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PubMed1998

Identification and expression of a novel isoform of cAMP response element modulator in the human heart.

In end-stage human heart failure, excessive beta-adrenergic stimulation of the cAMP-dependent signaling pathway due to enhanced endogenous catecholamines is hypothesized to contribute to expressional alterations of myocardial regulatory proteins. The cAMP response element modulator (CREM) regulates the transcription of cAMP-responsive genes and might be involved in the regulation of cardiac gene expression. Using the reverse transcription polymerase chain reaction, we identified a novel CREM mRNA, CREM-Ib deltaC-X, in the human heart. Overexpression of CREM-Ib deltaC-X decreased cAMP response element (CRE) -mediated gene transcription in HIT-T15 cells, and this activity was assigned to the part of the sequence encoding putative internally translated proteins. Two of three possible internally translated proteins were immunologically identified in cells overexpressing CREM-Ib deltaC-X tagged with the hemagglutinin epitope of the influenza virus. Both proteins were expressed in bacteria and showed CRE-specific DNA binding, formation of heterodimers with the cAMP response element binding protein (CREB), and inhibition of CREB's binding to the CRE. CREM expression was detected on the mRNA and protein levels in the human heart. We conclude that CREM-Ib deltaC-X generates internally translated repressors of CRE-mediated gene transcription, suggesting the first example for the existence and function of human cardiac CREM.

Animals↗
PubMed1999

Cas mediates transcriptional activation of the serum response element by Src.

The Src substrate p130(Cas) is a docking protein containing an SH3 domain, a substrate domain that contains multiple consensus SH2 binding sites, and a Src binding region. We have examined the possibility that Cas plays a role in the transcriptional activation of immediate early genes (IEGs) by v-Src. Transcriptional activation of IEGs by v-Src occurs through distinct transcriptional control elements such as the serum response element (SRE). An SRE transcriptional reporter was used to study the ability of Cas to mediate Src-induced SRE activation. Coexpression of v-Src and Cas led to a threefold increase in SRE-dependent transcription over the level induced by v-Src alone. Cas-dependent activation of the SRE was dependent on the kinase activity of v-Src and the Src binding region of Cas. Signaling to the SRE is promoted by a serine-rich region within Cas and inhibited by the Cas SH3 domain. Cas-dependent SRE activation was accompanied by an increase in the level of active Ras and in the activity of the mitogen-activated protein kinase (MAPK) Erk2; these changes were blocked by coexpression of dominant-negative mutants of the adapter protein Grb2. SRE activation was abrogated by coexpression of dominant-negative mutants of Ras, MAPK kinase (Mek1), and Grb2. Coexpression of Cas with v-Src enhanced the association of Grb2 with the adapter protein Shc and the protein tyrosine phosphatase Shp-2; coexpression of Shc or Shp-2 mutants significantly reduced SRE activation by Cas and v-Src. Cas-induced Grb2 association with Shp-2 and Shc may account for the Cas-dependent activation of the Ras/Mek/Erk pathway and SRE-dependent transcription. 14-3-3 proteins may also play a role in Cas-mediated signaling to the SRE. Overexpression of Cas was found to modestly enhance epidermal growth factor (EGF)-induced activation of the SRE. A Cas mutant lacking the Src binding region did not potentiate the EGF response, suggesting that Cas enhances EGF signaling by binding to endogenous cellular Src or another Src family member. These observations implicate Cas as a mediator of Src-induced transcriptional activation.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Regulation of human C-reactive protein gene expression by two synergistic IL-6 responsive elements.

To study the mechanism of interleukin-6 (IL-6) induction of human C-reactive protein (CRP) gene expression, we have utilized a human hepatoma (PLC/PRF/5) cell culture system to analyze the trans-acting factors which bind to the 300 bp 5'-flanking region of human CRP gene. In vitro gel mobility shift analyses and methylation interference assays demonstrated that NFIL-6 alpha interacted with two IL-6 responsive elements, and HNF-1 alpha and HNF-3/Octamer-like factors interacted with the downstream IL-6 responsive element in the human CRP promoter. In vivo functional analysis by transient transfection of plasmid constructs containing site-specific mutations in one or two IL-6 responsive elements in the CRP promoter fused to a reporter gene, chloramphenicol acetyl transferase (CAT), demonstrated that the binding of NFIL-6 alpha to two IL-6 responsive elements resulted in synergistic induction of the gene. When HNF-1 alpha or HNF-3/Octamer-like factors were independently bound to their corresponding sites, they had either a positive or negative effect, respectively, on IL-6 inducible transcriptional activity.

Base Sequence↗
PubMed2004

Retinoids increase alpha-1 acid glycoprotein expression at the transcriptional level through two distinct DR1 retinoic acid responsive elements.

In the present study, we analyzed the influence of retinoic acids on the expression of alpha-1 acid glycoprotein (AGP). We show that in rat primary hepatocytes, 9-cis retinoic acid and all-trans retinoic acid increase AGP gene expression at the transcriptional level. Transient transfections of rat primary hepatocytes with a reporter construct driven by the rat AGP gene promoter indicated that retinoids regulate AGP gene expression via the -763/-138 region of the AGP promoter. Furthermore, cotransfection experiments with retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha) expression vectors in NIH3T3 cells demonstrated that both RXRalpha/RXRalpha homodimer and RXRalpha/RARalpha heterodimer are competent for ligand-induced transactivation of the AGP promoter. Unilateral deletion and site-directed mutagenesis identified two retinoic-acid responsive elements (RARE), RARE-I and RARE-II, which interestingly correspond to a direct repeat of two TGACCT-related hexanucleotides separated by a single bp only (DR1-type response element). Cotransfection assays showed that RXRalpha and RARalpha activate AGP gene transcription through these two elements either as a homodimer (RXRalpha/RXRalpha) or as a heterodimer (RXRalpha/RARalpha). The RXRalpha/RXRalpha homodimer acts most efficiently through the RARE-I response element to promote AGP transactivation, whereas the RXRalpha/RARalpha heterodimer mediates transactivation better via the RARE-II responsive element.

Alitretinoin↗
PubMed1997

DNA sequences downstream from the vitamin D response element of the rat osteocalcin gene are required for ligand-dependent transactivation.

The sequences in the rat osteocalcin gene that lie 3' to the vitamin D response element (VDRE) have been shown to augment transcriptional activation by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. These DNA sequences, however, are unable to bind the VDR or mediate 1,25-(OH)2D3 responsiveness independently of the VDRE. To further characterize this region, the functional properties of a series of mutant oligonucleotides were examined in transiently transfected ROS 17/2.8 cells. When these mutant oligonucleotides were expressed upstream of the heterologous herpes simplex virus thymidine kinase promoter, the bases between -420 and -414 of the rat osteocalcin gene were identified as critical for maximal transactivation by 1,25-(OH)2D3. Furthermore, mutation of these sequences in the context of the native osteocalcin promoter and enhancer totally abolished the ability of the VDRE to mediate 1,25-(OH)2D3 responsiveness. These bases, which are essential for the 1,25-(OH)2D3 responsiveness of the rat osteocalcin gene, are also present in a similar position, relative to the VDRE, in the human osteocalcin gene. To explore whether these sequences could enhance transactivation by other inducible transcription factors, they were examined for their ability to synergize with the chick vitellogenin estrogen response element and the rat somatostatin cAMP response element. When placed upstream to the herpes simplex virus thymidine kinase promoter and transfected into ROS 17/2.8 cells, these sequences were able to enhance transcriptional responsiveness to 17beta-estradiol and forskolin, respectively, demonstrating that they also contribute to transactivation by other inducible transcription factors.

Animals↗
PubMed2000

Individual metal responsive elements of the human metallothionein-IIA gene independently mediate responses to various heavy metal signals.

Metallothioneins (MTs) are small metal-binding proteins that have a role in the defense against heavy metals. Mammalian MT genes are transcriptionally activated by metals such as Cd and Zn through multiple copies of the metal responsive element (MRE) present in the 5'-flanking region. To examine whether each MRE in a single promoter has a distinct role, we characterized seven MREs located upstream of the human MT-IIA gene. By transient transfection experiments using MRE-driven reporter gene constructs, individual MREs were assayed for the activity to mediate transcription in response to several heavy metal species. Four MREs including MREs a, b, e and g independently mediated reporter gene expression in response to Zn, Cd and Hg, while other MREs were not responsive to any of these metals. These results suggest that the multiplicity of MRE contributes to enhancing its activity, rather than providing functional diversity.

DNA-Binding Proteins↗
PubMed2000

Regulation of endothelin-1 gene expression in human microvascular endothelial cells by hypoxia and cobalt: role of hypoxia responsive element.

Endothelin-1 (Et-1) is a vasoconstrictor peptide that plays an important role in the pathophysiology of hypertension, myocardial ischemia, and other diseases. We examined the mechanism of regulation the Et-1 mRNA expression in human microvascular endothelial cells (HMEC-1) in response to hypoxia and cobalt. To determine whether the 5'-flanking region of Et-1 gene mediate transcriptional responses to cellular hypoxia, we constructed reporter plasmids in which Et-1 5'-flanking sequences of Et-1 gene were fused to luciferase coding sequences. Constructs, which contain native Et-1 sequence 5'-AACGTGCA-3', located between -118 and -125 in the opposite orientation as the transcriptional unit, mediate transcriptional response to hypoxia and cobalt. This responsiveness was inhibited by genistein, a tyrosine kinase selective inhibitor. Both hypoxia and cobalt induced binding of HIF-1 (hypoxia inducible-1 factor) to this Et-1 hypoxia responsive element in gel shift assays. Mutation in this sequence eliminated both the hypoxia-induced HIF-1 binding and luciferase expression. Using the supershift assay we have shown that this hypoxia responsive element binds HIF-1alpha and HIF-1beta proteins. Interestingly, genistein only slightly affected HIF-1 binding. These results indicate that the Et-1 gene contains HIF-1 binding hypoxia responsive elements which mediate transcriptional responses to hypoxia and cobalt in microvascular endothelial cells. Genistein appears to inhibit this response by affecting the transcriptional activity of the HIF-1 complex, without significantly affecting its DNA-binding properties.

Cell Hypoxia↗
PubMed2000

Nuclear factor-kappaB and cAMP response element binding protein mediate opposite transcriptional effects on the Flk-1/KDR gene promoter.

-The vascular endothelial growth factor receptor Flk-1/KDR is highly expressed during development and almost disappears in adult tissues. Despite its biological relevance, little is known about the molecular mechanisms controlling its expression. In the present work, it is shown that cAMP response element binding protein (CREB) and nuclear factor-kappaB (NF-kappaB)-related antigens bind specific sequences in the Flk-1/KDR promoter. Functional studies demonstrate that cAMP represses whereas tumor necrosis factor-alpha, an activator of NF-kappaB, stimulates promoter activity. Histone acetyltransferases (HATs) P/CAF and CBP/p300 together with p65/RelA, the catalytic subunit of NF-kappaB, increase Flk-1/KDR promoter activity 10- to 20-fold. Consistently, inhibition by cAMP is reverted by increasing intracellular HATs and is completely abolished by site-specific mutagenesis of the cAMP response element. In contrast, specific mutations in the NF-kappaB response element abolish responsiveness to p65/RelA and HATs without affecting cAMP-dependent repression. These results suggest that opposing signaling pathways, activating NF-kappaB or CREB and requiring HAT molecules, control Flk-1/KDR promoter activity.

Acetyltransferases↗
PubMed1999

A novel positive regulatory element that enhances hamster CYP2A8 gene expression mediated by xenobiotic responsive element.

CYP2A8 is a major form of cytochrome P-450 inducible by 3-methylcholanthrene in Syrian hamster liver. To identify DNA elements necessary for the transcriptional activation of the CYP2A8 gene, we analyzed the regulatory region of the CYP2A8 gene and conducted transient transfection experiments of CYP2A8-luciferase fusion plasmids in primary cultures of hamster hepatocytes. We analyzed up to -5 kb of the 5'-flanking region and found the region sufficient for the 3-methylcholanthrene-inducible gene expression. This region contained a consensus sequence for xenobiotic responsive element (XRE) between -2366 and -2349, which was shown to be essential for induction of the gene expression. Furthermore, we found a novel positive regulatory element for XRE-mediated gene expression (PREX) located upstream of the XRE. This element is not identified in any genes inducible by 3-methylcholanthrene so far reported. Without PREX, the XRE-mediated promoter activity was enhanced nearly 10-fold, whereas with PREX, the activity was enhanced 20-fold over the basal level. Gel mobility shift assays revealed specific binding of nuclear proteins to PREX. Mutations and deletions of PREX caused a loss of the binding and promoter-enhancing activities, respectively. Moreover, transient expression experiments showed that the enhancing activity of PREX was not observed in Drosophila Schneider's line 2 cells, which were shown to lack the PREX binding proteins.

Animals↗
PubMed1995

Retinoid-X receptor (RXR) differentially augments thyroid hormone response in cell lines as a function of the response element and endogenous RXR content.

Retinoid-X receptor (RXR) forms heterodimers with thyroid hormone receptor (TR) and significantly enhances binding to thyroid hormone response elements (TREs). Expression of RXR in a transient transfection assay augments the T3 response, but the influences of the specific cell line and TRE used have not been systematically studied. We determined RXR alpha and -beta augmentation of the TR alpha-mediated T3 response in transient transfection assays of COS, JEG, and mouse embryonic stem (ES) cell lines for a series of eight wild-type thyroid hormone (T3) and retinoic acid response elements (previously shown to bind TR). RXR augmented T3-induced expression in COS and ES cells (1.5- to 4-fold greater expression with added RXR compared to TR alone), but had minimal effect on augmentation of response in JEG cells. For most elements studied there was a proportional augmentation of basal and T3-stimulated expression. TREs from rat GH and laminin-B1, however, had relatively higher levels of T3-induced expression as a result of RXR cotransfection (T3 induction ratios increased 2-fold or greater). Previous characterization of these elements demonstrates that they contain more than two hexameric binding domains, all of which can simultaneously bind TR. The influence of endogenous RXR expression in a cell line on RXR augmentation of the T3 response was determined. RXR alpha and -beta messenger RNA (mRNA) expression was quantitated by Northern blot in each cell line. COS and JEG cells expressed almost exclusively RXR alpha mRNA, although expression was almost 2-fold higher in JEG compared to COS cells (12 +/- 2.5 vs. 6.8 +/- 0.5 density units relative to actin; mean +/- SE; P < 0.05). ES cells expressed only RXR beta mRNA, but at a very low level (0.4 +/- 0.1). Nuclear extracts prepared from JEG and COS cells augmented TR binding proportional to the endogenous RXR mRNA expression, and the heterodimer band was supershifted by the addition of antibody to RXR alpha. Nuclear extracts from ES cells had no detectable TR heterodimer binding to a range of response elements. RXR augmentation of the T3 response differs among cell lines and is greater in those with reduced endogenous RXR. Furthermore, the functional augmentation of the T3 response ratio by RXR is likely to require additional sequences contained in only a subset of elements in which RXR augments TR binding.

Animals↗
PubMed2002

Signaling cross-talk between hypoxia and glucose via hypoxia-inducible factor 1 and glucose response elements.

The substrates oxygen and glucose are important for the appropriate regulation of metabolism, angiogenesis, tumorigenesis and embryonic development. The knowledge about an interaction between these two signals is limited. We demonstrated that the regulation of glucagon receptor, insulin receptor and L-type pyruvate kinase (L-PK) gene expression in liver is dependent upon a cross-talk between oxygen and glucose. The periportal to perivenous drop in O2 tension was proposed to be an endocrine key regulator for the zonated gene expression in liver. In primary rat hepatocyte cultures, the expression of the glucagon receptor and the L-PK mRNA was maximally induced by glucose under arterial pO2 whereas the insulin receptor was maximally induced under perivenous pO2. It was demonstrated for the L-PK gene that the modulation by O2 of the glucose-dependent induction occured at the glucose-responsive element (Glc(PK)RE) in the L-PK gene promoter. The reduction of the glucose-dependent induction of the L-PK gene expression under venous pO2 appeared to be mediated via an interference between hypoxia-inducible factor 1 (HIF-1) and the glucose-responsive transcription factors at the Glc(PK)RE. The glucose response element (GlcRE) also functioned as a hypoxia response element and, vice versa, a hypoxia-responsive element was functioning as a GlcRE. Thus, our findings implicate that the cross-talk between oxygen and glucose might have a fundamental role in the regulation of several physiological and pathophysiological processes.

Animals↗
PubMed1999

Identification of a hypoxia response element in the transferrin receptor gene.

Expression of the transferrin receptor, which mediates iron uptake from transferrin, is negatively regulated post-transcriptionally by intracellular iron through iron-responsive elements in the 3'-untranslated region of the transferrin receptor mRNA. Transcriptional mechanisms are also involved in receptor expression, but these are poorly understood. In this study we have characterized the transferrin receptor promoter region and identified a functional hypoxia response element that contains a binding site for hypoxia-inducible factor-1 (HIF-1). Exposure of K562 and HeLa cells to hypoxia for 16 h resulted in a 2- to 3-fold increase in transferrin receptor mRNA expression. A motif with multipartite organization similar to the hypoxia response element of a number of hypoxia-inducible genes such as erythropoietin was identified within a 100-base pair sequence upstream of the transcriptional start site. Mutation of a site similar to the consensus HIF-binding site (HBS) in this motif attenuated the hypoxic response by 80%. Transient co-expression of the two HIF-1 subunits (HIF-1alpha and HIF-1beta) enhanced the wild type transferrin receptor promoter activity, but that which contained a mutated HBS yielded no such response. Electrophoretic mobility shift assays revealed that HIF-1 was stimulated and bound to the transferrin receptor HBS upon hypoxic challenge. Our results indicate that the transferrin receptor is a target gene for HIF-1.

Base Sequence↗
PubMed1995

Accessibility of a glucocorticoid response element in a nucleosome depends on its rotational positioning.

Gene expression requires binding of transcription factors to their cognate DNA response elements, the latter being often integrated into sequence-specifically positioned nucleosomes. To investigate the constraints imposed on factor-DNA recognition by the nucleosomal organization, we studied the binding of glucocorticoid receptor to a single glucocorticoid response element (GRE) displaying four different rotational frames in three different translational positions in reconstituted nucleosomes. We demonstrate that rotational setting of the GRE per se is important for its accessibility. Furthermore, the effects of rotational positioning of the GRE are different for different translational positions of the GRE in the nucleosome. A GRE placed near the nucleosomal dyad is totally blocked by rotating it 180 degrees so that the major groove of the GRE faces the histone octamer. If, on the other hand, the GRE is placed about 40 bp from the nucleosome dyad, then the 180 degrees rotation of the GRE still allows glucocorticoid receptor binding, albeit with a sixfold lower affinity than the peripherally oriented GRE. This suggests that both the rotational positioning and the translational positioning function as a framework for transcription factor response elements in gene regulation.

Base Sequence↗
PubMed1995

A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter.

Picolinic acid, a catabolite of L-tryptophan, activates the transcription of the inducible nitric oxide synthase gene (iNOS) in IFN-gamma-treated murine macrophages. We performed functional studies on the 5' flanking region of the iNOS gene linked to a CAT reporter gene to identify the cis-acting element(s) responsible for the activation of iNOS transcription by picolinic acid. Transient transfection assays showed that the full-length iNOS promoter in the murine macrophage cell line ANA-1 was activated by the synergistic interaction between IFN-gamma and picolinic acid. Deletion or mutation of the iNOS promoter region from -227 to -209, containing a sequence homology to a hypoxia-responsive enhancer (iNOS-HRE), decreased picolinic acid- but not LPS-induced CAT activity by more than 70%. Functional studies using a tk promoter-CAT reporter gene plasmid demonstrated that the iNOS-HRE was sufficient to confer inducibility by picolinic acid but not by IFN-gamma or LPS. Electrophoretic mobility shift assays confirmed that picolinic acid alone induced a specific binding activity to the iNOS-HRE. Furthermore, we found that the iNOS-HRE activity was inducible by hypoxia and that hypoxia in combination with IFN-gamma activated the iNOS promoter in transient transfection assays and induced iNOS transcription and mRNA expression. These data establish that the iNOS-HRE is a novel regulatory element of the iNOS promoter activity in murine macrophages and provide the first evidence that iNOS is a hypoxia-inducible gene.

Animals↗
PubMed2000

Cooperative mechanism of transcriptional activation by a cyclic AMP-response element modulator alpha mutant containing a motif for constitutive binding to CREB-binding protein.

Cyclic AMP-response element modulator alpha (CREMalpha) is a transcription factor that is highly related to cAMP-response element-binding protein (CREB) but represses cAMP-induced gene expression from simple artificial promoters containing a cAMP-response element (CRE). CREMalpha lacks two glutamine-rich Q regions that, in CREB, are thought to be necessary for transcriptional activation. Nevertheless, protein kinase A stimulation induces CREMalpha to activate the complex native promoter in the phosphoenolpyruvate carboxykinase (PEPCK) gene. To study this phenomenon in the absence of protein kinase A stimulation, we introduced a mutation into CREMalpha to allow constitutive binding to the coactivator CREB-binding protein. This mutant, CREMalpha(DIEDML), constitutively activated the PEPCK promoter. By engineering the leucine zipper regions of CREMalpha(DIEDML) and CREB(DIEDML) to direct their patterns of dimerization, we found that only CREMalpha(DIEDML) homodimers fully activated the PEPCK promoter. By using a series of deletion and block mutants of the PEPCK promoter, we found that activation by CREMalpha(DIEDML) depended on the CRE and two CCAAT/enhancer-binding protein (C/EBP) sites. A dominant negative inhibitor of C/EBP, A-C/EBP, suppressed activation by CREMalpha(DIEDML). Furthermore, a GAL4-C/EBPalpha fusion protein and CREMalpha(DIEDML) cooperatively activated a promoter containing three GAL4 sites and the PEPCK CRE. Thus, we propose that the C/EBP sites in the PEPCK promoter allow CREMalpha to activate transcription despite its lack of Q regions.

Amino Acid Motifs↗
PubMed1995

Ultraviolet light-responsive element (TGACAACA)-binding proteins in cells of xeroderma pigmentosum patients.

The ultraviolet light (UV)-responsive element (URE) is an octamer sequence, TGACAACA, that shares homology with cyclic AMP-responsive element and activator protein 1 target sequences. Because URE-binding proteins have been shown to play a role in cellular response to DNA damage, we determined their expression and DNA-binding activities in repair-deficient cells. Of the complementation groups tested, only xeroderma pigmentosum (XP)-C cells induced expression of c-jun after UV irradiation; this correlated with XP-C binding to the URE and resembled the pattern observed with normal human fibroblasts. In other cases either a decrease (XP-A) or no change (XP-D) in URE-binding activities was noticed, which may be associated with decreased c-fos and poor c-jun expression after UV irradiation. That XP-C cells were the only complementation group exhibiting URE-binding activities similar to those of repair-proficient cells points to the possible correlation between proper repair of transcriptionally active genes and the expression and activities of proteins implicated in the cellular response to UV irradiation.

Base Sequence↗
PubMed1989

H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element.

Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, but not to other MHC cis-acting sequences or to mutant region II sequences, similar to the naturally occurring region II factor in mouse cells. The deduced amino acid sequence of H-2RIIBP revealed two putative zinc fingers homologous to the DNA-binding domain of steroid/thyroid hormone receptors. Although sequence similarity in other regions was minimal, H-2RIIBP has apparent modular domains characteristic of the nuclear hormone receptors. Further analyses showed that both H-2RIIBP and the natural region II factor bind to the estrogen response element (ERE) of the vitellogenin A2 gene. The ERE is composed of a palindrome, and half of this palindrome resembles the region II binding site of the MHC CRE. These results indicate that H-2RIIBP (i) is a member of the superfamily of nuclear hormone receptors and (ii) may regulate not only MHC class I genes but also genes containing the ERE and related sequences. Sequences homologous to the H-2RIIBP gene are widely conserved in the animal kingdom. H-2RIIBP mRNA is expressed in many mouse tissues, in agreement with the distribution of the natural region II factor.

Amino Acid Sequence↗
PubMed2003

The cyclic adenosine 5'-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism.

The production of IL-2 is tightly controlled by several transcription factors that bind to the IL-2 promoter. The cAMP response element modulator (CREM) is known to form complexes with CREB and bind to the -180 site of the IL-2 promoter in anergic and in systemic lupus erythematosus T cells. In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. Transfection of an antisense CREM plasmid into T cells blocked the expression and binding of CREM to the IL-2 promoter and the decrease of IL-2 production, which follows the early increase after T cell stimulation with CD3 and CD28. In addition, as assessed by chromatin immunoprecipitation experiments, antisense CREM prevented the binding of protein 300 and cAMP response element binding protein and promoted the acetylation of histones. Antisense CREM also enhanced the accessibility of the IL-2 promoter to endonucleases and prevented the condensation of chromatin in vivo. Our data suggest that upon T cell activation, CREM gradually replaces phosphorylated CREB at the -180 site of the IL-2 promoter. CREM, in turn, binds protein 300 and cAMP response element binding protein, but CREM is unable to activate its histone acetyltransferase activity, which results in condensation of chromatin and down-regulation of IL-2 production.

Acetyltransferases↗