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PubMed1996

The Ig kappa 3'-enhancer triggers gene expression in early B lymphocytes but its activity is enhanced on B cell activation.

Ig kappa gene expression is controlled by two enhancers, one located within the major intron (Ei) and the other located downstream of C kappa (E3'). Whereas loss of E3' has previously been shown to diminish kappa expression, we show here that a rearranged kappa transgene lacking Ei is well expressed, even at the pre-B cell stage. This suggests that E3' alone might be sufficient to give properly regulated transcription throughout B cell development. Indeed, we show that a transgene composed of a beta-globin reporter linked to E3' is expressed in a B cell-specific manner, becoming activated at the late pro-B to pre-B cell stage but with dramatically enhanced activity on B cell activation. Thus, E3' becomes active as a transcription enhancer at the stage when V kappa-J kappa rearrangement is being initiated and is sufficient to yield an expression pattern in a linked reporter gene similar to that of fully rearranged kappa genes.

Animals↗
PubMed1988

Foreign transcriptional enhancers in yeast. II. Interplay of the polyomavirus transcriptional enhancer and Saccharomyces cerevisiae promoter elements.

In this paper, to further analyze the function of the polyoma enhancer in Saccharomyces cerevisiae, we use as reporter-genes derivatives of the yeast HIS3 gene flanked by two types of partially deleted promoters: in one, UAS elements are removed by deletion of sequences upstream of nt -80 (pGM3181) in the second both TATA boxes and UAS elements are removed by deletion of sequences upstream of nt -35 (pGM2809). These constructs have been studied both as free plasmids and after integration at the TRP1 chromosomal locus. We find that in general the polyoma holoenhancer (A + B domains) elicits transcription from the physiological HIS3 RNA start sites when the native TATA boxes are present. In contrast, an altered enhancer B-domain from polyoma mutant Py-B78, although active when inserted downstream of the test-gene or when coupled to a pseudopromoter (Ciaramella et al, accompanying manuscript), does not work properly in concert with the native yeast TATA boxes. We describe experiments that suggest an important role for the foreign enhancer in RNA start-site selection in yeast.

Blotting, Northern↗
PubMed1998

Repression of the mouse M-lysozyme gene involves both hindrance of enhancer factor binding to the methylated enhancer and histone deacetylation.

In many cases, gene repression mediated by CpG methylation has been demonstrated. Two different mechanisms have been postulated to explain the repressive effect of methylated CpG DNA: establishment of a repressive chromatin configuration and inhibition of DNA binding of transactivating factors. Using the M-lysozyme gene, we analyzed gene expression, CpG demethylation and the in vivo formation of enhancer/protein complexes after inducing demethylation or inhibiting histone deacetylases. We show that trans-cription of a methylated and silent mouse M-lysozyme gene can be induced upon the inhibition of histone deacetylases in the absence of demethylation or in vivo transactivating factor binding to the enhancer. In contrast, DNA demethylation induces both gene activity as well as enhancer complex formation. Therefore, both mechanisms play a role in lysozyme gene repression mediated by methylated DNA: (i) the enhancer cannot be loaded with transacting factors; and (ii) histone deacetylation inhibits transcription.

Acetylation↗
PubMed2005

An egg apparatus-specific enhancer of Arabidopsis, identified by enhancer detection.

Despite a central role in angiosperm reproduction, few gametophyte-specific genes and promoters have been isolated, particularly for the inaccessible female gametophyte (embryo sac). Using the Ds-based enhancer-detector line ET253, we have cloned an egg apparatus-specific enhancer (EASE) from Arabidopsis (Arabidopsis thaliana). The genomic region flanking the Ds insertion site was further analyzed by examining its capability to control gusA and GFP reporter gene expression in the embryo sac in a transgenic context. Through analysis of a 5' and 3' deletion series in transgenic Arabidopsis, the sequence responsible for egg apparatus-specific expression was delineated to 77 bp. Our data showed that this enhancer is unique in the Arabidopsis genome, is conserved among different accessions, and shows an unusual pattern of sequence variation. This EASE works independently of position and orientation in Arabidopsis but is probably not associated with any nearby gene, suggesting either that it acts over a large distance or that a cryptic element was detected. Embryo-specific ablation in Arabidopsis was achieved by transactivation of a diphtheria toxin gene under the control of the EASE. The potential application of the EASE element and similar control elements as part of an open-source biotechnology toolkit for apomixis is discussed.

Arabidopsis↗
PubMed1987

Activation of mutated simian virus 40 enhancers by amplification of wild-type enhancer elements.

We show that duplication of any one of three separate simian virus 40 enhancer elements, A, B, or C, can compensate for loss of function in the remaining two. Simian virus 40 revertants containing point mutations within the A and C (dpm16) or B and C (dpm26) enhancer elements contain tandem duplications that include the remaining wild-type element. These simple tandem duplications can create enhancers 25-fold more active than that of the parental mutant. These revertants can arise by illegitimate recombination between heterologous viral genomes. This was demonstrated by the recombinants resulting from a mixed infection with the viruses dpm16 and dpm2, which contain mutations in the A and C elements and the B element, respectively.

Base Sequence↗
PubMed2000

The region between amino acids 245 and 265 of the bovine leukemia virus (BLV) tax protein restricts transactivation not only via the BLV enhancer but also via other retrovirus enhancers.

Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis and is closely related to human T-cell leukemia virus type 1 (HTLV-1). The Tax protein of BLV acts through the 5' long terminal repeat (LTR) of BLV and activates the transcription of BLV. In this study, we amplified tax genes from BLV-infected cattle using PCR. We cloned the genes and monitored the transcriptional activities of the products. Seven independent mutant Tax proteins, with at least one amino acid substitution between residues 240 and 265, exhibited a markedly stronger ability to stimulate the viral LTR-directed transcription than the wild-type Tax protein. Analysis of chimeric Tax proteins derived from wild-type and mutant Tax proteins clearly demonstrated that a single substitution between residue 240 and 265 might be critical for the higher activities of the Tax mutant proteins. Furthermore, it appeared that transient expression of a Tax mutant protein was better able to increase the production of viral proteins and particles from a defective recombinant proviral clone of BLV than was wild-type Tax. Analysis of mutations within the U3 region of the LTR revealed that a cyclic AMP-responsive element in Tax-responsive element 2 might be sufficient for the enhanced activation mediated by the mutant proteins. In addition to the LTR of BLV, other viral enhancers, such as the enhancers of HTLV-1 and of mouse mammary tumor virus, which cannot be activated by wild-type BLV Tax protein, were activated by a Tax mutant protein. Our observations suggest that the transactivation activity and target sequence specificity of BLV Tax might be limited or negatively regulated by the region of the protein between amino acids 240 and 265.

Animals↗
PubMed1995

A novel enhancer, the pro-B enhancer, regulates Id1 gene expression in progenitor B cells.

The helix-loop-helix (HLH) Id proteins have been reported to function as inhibitors of various differentiation programs. The HLH motif mediates dimer formation between Id and the basic HLH transcription factors. Since Id proteins lack the basic region responsible for DNA binding, the heterodimers cannot bind to DNA. Id proteins have also been found to be involved in early B-cell differentiation. They are expressed at high levels in progenitor B cells (pro-B cells), and the expression is diminished in pre-B cells and mature B cells. This expression pattern correlates inversely with basic HLH protein activity and immunoglobulin enhancer function in B-cell development. Regulation of Id expression may play an important role in transcriptional control of immunoglobulin genes and therefore in B-cell differentiation. We have characterized the regulatory elements of the Id1 gene. Using stable transfectants, transient transfection, and mobility shift assays, we have identified an 8-bp element designated PBE (pro-B enhancer) downstream of the Id1 gene that is responsible for a pro-B-cell-specific enhancer activity. A pro-B-cell-specific protein complex was found to bind to the 8-bp PBE element. Substitution mutagenesis at this binding site showed that it is indeed of functional importance in regulating the pro-B-cell-specific expression of the Id1 gene.

Animals↗
PubMed2004

FoxA proteins regulate H19 endoderm enhancer E1 and exhibit developmental changes in enhancer binding in vivo.

Multiple enhancers govern developmental and tissue-specific expression of the H19-Igf2 locus, but factors that bind these elements have not been identified. Using chromatin immunoprecipitation, we have found two FoxA binding sites in the H19 E1 enhancer. Mutating these sites diminishes E1 activity in hepatoma cells. Additional chromatin immunoprecipitations show that FoxA binds to E1 in fetal liver, where H19 is abundantly expressed, but that binding decreases in adult liver, where H19 is no longer transcribed, even though FoxA proteins are present at both times. FoxA proteins are induced when F9 embryonal carcinoma cells differentiate into visceral endoderm (VE) and parietal endoderm (PE). We show that FoxA binds E1 in VE cells, where H19 is expressed, but not in PE cells, where H19 is silent. This correlation between FoxA binding and H19 expression indicates a role for FoxA in regulating H19, including developmental activation in the yolk sac and liver and postnatal repression in the liver. This is the first demonstration of a tissue-specific factor involved in developmental control of H19 expression. These data also indicate that the presence of FoxA proteins is not sufficient for binding but that additional mechanisms must govern the accessibility of FoxA proteins to their cognate binding sites within the H19 E1 enhancer.

Acetylation↗
PubMed1987

Phorbol ester enhances human immunodeficiency virus-promoted gene expression and acts on a repeated 10-base-pair functional enhancer element.

T-cell activation pathways are involved in the regulation of human immunodeficiency virus (HIV) expression. Phorbol 12-myristate 13-acetate (PMA) is a potent inducer of T-cell immune functions and has recently been demonstrated to increase viral replication in cell lines infected with HIV. To define sequences required for viral induction by PMA. T-cell lines were transiently transfected with viral long terminal repeat (LTR) sequences directing chloramphenicol acetyltransferase (CAT) gene expression. PMA added to transfected cell cultures 24 h before harvest reproducibly increased both CAT mRNA and enzyme expression 2- to 2-fold. Sequences necessary for basal and PMA-induced levels of CAT expression were determined by deletion and enhancer reconstitution constructs with fragments and oligonucleotides from the original LTR-CAT expression plasmid. PMA-inducible and basal activity required tandem repeats of a core enhancer element (GGGACTTTCC) located in the LTR between -105 and -82 relative to the RNA start site. The enhancerlike sequence could be inserted at a site distant to the CAT gene open reading frame and functioned in a position- and orientation-independent manner. The data thus define a transcriptionally active regulatory-enhancer element critical to the control of HIV gene expression.

Chromosome Mapping↗
PubMed2004

Acute myocardial infarction: evaluation with first-pass enhancement and delayed enhancement MR imaging compared with 201Tl SPECT imaging.

PURPOSE: To evaluate acute myocardial infarction by using first-pass enhancement (FPE) and delayed enhancement (DE) magnetic resonance (MR) imaging compared with thallium 201 ((201)Tl) single photon emission computed tomography (SPECT). MATERIALS AND METHODS: Contrast material-enhanced FPE MR, inversion-recovery DE MR, and rest-redistribution (201)Tl SPECT images were obtained in 60 consecutive patients (53 men, seven women; mean age [+/- SD], 56 years +/- 13; range, 30-78 years) at 6 days +/- 3 after reperfused first myocardial infarction. Presence of microvascular obstruction was determined on FPE MR images. Infarct size was defined on DE MR images as percentage of left ventricular (LV) area and compared with uptake defect on redistribution (201)Tl SPECT images. Differences in continuous data were analyzed with Student t test. Linear regression and Bland-Altman analysis were used to compare measurements of infarct size. RESULTS: Mean infarct size was not significantly different between DE MR imaging (20.7% +/- 11.5% of LV area) and (201)Tl SPECT (19.4% +/- 14.3% of LV area; P =.26); good correlation (r = 0.73; P <.001) and agreement were found, with a mean difference of +1.3% +/- 9.8% of LV area. (201)Tl SPECT failed to depict infarct in six (20%) of 30 patients with inferior myocardial infarction (mean size, 6.4% +/- 5.7% of LV area on DE MR images), whereas DE MR images showed the infarct in all patients (P <.01). FPE MR images depicted microvascular obstruction in 23 (38%) of 60 patients; these patients had larger infarctions at DE MR imaging than did patients without microvascular obstruction (30.4% +/- 9.0% vs 15.1% +/- 8.4% of LV area, P <.001). (201)Tl SPECT showed larger infarcts in patients with microvascular obstruction (26.7% +/- 16.2% vs 15.0% +/- 11.2% of LV area, P <.01). CONCLUSION: Good correlation and agreement with (201)Tl SPECT indicate DE MR imaging may be used to estimate infarct size 6 days after reperfused acute myocardial infarction. DE MR imaging is more sensitive for detection of inferior infarction than is (201)Tl SPECT. Patients with microvascular obstruction on FPE MR images have larger infarcts.

Adult↗
PubMed1991

Nonneoplastic enhancing lesions mimicking intracanalicular acoustic neuroma on gadolinium-enhanced MR images.

The authors describe five patients with nonneoplastic lesions of the facial and/or vestibulocochlear nerves that demonstrated focal enhancement within the internal auditory canal on magnetic resonance (MR) images. MR and surgical findings for four patients with unilateral sensorineural hearing loss and one with Ramsay Hunt syndrome were reviewed. Three patients with hearing loss underwent surgical exploration and decompression of the internal auditory canal. The MR findings in all four patients with hearing loss were similar: Focal enhancement of the internal auditory canal was depicted on postcontrast T1-weighted images. Nonneoplastic lesions of the seventh and eighth cranial nerves may show focal enhancement on MR images, which mimics the appearance of a small intracanalicular neuroma. This potential for misdiagnosis may have important therapeutic implications.

Cranial Nerve Diseases↗
PubMed1993

Skull base tumors: gadodiamide injection--enhanced MR imaging--drop-out effect in the early enhancement pattern of paragangliomas versus different tumors.

A phase III trial was conducted in 40 patients with known or suspected skull base tumors to evaluate the safety and efficacy of high-dose gadodiamide injection for use as a paramagnetic contrast medium in conventional and dynamic magnetic resonance (MR) imaging. Contrast material enhancement was assessed dynamically with use of a gradient-recalled sequence. The time-intensity curve of selected regions of interest showed a reproducible dropout effect in the form of a dip in the curve during the early enhancement of the sigmoid sinus and jugular bulb; the same phenomenon was observed in all glomus tumors of the skull base, regardless of size or location. In contrast, schwannomas, meningiomas, and a variety of other lesions showed a continuous increase in the time-intensity curve. The drop-out sign, which is probably a result of a paramagnetic phenomenon during the early phase of enhancement, seems to be specific for glomus tumors. High-dose gadodiamide injection may show a specific dynamic pattern for glomus tumors, allowing differentiation from other tumors of the middle and posterior skull base.

Drug Combinations↗
PubMed2000

Prolactin enhances CCAAT enhancer-binding protein-beta (C/EBP beta) and peroxisome proliferator-activated receptor gamma (PPAR gamma) messenger RNA expression and stimulates adipogenic conversion of NIH-3T3 cells.

Extracellular stimuli trigger adipocyte differentiation by inducing the complex cascades of transcription. Transcription factors CCAAT enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) play crucial roles in this process. Although ectopic expression of these factors in NIH-3T3 cells, a multipotential mesenchymal stem cell line, results in adipogenic conversion, little is known as to hormonal factors that regulate adipogenesis in these cells. In this report we demonstrate that PRL, a lactogenic hormone, enhances C/EBPbeta and PPARbeta mRNA expression and augments adipogenic conversion of NIH-3T3 cells. Moreover, we show that ectopic expression of the PRL receptor in NIH-3T3 cells results in efficient adipocyte conversion when stimulated with PRL and a PPARgamma ligand, as evidenced by expression of the adipocyte differentiation-specific genes as well as the presence of fat-laden cells. We further demonstrate that signal transducer and activator of transcription 5 (Stat5), a PRL signal transducer, activates aP2 promoter in a PRL-dependent manner. These results suggest that PRL acts as an adipogenesis-enhancing hormone in NIH-3T3 cells.

3T3 Cells↗
PubMed1996

Time-course changes of contrast enhancement in iron colloid enhanced MRI in patients with hepatocellular carcinoma.

Time-course changes in contrast enhancement of chondroitin sulphate iron colloid (CSIC), an MR contrast agent, were determined in 12 patients with 20 lesions of classical hepatocellular carcinoma (HCC). Spin echo T1 weighted (T1WI) and T2 weighted images (T2WI) were obtained before administration of CSIC and 1, 6 and 24 h after injection. The signal-to-noise ratio (SNR) in the tumour region and the liver and the tumour-to-liver contrast-to-noise ratio (CNR) were calculated, and time-course changes of these ratios were determined. SNRs for tumour before the administration of contrast medium did not differ significantly from SNRs after administration on T1WI or T2WI. SNRs for the liver on both T1WI and T2WI were significantly lower at each time point after administration than before administration. The tumour-to-liver CNRs for both T1WI and T2WI were significantly higher after administration than before administration. The maximum CNR was observed 6 h after administration on both T1WI and T2WI. The contrast enhancement was maintained for at least 24 h, with a peak at 6 h after administration. The prolonged enhancement obtained with CSIC has extended the time during which effective contrast is maintained.

Aged↗
PubMed2001

HS1,2 enhancer regulation of germline epsilon and gamma2b promoters in murine B lymphocytes: evidence for specific promoter-enhancer interactions.

During an immune response, activated B cells develop into high rate Ig-secreting plasma cells. They also switch from production of IgM to IgG, IgA, or IgE. This process requires a DNA recombination event, which is regulated at the transcriptional level by the production of isotype-specific, sterile germline (GL) transcripts. Induction of these transcripts is controlled by GL promoters and, possibly, by IgH 3' enhancers. We investigated the interaction of the GL epsilon and gamma2b promoters with the HS1,2 enhancer using transiently transfected mouse primary B cells and cell lines. The constructs used for the transfections contained a GL promoter upstream and HS1,2 downstream of a luciferase reporter gene. Both GL epsilon and gamma2b promoters synergized strongly with the HS1,2 enhancer in activated primary B cells, a mature B cell line, and a plasma cell line. We show that the major activity of HS1,2 in activated primary B cells occurs within a 310-bp fragment that includes NF-kappaB, OCT, and NF of activated B cells (Ets/AP-1) sites. By mutating the consensus sequences for various transcription factors, we have determined which sites in HS1,2 are important for synergy with the GL epsilon and gamma2b promoters. Our findings indicate that different sites in HS1,2 might selectively interact with the GL epsilon and gamma2b promoters. We also provide evidence that B cell-specific activator protein is not an absolute suppressor of HS1,2 activity.

Animals↗
PubMed2004

Developmental activation of the TCR alpha enhancer requires functional collaboration among proteins bound inside and outside the core enhancer.

The TCR delta enhancer (Edelta) and TCR alpha enhancer (Ealpha) play critical roles in the temporal and lineage-specific control of V(D)J recombination and transcription at the TCR alphadelta locus, working as a developmental switch controlling a transition from TCR delta to TCR alpha activity during thymocyte development. Previous experiments using a transgenic reporter substrate revealed that substitution of the 116-bp minimal Ealpha, denoted Talpha1-Talpha2, for the entire 1.4-kb Ealpha led to a premature activation of V(D)J recombination. This suggested that binding sites outside of Talpha1-Talpha2 are critical for the strict developmental regulation of TCR alpha rearrangement. We have further analyzed Ealpha to better understand the mechanisms responsible for appropriate developmental regulation in vivo. We found that a 275-bp Ealpha fragment, denoted Talpha1-Talpha4, contains all binding sites required for proper developmental regulation in vivo. This suggests that developmentally appropriate enhancer activation results from a functional interaction between factors bound to Talpha1-Talpha2 and Talpha3-Talpha4. In support of this, EMSAs reveal the formation of a large enhanceosome complex that reflects the cooperative assembly of proteins bound to both Talpha1-Talpha2 and Talpha3-Talpha4. Our data suggest that enhanceosome assembly is critical for developmentally appropriate activation of Ealpha in vivo, and that transcription factors, Sp1 and pCREB, may play unique roles in this process.

Animals↗
PubMed2001

Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter.

We previously reported that the retroviral vector expressing the herpes simplex virus-thymidine kinase gene under the control of 0.3-kb human alpha-fetoprotein (AFP) gene promoter (AF0.3) provided the cytotoxicity to ganciclovir (GCV) in high-AFP-producing human hepatoma cells but not in low-AFP-producing cells. Therefore, specific enhancement of AFP promoter activity is likely to be required to induce enough cytotoxicity in low-AFP-producing hepatoma cells. In this study, we constructed a hybrid promoter, [HRE]AF, in which a 0.4-kb fragment of human vascular endothelial growth factor 5'-flanking sequences containing hypoxia-responsive element (HRE) was fused to AF0.3 promoter. By means of the reporter gene transfection assay, hypoxia-inducible transcriptions that were mediated by [HRE]AF promoter were detected in low- and non-AFP-producing human hepatoma cells, but not in nonhepatoma cells. When the herpes simplex virus-thymidine kinase gene controlled by [HRE]AF promoter was transduced into hepatoma and nonhepatoma cells by a retroviral vector, the exposure to 1% O2 induced GCV cytotoxicity specifically in the hepatoma cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors consisting of the virus-infected hepatoma cells gradually disappeared by GCV administration. These results indicate that the hypoxia-inducible enhancer of the human vascular endothelial growth factor gene, which is directly linked to human AFP promoter, involves selective and enhanced tumoricidal activity in gene therapy for hepatocellular carcinoma.

Animals↗