion structural proteins that are normally excluded from the cytoplasm. Although the Rex proteins of HTLV-I and HTLV-II can also function via the related Rev response element present in the env gene of the type I human immunodeficiency virus (HIV-1), the analogous HIV-1 Rev protein is unable to act on the HTLV-I Rex response element. This nonreciprocal pattern of genetic complementation by Rex and Rev suggests that these viral trans-regulators may interact directly with their RNA response elements.

Base Sequence↗
PubMed1998

A short proximal promoter and the distal hepatic control region-1 (HCR-1) contribute to the liver specificity of the human apolipoprotein C-II gene. Hepatic enhancement by HCR-1 requires two proximal hormone response elements which have different binding specificities for orphan receptors HNF-4, ARP-1, and EAR-2.

We have identified the regulatory elements, some of the factors and potential regulatory mechanisms which determine the tissue specificity of the human apoC-II gene. The -545/+18 apoC-II promoter directs high levels of expression of the reporter CAT gene in cells of hepatic origin (HepG2), low levels of expression in cells of intestinal origin (CaCo-2) and basal expression in HeLa cells. Deletion analysis identified negative regulatory elements within the -545/-388 region and positive regulatory elements within the -388/-55 region. Linkage of different apoC-II promoter segments to the hepatic control region-1 (HCR-1) enhanced the promoter activity 2.5-11-fold in HepG2 cells but did not affect its activity in CaCo-2 or COS-1 cells. DNase I footprinting analysis using rat liver nuclear extracts identified five protected regions within the -545/+18 apoC-II promoter as follows: CIIA (-74/-44), CIIB (-102/-81), CIIC (-159/-116), CIID (-288/-265), and CIIE (-497/-462). Elements CIIB and CIIC contain hormone response elements. CIIB is recognized by hepatic nuclear factor-4 (HNF-4) but not ARP-1 or EAR-2, whereas CIIC is recognized by ARP-1 and EAR-2 but not by HNF-4. HNF-4 transactivated the apoC-II promoter or the apoC-II promoter linked to the HCR-1 in COS-1 cells. A double mutation in elements CIIB and CIIC that eliminated binding of HNF-4 or ARP-1 and EAR-2, respectively, to these sites abolished the enhancer activity of HCR-1. The combined data suggest that the apoC-II promoter/HCR-1 cluster can direct expression in cells of hepatic origin and that optimal enhancer activity requires synergistic interactions between factors bound to the distal HCR-1 and nuclear receptors bound to the two proximal hormone response elements.

Animals↗
PubMed1996

GABAB receptors negatively regulate transcription in cerebellar granular neurons through cyclic AMP responsive element binding protein-dependent mechanisms.

GABAB receptors affect short-term signalling in various cell types. However, nothing is known about possible long-term effects on transcription. To analyse such effects in the CNS, we studied GABAB receptor-mediated gene regulation in primary cultures of cerebellar granule neurons. Transcription was followed using a chloramphenicol acetyl transferase reporter gene driven by the minimal cyclic AMP-responsive element (TGACGTCA). Transcription was stimulated by activation of both the cyclic AMP (forskolin: 5 x 10(-6) M) and the Ca2+ dependent (KCl: 30 mM) pathways (-)-Baclofen (10(-6) M to 10(-4) M), a specific GABAB receptor agonist, reduced by 50-70% the transcriptional stimulation evoked by both forskolin and KCl, whereas isoguvacine, a GABAA receptor agonist, was without effect. Moreover, the GABAB antagonist CGP 35348 abrogated the inhibitory effects of both GABA and baclofen, indicating that GABAB receptors were specifically implicated in this response. Measurements of cyclic AMP levels suggested that (-) baclofen inhibits forskolin-initiated transcription by reducing cyclic AMP production. Direct transcriptional activation, via the cyclic AMP pathway, by overexpression of the catalytic subunit of the cyclic AMP-dependent protein kinase, was not significantly altered by (-) baclofen. This indicates again that (-) baclofen-dependent inhibitory mechanisms operate upstream of cyclic AMP-dependent protein kinase at the level of second messenger formation. Further, we used a yeast transcriptional activator GAL4-cyclic AMP-responsive element binding protein to analyse whether GABAB receptor-mediated inhibition of cyclic AMP-responsive element transcription implicated the transacting factor cyclic AMP-responsive element binding protein. We show that the negative effects of (-) baclofen implicate this transcription factor and this holds good for both the forskolin and KCl-stimulated pathways. The results indicate that GABAB receptors negatively regulate cyclic AMP-responsive element binding protein-mediated transcription in the CNS.

Animals↗
PubMed1991

Phosphate-sensitive binding of the estrogen receptor to its response elements.

Although the nucleotide bases that constitute the consensus DNA sequence of the estrogen response element (ERE) have been identified, the involvement of electrostatic contacts between the sugar-phosphate backbone of the ERE and the estrogen receptor (ER) is not known. Moreover, the contribution of these contacts to sequence-specific DNA binding has not been determined. Therefore, the interactions of highly purified ER with the phosphate residues of the ERE derived from the chick vitellogenin (cVit)-II gene were examined by phosphate ethylation interference. Specific ER-DNA complexes were evident in electrophoretic gel mobility shift assays using DNA fragments containing either the perfect ERE (-625 relative to gene start site; 5'-GGTCAGCGTGACC) or the imperfect ERE (-353; 5'-GGTCAACATAACC). The phosphate ethylation interference footprint identified a 2-fold, symmetrical exclusion of phosphate residues essential for specific binding to the perfect ERE with a 5' stagger, indicating that each monomer of the ER dimer is bound in the major groove of the DNA. The interference footprint of the imperfect ERE did not detect interactions between the receptor and the phosphate residues in the 3' half of the response element on the noncoding strand. In contrast, the corresponding footprint of the perfect ERE displayed strong interactions between the ER and the phosphate backbone of the DNA. Consequently, the absence of these electrostatic contacts very likely accounts for the reduced binding affinity of the ER for the imperfect ERE. These results indicate that specific contacts between the ER and the sugar-phosphate backbone of its cognate response elements are an important aspect of DNA sequence recognition and high affinity binding.

Base Sequence↗
PubMed2005

The switch in alternative splicing of cyclic AMP-response element modulator protein CREM{tau}2{alpha} (activator) to CREM{alpha} (repressor) in human myometrial cells is mediated by SRp40.

The transcription factor cAMP-response element modulator (CREM) protein, plays a major role in cAMP-responsive gene regulation. Biological consequences resulting from the transcriptional stimuli of CREM are dictated by the expression of multiple protein isoforms generated by extensive alternative splicing of its precursor mRNA. We have previously shown that alternative splicing enables the expression of the CREM gene to be "switched" within the human myometrium during pregnancy from the production of CREMtau(2alpha), a potent transcriptional activator to the synthesis of CREMalpha, a transcriptional repressor. Furthermore we have recently reported that this change in the expression of CREM spliced variants is likely to have important ramifications on the regulation of downstream cAMP-response element-responsive target genes involved in uterine activity during gestation. We have investigated the splicing factors involved in controlling the expression of myometrial CREM splice variants. Data presented here from transient transfections indicate that the switch in the synthesis of CREMtau(2)alpha to CREMalpha that occurs during pregnancy is regulated primarily by an SR protein family member, SRp40. We also show that expression of this splicing factor is tightly regulated in the myometrium during pregnancy. SRp40 regulates the splicing of CREM via its interactions with multiple ESE motifs present in the alternatively exons of CREM. In vitro splicing and electrophoretic mobility shift assays were employed to confirm the functionality of the SRp40-binding ESEs, thus providing a mechanistic explanation of how SRp40 regulates the switch in splicing from production of CREMtau(2)alpha to CREMalpha.

Alternative Splicing↗
PubMed1993

A composite hormone response element mediates the transactivation of the rat oxytocin gene by different classes of nuclear hormone receptors.

Transcription factors of the steroid/thyroid hormone receptor superfamily are mediators of development and regulation of the brain. Previous studies have shown that the hypothalamic oxytocin (OT) gene is a potential target of these receptors, since its promoter is stimulated by estrogens and thyroid hormone. Here it is shown that the rat OT promoter is stimulated (at least 20-fold) by retinoic acid through two distinct regions in the 5'-flanking region. The major retinoic acid response element was located between nucleotides -172 and -148 and a minor one between nucleotides -112 and -77, as concluded from the transactivation of 5'-deletion mutants and binding to promoter elements by the retinoic acid receptor. Since the -172/-148 element also conferred estrogen and thyroid hormone responsiveness, it can be considered a composite hormone response element. This element contains a natural variant of the direct repeat of the half-site AGGTCA with spacing zero (DR-0) as well as a palindrome. Analysis of the core sequences of this element by site-directed mutagenesis showed that each of the three TGACC motifs integral to this element contributes to the multihormone sensitivity, but the contribution of each motif is different for the individual receptors. In neonatal rats, vitamin A deficiency and retinoic acid supplementation did not cause changes in hypothalamic OT mRNA levels and OT peptide levels in the pituitary gland and plasma. Gel-retarded protein-DNA complexes were formed between the composite hormone response element and extracts of the hypothalamic supraoptic and paraventricular nuclei. The composite hormone response element has a unique configuration and integrates responses of multiple members of the steroid/thyroid hormone receptor superfamily.

Animals↗
PubMed2003

Oltipraz is a bifunctional inducer activating both phase I and phase II drug-metabolizing enzymes via the xenobiotic responsive element.

Oltipraz, a promising cancer chemopreventive agent, has been recognized as a monofunctional inducer selectively activating phase II carcinogen-detoxifying enzymes via the antioxidant responsive element (ARE). However, we report here that oltipraz also induces rat glutathione S-transferase A5 (GSTA5), a potent phase II detoxifying enzyme, by means of the xenobiotic responsive element (XRE). Although an ARE sequence exists in the 5' upstream of the rGSTA5 gene, this cis-acting regulatory element loses its responsiveness to oltipraz treatment because of extensive mutations in its distal-half site. Our data indicate that a XRE sequence, located downstream of the transcription initiation site of the gene, is another oltipraz-responsive element. Electrophoretic mobility shift assay showed that oltipraz steadily induces XRE-aryl hydrocarbon receptor (AhR) binding, which can be blocked specifically by excess XRE oligonucleotides or by AhR antibody. By cloning different XREs into the pGL3-promoter vector, we found that oltipraz can activate XRE enhancers from several phase II drug metabolism enzymes, including rGSTA5, rGSTA2, NAD(P)H:quinone reductase, and it also activates XRE from the phase I metabolism enzyme CYP1A1. Oltipraz's effect on XRE is AhR-dependent and is independent of the presence of active CYP1A1. Reverse transcriptase-polymerase chain reaction experiments revealed that oltipraz induces gene expression of both phase I and II drug-metabolizing enzymes in rat hepatoma cells. Thus, we conclude that, like ARE, the XRE pathway constitutes an important part of the molecular mechanism contributing to oltipraz-induced expression of the phase II metabolism enzymes. Oltipraz is a bifunctional inducer, modulating both phase I and II drug-metabolizing enzymes to enhance carcinogen detoxification.

Animals↗
PubMed2001

Regulation of prothymosin alpha gene expression by estrogen in estrogen receptor-containing breast cancer cells via upstream half-palindromic estrogen response element motifs.

Prothymosin alpha (PTalpha), a protein associated with cell proliferation and chromatin remodeling, and found to selectively enhance ER transcriptional activity by interacting with a repressor of ER activity, is shown to be a primary response gene to estrogen. Prothymosin alpha mRNA was rapidly increased by estrogen, followed by a 6-fold increase in prothymosin alpha protein content in ER-containing breast cancer cells. Analysis of the prothymosin alpha promoter and 5'-flanking region, and electrophoretic gel mobility shift studies showed the strong inducibility by the estradiol-ER complex to be mediated by two consensus half-palindromic estrogen response elements at -750 and -1051, which directly bind the ER. Estrogenic stimulation of prothymosin alpha required a DNA binding form of ER with a functional activation function-2 domain. The prothymosin alpha 5'-regulatory region also contains multiple Sp1 sites. Although addition of Sp1 did not further enhance estradiol-ER stimulated prothymosin alpha transcriptional activity in breast cancer cells, transfection and response element mutagenesis studies using Drosophila cells, which are deficient in Sp1, revealed that Sp1 and the estradiol occupied-ER can each activate the prothymosin alpha gene independently of the other and act in an additive manner. These observations, documenting robust prothymosin alpha up-regulation by the estradiol-ER complex via widely spaced half-palindromic estrogen response element motifs, are reminiscent of those shown previously for the ovalbumin gene and suggest that the use of multiple half response elements may be a more common mode for regulation of gene expression by the ER than previously appreciated. In addition, these observations suggest interrelationships between cell proliferation and gene transcriptional activities and indicate a positive mechanism by which PTalpha, which increases ER transcriptional effectiveness, is itself up-regulated by the estrogen-ER complex.

Amino Acid Motifs↗
PubMed2004

Activation of estrogen response element dependent transcription by thyroid hormone with increase in estrogen receptor levels in a rat pituitary cell line, GH3.

Interrelationships between thyroid hormone and estrogen actions have been documented with regard to a variety of physiological functions. Both hormones stimulate transcription of target genes by binding to their nuclear receptors that interact with specific responsive elements (estrogen and thyroid hormone response elements, i.e ERE and TRE, respectively) in the regulatory regions of the gene. In vitro studies have suggested that interplay between the two hormones might be due to cross-talk at hormone responsive elements, with the respective hormone receptors and ligands able to interact, although physiological relevance has yet to be proved. We have proposed a simpler mechanism for thyroid hormone effects on estrogen responses via increase in estrogen receptor alpha (ERalpha) with resultant increase in progesterone receptors, prolactin production and tumor growth. A pituitary cell line, GH3, has been widely used to investigate the function of mammo-somatotropic cells, especially regarding regulation of GH and prolactin production. In the present study, an ERE-luc reporter was transfected into GH3 cells and the responses to endogenous ERalpha were examined. We demonstrated that: (1)l -3,5,3'-triiodothyronine (T3) induces mRNA expression of ERalpha; (2) T3 alone is able to induce ERE-luc activity and this is inhibited by OH-tamoxifen; (3) T3 synergistically acts on estradiol (E2)-induced ERE responses; and (4) ERE-luc activity is enchanted by co-transfection of an ERalpha expression vector. These results support the hypothesis that estrogen responses are potentiated by T3 through up-regulation of ERalpha levels.

Animals↗