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PubMed1996

Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain.

Estrogen treatment of ovariectomized rats rapidly increases immunoreactivity for the phosphorylated form of the cAMP response element binding protein (CREB)in neurons of the preoptic area and the bed nucleus of the stria terminalis. These effects were detected within 15 minutes after estrogen exposure. Since the antisera used for these studies detect CREB phosphorylation at ser133, which is important for transcriptional activation these data provide a possible explanation for estrogen's effects on neuronal genes lacking estrogen response elements (EREs) but which contain cAMP response elements (CREs). These data also provide evidence for non-genomic effects of steroid hormones involving protein kinase associated signal transduction pathways traditionally associated with effects at the cell membrane.

Animals↗
PubMed1994

Novel isoforms of human cyclic AMP-responsive element modulator (hCREM) mRNA.

The cyclic AMP-response element (CRE), a transcriptional enhancer, is regulated by CREB (CRE-binding protein) which is the leucine zipper protein phosphorylated by protein kinase A in response to cAMP signal. The highly homologous protein CREM (CRE-modulator) is thought to modulate CREB-stimulated transcription, and is also involved in transcriptional control during spermatogenesis. In this paper, we report two types of cDNAs of human CREM (hCREM), type 1 and type 2; type 1 is a group of human counterparts of the mouse CREM alpha and type 2 is a novel form having a distinct 5' exon which is unrelated to any species of the CREB and CREM isoforms so far described. This unique 5' region of type 2 hCREM may suggest its independent expression from type 1 CREM. The specific 5' region of type 2 hCREM consisted of 88 bp, containing an initiation codon for translation, but no possible phosphorylation site, suggesting different roles from type 1 CREM. Both type 1 and 2 hCREMs are expressed in lymphoid and non-lymphoid cell lines. Their excess expression by transfection induced suppression of cAMP-mediated activation of transcription, suggesting their negative regulation of CRE-mediated transcription.

Activating Transcription Factor 2↗
PubMed2004

p53 Transactivates the phosphatase MKP1 through both intronic and exonic p53 responsive elements.

The tumor suppressor p53 protein can negatively regulate mitogen-activated protein kinase (MAPK) signaling via the induction of MAPK phosphatases. We have recently described that MKP1, a member of the MAPK phosphatase family, is transcriptionally regulated by p53 via a p53 responsive element located in the second intron of the MKP1 gene. Here, we identify an additional p53 responsive element located in the third exon of the MKP1 gene. We demonstrated in reporter gene assays that p53 binds to this exonic element and transactivates MKP1. Furthermore, we showed that this exonic responsive element could be bound by p53 both in vitro and in vivo as demonstrated by gel shift and ChIP assays, respectively. Mutation of either exonic or intronic site resulted in a ~50% decrease in luciferase reporter activity, and loss of both sites completely abrogated p53-dependent transcription of MKP1. These results suggest that each element sufficiently confers p53 responsiveness and that both elements are required for its full activation. Thus, our results provide the mechanism by which p53 controls transcription of the MKP1 gene.

Carcinoma↗
PubMed1993

Human T-cell leukemia virus type 1 Tax activates transcription of the human fra-1 gene through multiple cis elements responsive to transmembrane signals.

We have shown that Tax1 of human T-cell leukemia virus type 1 stimulates the expression of several cellular immediate-early genes (M. Fujii, T. Niki, T. Mori, T. Matsuda, M. Matsui, N. Nomura, and M. Seiki, Oncogene 6:1023-1029, 1991). In this study, the 5'-flanking region of the human fra-1 gene, which is a Tax1-inducible fos-related gene, was isolated and Tax1 or serum-responsive cis elements were analyzed to obtain further insight into the mechanism of Tax1 action. The 62-bp sequence starting 46 nucleotides upstream from the translation initiation site showed 71% homology with the sequence surrounding the TATA box of the c-fos promoter. Regulatory motifs identified in the c-fos promoter, such as an Ets-binding site, E boxes, a CArG box, c-fos AP-1 sites, and two retinoblastoma control elements, were also found upstream of the c-fos homology region. A 502-bp fragment containing these motifs mediated transcriptional activation by Tax1 or by serum in a transient transfection assay. Three independent Tax1-responsive regions (TRRs) were identified, and mutations in each revealed that one of the retinoblastoma control elements in TRR1 and the c-fos AP-1 sites in TRR2 and TRR3 were essential for the activation. Although TRR2 contains a CArG box-like sequence, it was a weak binding site for p67SRF, if it bound at all, and was not required for activation. All three TRRs could also mediate the signals stimulated by serum. Thus, Tax1 appears to activate fra-1 gene expression by means of a part of the cellular machinery similar to that which mediates growth signals.

Base Sequence↗
PubMed1994

Identification of a vitamin D receptor homodimer-type response element in the rat calcitriol 24-hydroxylase gene promoter.

Calcitriol (1,25-dihydroxyvitamin D3, VD) controls multiple aspects of homeostasis, cell growth and differentiation by the action of its nuclear receptor (VDR), which binds to, and activates transcription from, response elements in the promoter region of its target genes. One of these target genes is calcitriol 24-hydroxylase, an enzyme that initiates the degradation of 25-dihydroxyvitamin D3 (calcidiol) and calcitriol. We screened the promoter of rat calcitriol 24-hydroxylase for potential VDR binding sites and identified a functional VD response element, between positions -250 and -233. This response element consists of two directly repeated hexameric core binding motifs spaced by six nucleotides and confers VD-dependent transactivation mediated by VDR homodimers or alternatively by heterodimers formed by VDR and retinoic acid receptor (RAR). Its structure and function are very similar to those of the homodimer-type response element of the human osteocalcin promoter.

Animals↗
PubMed2000

Blockade of cyclic AMP-responsive element DNA binding in the brain of CREB delta/alpha mutant mice.

The cAMP-responsive element binding protein (CREB) gene transcription factor has been implicated in the synaptic plasticity and memory. Here, we investigated the mechanisms of CREB and/or cyclic AMP-responsive element modulatory protein (CREM) binding to CRE sites in brain tissues. CRE-DNA binding was determined in nuclear extracts obtained from the several brain structures of wild-type and CREB delta/alpha mutant mice. It was found that antibodies to CREB, phosphorylated CREB, and CREM supershifted the CRE-DNA binding complex in cortical nuclear extracts from wild-type mice, which suggests that the CRE-DNA binding complex contains both CREB and CREM proteins. In contrast, CRE-DNA binding is abolished in the cortex, hippocampus, cerebellum, and amygdala of CREB delta/alpha mutant mice. Because the CREB delta and alpha isoforms have been deleted in CREB mutant mice, consequently, other forms of CREB, such as CREB-beta and CREM, are up-regulated. These results suggest that the binding of CREM to CRE sites requires the presence of CREB delta/alpha, and that CREB-beta may be inefficient in binding to CRE-sites. Thus, these results indicate that CREB delta/alpha mutant mice are a useful animal model for studying the functional role of CREB-dependent gene expression.

Animals↗
PubMed1995

The cAMP response element binding protein synergizes with other transcription factors to mediate cAMP responsiveness.

The cAMP responsiveness of the promoter for phosphoenolpyruvate carboxykinase (EC 4.1.1.32) is mediated by a synergistic interaction between a complex regulatory region, which binds liver-enriched transcription factors, and a typical cAMP response element (CRE). Although a role for the CRE-binding protein (CREB) in the cAMP-responsiveness of this promoter has been generally assumed, some uncertainty remains due to the observations that several C/EBP-related proteins bind with near equal affinity, relative to CREB, to this particular CRE. Thus, a detailed analysis of the involvement of CREB in this synergism was undertaken in HepG2 cells. Gel mobility shift assays demonstrate that a CRE probe is bound by CREB present in HepG2 cells. Furthermore, we show that a dominant repressor of CREB is able to significantly reduce the cAMP responsiveness of the PEPCK promoter in HepG2 cells. Finally, we demonstrate using a GAL4-CREB fusion protein that CREB is able to synergize with the liver-enriched factors bound upstream on the PEPCK promoter to mediate a liver-specific response to cAMP. Examination of several mutant forms of CREB allow us to conclude that the "synergy" domain of CREB resides within amino acid residues 83-203, and that residues 83-145 can mediate a partial synergistic response. This study establishes that CREB is able to synergize with liver-enriched transcription factors to mediate a tissue-specific response to cAMP.

Amino Acid Sequence↗
PubMedDate not supplied

Oestrogen and glucocorticoid responsive elements are closely related but distinct.

DNA sequences recognized by the glucocorticoid receptor are termed glucocorticoid-responsive elements because of their stimulatory effect on transcription. An oligonucleotide of 15 base pairs having partial or perfect symmetry is necessary for glucocorticoid induction and this same oligonucleotide is surprisingly also recognized by the progesterone receptor. Here we define a palindromic sequence of 15 base pairs, modelled after a sequence element shared by the vitellogenin genes of frog and chicken, which confers oestrogen inducibility on a heterologous promoter and can be converted into a glucocorticoid-responsive element by substitution of one or two bases at homologous positions in the palindrome. Considered with the observation that the DNA-binding domains of steroid receptors are closely related, this finding demonstrates that the steroid-responsive elements constitute a family of related DNA sequences.

Base Sequence↗
PubMed1991

Functional interaction of hybrid response elements with wild-type and mutant steroid hormone receptors.

Steroid hormone receptors can be divided into two subfamilies according to the structure of their DNA binding domains and the nucleotide sequences which they recognize. The glucocorticoid receptor and the progesterone receptor (PR) recognize an imperfect palindrome (glucocorticoid responsive element/progesterone responsive element [GRE/PRE]) with the conserved half-sequence TGTYCY, whereas the estrogen receptor (ER) recognizes a palindrome (estrogen responsive element) with the half-sequence TGACC. A series of symmetric and asymmetric variants of these hormone responsive elements (HREs) have been tested for receptor binding and for the ability to mediate induction in vivo. High-resolution analysis demonstrates that the overall number and distribution of contacts with the N-7 position of guanines and with the phosphate backbone of various HREs are quite similar for PR and ER. However, PR and glucocorticoid receptor, but not ER, are able to contact the 5'-methyl group of thymines found in position 3 of HREs, as shown by potassium permanganate interference. The ER mutant HE84, which contains a single amino acid exchange, Glu-203 to Gly, in the knuckle of ER, creates a promiscuous ER that is able to bind to GRE/PREs by contacting this thymine. Elements with the sequence GGTCAcagTGTYCT that represent hybrids between an estrogen response element and a GRE/PRE respond to estrogens, glucocorticoids, and progestins in vivo and bind all three wild-type receptors in vitro. These hybrid HREs could serve to confer promiscuous gene regulation.

Animals↗
PubMed1991

Glucocorticoid- and estrogen-responsive elements in the 5'-flanking region of the rat angiotensinogen gene.

We investigated the 5'-flanking region of the rat angiotensinogen gene to define the DNA elements conferring inducibility by glucocorticoids and estrogens. Two putative glucocorticoid-responsive elements (GREs) based on sequence comparison were identified. Here we report the functional importance of these sequences. We constructed several deletion mutants of the 5'-region in front of the bacterial reporter gene for chloramphenicol acetyltransferase (CAT). The angiotensinogen-CAT-reporter plasmids (pRagCAT) were transiently transfected into the rat hepatoma cells FTO 2B and Fe 33. All pRagCAT constructs in which the 5'-region contained at least one of the two GRE consensus sequences were stimulated by dexamethasone. On the other hand, deletion mutants containing no GRE sequences were not inducible with dexamethasone. In additional experiments, the transcriptional functions of the two putative GREs were assessed by cloning synthetic oligonucleotides encompassing the GRE sequences directly in front of the heterologous herpes simplex virus thymidine-kinase promoter. Our results showed that each synthetic GRE was capable of stimulating the heterologous TK promoter after administration of dexamethasone and that both GREs together act synergistically. We also investigated the transcriptional control of angiotensinogen by estrogen. Although no estrogen-responsive element consensus sequences were detectable by sequence comparison, we did identify sequences between -60 to -92 which conferred estrogen inducibility to the rat angiotensinogen gene. In this region, a so-called half-palindromic estrogen-responsive element is localized at nucleotides -87 to -91.

Amino Acid Sequence↗
PubMed1990

Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene.

A sequence that confers transcriptional responsiveness to retinoic acid was identified in the promoter of the mouse retinoic acid receptor (RAR) beta gene. This response element consists of a direct repeat of the sequence GTTCAC, separated by five nucleotides. Direct binding of the RAR to this sequence was demonstrated by gel retardation and immunoprecipitation assays. This element conferred retinoic acid responsiveness on heterologous promoters via all three subtypes of RAR yet failed to support transcriptional activation by the thyroid hormone, estrogen, glucocorticoid, or vitamin D receptors. Surprisingly, a high level of retinoic acid-dependent activation was seen in the absence of transfected RAR in 10 of 10 vertebrate cell lines, many functionally characterized previously as lacking endogenous receptor. This demonstrates an unusually high sensitivity of the retinoic acid response element to low levels of receptor and suggests expression of RAR in a wide variety of tissue types.

Amino Acid Sequence↗
PubMed1991

Molecular cloning and characterization of interferon alpha/beta response element binding factors of the murine (2'-5')oligoadenylate synthetase ME-12 gene.

Seven clones encoding interferon response element binding factors have been isolated from a mouse fibroblast lambda gt11 cDNA library by using a 32P end-labeled tandem trimer of the mouse (2'-5')oligoadenylate synthetase gene interferon response element as a probe. Clone 16 shares strong similarity (95%) at both DNA and amino acid level with YB-1, a human major histocompatibility complex class II Y-box DNA-binding protein, and with dbpB, a human epidermal growth factor receptor gene enhancer region binding protein. The product of the gene represented by clone 16 may represent a factor that regulates multiple genes by binding to a variety of 5' regulatory elements. Clone 25 is a 2407-base-pair-long cDNA and contains a putative 311-amino acid open reading frame corresponding to an estimated mass of 35.5 kDa. This putative protein, designated as interferon response element binding factor 1 (IREBF-1), contains an acidic domain, three heptad repeat leucine arrays, and a region that shares similarity with the yeast transcriptional factor GAL4 DNA-binding domain. Furthermore, the C terminus of IREBF-1 shows an unusual amphipathic property: within a 79-amino acid range, one side of the alpha-helical region contains a preponderance of hydrophobic amino acids and the other side contains hydrophilic amino acids. This type of structure provides a strong hydrophobic force for protein-protein interaction.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Fibrates increase human REV-ERBalpha expression in liver via a novel peroxisome proliferator-activated receptor response element.

Fibrates are widely used hypolipidemic drugs that act by modulating the expression of genes involved in lipid and lipoprotein metabolism. Whereas the activation of gene transcription by fibrates occurs via the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) interacting with response elements consisting of a direct repeat of the AGGTCA motif spaced by one nucleotide (DR1), the mechanisms of negative gene regulation by fibrates and PPARalpha are largely unknown. In the present study, we demonstrate that fibrates induce the expression of the nuclear receptor Rev-erbalpha, a negative regulator of gene transcription. Fibrates increase Rev-erbalpha mRNA levels both in primary human hepatocytes and in HepG2 hepatoblastoma cells. In HepG2 cells, fibrates furthermore induce Rev-erbalpha protein synthesis rates. Transfection studies with reporter constructs driven by the human Rev-erbalpha promoter revealed that fibrates induce Rev-erbalpha expression at the transcriptional level via PPARalpha. Site-directed mutagenesis experiments identified a PPAR response element that coincides with the previously identified Rev-erbalpha negative autoregulatory Rev-DR2 element. Electromobility shift assay experiments indicated that PPARalpha binds as heterodimer with 9-cis-retinoic acid receptor to a subset of DR2 elements 5' flanked by an A/T-rich sequence such as in the Rev-DR2. PPARalpha and Rev-erbalpha bind with similar affinities to the Rev-DR2 site. In conclusion, these data demonstrate human Rev-erbalpha as a PPARalpha target gene and identify a subset of DR2 sites as novel PPARalpha response elements. Finally, the PPARalpha and Rev-erbalpha signaling pathways cross-talk through competition for binding to those response elements.

Binding Sites↗
PubMed1998

Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2.

The interleukin-2 CD28 response element (CD28RE) acts as a composite enhancer, in conjunction with a 3'-12-O-tetradecanoylphorbol-13-acetate response element (TRE)-like element, to confer CD28 receptor-dependent inducibility to the interleukin-2 promoter in T-cells. When inserted as a single copy upstream of a basal promoter, this composite enhancer, termed the CD28RE-TRE, is both highly active and CD28-inducible in transactivation assays. A multicomponent nuclear protein complex that binds the CD28RE-TRE was isolated by DNA affinity chromatography from nuclear extracts of mitogen- and CD28 receptor-costimulated human T-cells. Immunological and biochemical analyses of this complex reveal the presence of c-Rel, ATF-1, and CREB2 as major DNA-binding components. Coexpression of c-Rel in combination with ATF-1, CREB2, or ATF-1/CREB2 leads to synergistic transactivation of a CD28RE-TRE reporter plasmid in quiescent Jurkat T-cells. Furthermore, CD28-dependent transactivation of the CD28RE-TRE is specifically inhibited by cAMP response element-binding protein (CREB) dominant-negative expression vectors. Moreover, mutant promoter constructs in which the internal 5'-CD28RE and 3'-TRE-like sequences have been topologically positioned 180 degrees out of phase with one another show loss of mitogen- and CD28-dependent inducibility. Finally, the addition of the CREB-binding transcriptional coactivator p300 leads to a dramatic CREB-dependent increase in both mitogen- and CD28-mediated transactivation of the CD28RE-TRE. These findings demonstrate that full physiological responsiveness to CD28 receptor stimulation in T-cells is dependent on topologically linked sequences within the CD28RE-TRE composite enhancer and provide strong support of a direct role for the CREB family of transcription factors and p300/CREB-binding protein coactivator proteins in cytokine gene induction during T-cell activation.

Activating Transcription Factor 1↗
PubMed1998

Drosophila ferritin mRNA: alternative RNA splicing regulates the presence of the iron-responsive element.

Several mRNAs encoding the same ferritin subunit of Drosophila melanogaster were identified. Alternative RNA splicing and utilisation of different polyadenylation sites were found to generate the transcripts. The alternative RNA splicing results in ferritin transcripts with four unique 5' untranslated regions. Only one of them contains an iron-responsive element. The iron-responsive element was found to bind in vitro specifically to human recombinant iron regulatory protein 1. Furthermore, the ferritin subunit mRNAs are differentially expressed during development. Our data provides the first molecular evidence that the presence of iron-responsive element in a ferritin mRNA is regulated by alternative RNA splicing.

Alternative Splicing↗
PubMed2000

Identification of an involucrin promoter transcriptional response element with activity restricted to keratinocytes.

The involucrin proximal promoter was examined for response elements that confer cell-type specificity. Using a segment spanning positions -157 to +41, three possible response elements were identified by their protein-binding activity using DNase I footprinting. From distal to proximal, they were: an activator protein-1 (AP-1) site (previously identified) overlapping an Ets-like site; a second Ets-like site located 13 bp more proximally; and an extended region designated footprinted site A (FPA). Mutation of the distal Ets-like site had essentially no effect on the transcriptional activity in transfections, while mutation of the proximal site reduced the activity by half. FPA was shown by electrophoretic mobility-shift assay (EMSA) to be comprised of two separable binding sites, FPA1 (distal) and FPA2 (proximal). While mutation of FPA2 had only a modest effect on transcriptional activity in transient transfections, mutation of FPA1 reduced transcriptional activity to approx. 20% of that obtained with the intact promoter. Additional mutations of FPA1 indicated that the active region comprises positions -85 to -73 (GTGGTGAAACCTGT). The molecular masses of the major proteins binding to this site were shown by UV cross-linking to be approx. 40 and 50 kDa, while minor bands were observed at 80 and 110 kDa. Since the involucrin promoter exhibits much higher transcriptional activity in keratinocytes than in other cell types in transfection assays (indicating that cell type specificity of expression is retained), the comparative influence of FPA1 was examined. While mutation of the AP-1 site affected transcriptional activity similarly in all cell lines tested, mutation of FPA1 decreased activity substantially in keratinocytes, but not in NIH-3T3 and HeLa cells, evidence for a contribution to cell-type specificity of expression. Furthermore, a correlation between the sensitivity to FPA1 mutation and amount of involucrin expression in different keratinocyte cell lines was evident. EMSA showed that NIH-3T3 and HeLa cells lacked the same FPA1 DNA-protein complex as keratinocytes. However, the amount of complex formed with nuclear extracts from several keratinocyte lines did not correlate well with the level of involucrin expression. Other factors, such as differences in post-translational modification or co-activators, must account for varied transcriptional response mediated by this site among keratinocyte lines.

3T3 Cells↗
PubMed1992

A negative retinoic acid response element in the rat oxytocin promoter restricts transcriptional stimulation by heterologous transactivation domains.

Retinoic acid receptors are ligand-dependent transcription factors that stimulate gene transcription from promoters containing retinoic acid or thyroid hormone response elements. We describe a high-affinity binding site from the rat oxytocin promoter that mediates negative transcriptional regulation by the retinoic acid receptor. To examine whether strong, constitutive transactivation domains would be capable of stimulating gene transcription when bound to this DNA binding site that normally mediates transcriptional repression, we fused the transactivation domain of the herpes simplex viral protein VP16 to the amino terminus of the retinoic acid receptor and tested the activity of the chimeric protein on the negative retinoic acid response element. This chimeric retinoic acid receptor acted as a strong, constitutive transactivator when bound to promoters containing palindromic thyroid hormone/retinoic acid response elements but surprisingly it still repressed gene transcription when bound to promoters containing the oxytocin-negative retinoic acid response element. These results suggest that a negative DNA binding site itself can inhibit the function of even potent constitutive transactivation domains, and provide evidence that tethering of a constitutive transactivation domain to DNA is insufficient to activate gene transcription.

Animals↗
PubMed1996

Identification of natural monomeric response elements of the nuclear receptor RZR/ROR. They also bind COUP-TF homodimers.

The receptor RZR/ROR is an important member of the nuclear receptor superfamily and has recently been shown to be the nuclear receptor for the pineal gland hormone melatonin. RZR/ROR binds as a monomer to DNA, and the human 5-lipoxygenase gene has been identified as the first RZR/ROR/melatonin-responding gene. Another prominent nuclear receptor is COUP-TF, which binds as a dimer to DNA. In this study, the sequences of known promoter regions of genes that may be involved in the physiological action of melatonin have been screened for putative monomeric RZR/ROR response elements. The binding of RZR/ROR and COUP-TF was compared and quantified on a set of 12 putative response elements. Interestingly, COUP-TF homodimers were found to bind with high affinity to some of the monomeric RZR/ROR response elements. Four RZR/ROR response elements, found in the genes of the mouse bifunctional enzyme, the rat bone sialoprotein, mouse Purkinje cell protein 2, and human p21(WAF1/CIP1), were shown to be inducible by melatonin under conditions of low constitutive activity. Surprisingly, the constitutive activity of COUP-TF was also stimulated by an unknown serum compound. The novel Purkinje cell protein 2 and p21(WAF1/CIP1) RZR/ROR/melatonin-responding genes may be the key for understanding the role of RZR/RORalpha in the mouse mutation staggerer and the antiproliferative action of melatonin, respectively.

3-Hydroxyacyl CoA Dehydrogenases↗