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PubMed1990

Detection of hepatic metastases: comparison of contrast-enhanced CT, unenhanced MR imaging, and iron oxide-enhanced MR imaging.

Diagnostic accuracy of contrast-enhanced CT, unenhanced MR imaging, and MR images enhanced with superparamagnetic iron oxide was evaluated in 10 patients with histologically proved hepatic metastases. First, diagnostic performance of the imaging technique with respect to the ability of radiologists to recognize the presence or absence of a metastasis was measured by using receiver-operating-characteristic (ROC) analysis of single images. Second, the total number of lesions (N = 108) detected by "complete" CT and MR examinations was counted. Finally, lesion-liver contrast-to-noise ratios (CNR) were measured in all MR sequences. The area under the ROC curve was .67 +/- .03 for contrast-enhanced CT, .81 +/- .07 for the unenhanced SE 260/14 sequence, and .92 +/- .01 for the iron oxide-enhanced SE 1500/40 sequence. The enhanced SE 1500/40 sequence yielded significantly (p less than .005) greater accuracy than did contrast-enhanced CT. The same sequence detected significantly (p less than .05) more lesions than all other imaging techniques (19% more than the best unenhanced MR sequence and 36% more than contrast-enhanced CT). The enhanced SE 1500/40 sequence also yielded the highest CNR value (19.5 +/- 10.2) of all MR sequences. These results indicate that iron oxide-enhanced MR imaging is a superior imaging technique for the detection of hepatic lesions.

Adult↗

PubMed2004

Detection of hepatocellular carcinoma: comparison of ferumoxides-enhanced and gadolinium-enhanced dynamic three-dimensional volume interpolated breath-hold MR imaging.

The purpose was to compare the diagnostic accuracy of ferumoxides-enhanced MR imaging and gadolinium-enhanced dynamic MR imaging using three-dimensional (3D) volume interpolated breath-hold examination (VIBE) for the detection of hepatocellular carcinoma (HCC). Forty-nine patients with 61 HCCs, who underwent ferumoxides-enhanced and gadolinium-enhanced dynamic MR imaging, were included prospectively in this study. Ferumoxides-enhanced MR imaging was performed 24 h after completion of the dynamic study using 3D-VIBE. Three radiologists independently interpreted the images. The diagnostic accuracy was evaluated using the receiver-operating characteristic method, and the sensitivity of each imaging technique was compared using McNemar's test. The mean diagnostic accuracy of dynamic MR imaging (Az=0.95) was higher than that of ferumoxides-enhanced MR imaging (Az=0.90), but failed to reach a statistical significance (P=0.057). The mean sensitivity of dynamic MR imaging (90.7%) was significantly superior to that of ferumoxides-enhanced MR imaging (80.9%, P=0.03). Furthermore, for lesions smaller than 15 mm, the mean sensitivity of dynamic MR imaging was significantly higher than that of ferumoxides-enhanced MR imaging (85.2% vs. 69.2%, P<0.05). Dynamic MR imaging showed a trend toward better diagnostic accuracy for than ferumoxides-enhanced MR imaging for the detection of HCCs.

Aged↗

PubMed2002

Enhancement effects of (R) and (S) enantiomers and the racemate of a model enhancer on permeation of theophylline through human skin.

The conformation of a permeation enhancer, given their mechanism of action, could influence its enhancing properties, since the stratum corneum components form essentially a chiral environment. The racemate and both enantiomers of 6-aminohexanoic acid 2-octylester as model enhancers with one chiral center were synthesized and their ability to enhance in vitro theophylline permeation through human skin was tested. The MTMT concept could not be applied in this study (the melting points of the substances were lower than 20 masculine C) and we observed no significant difference in enhancement ratios (ERs) of racemic 6-aminohexanoic acid 2-octylester and that of each enantiomer. However, differences in permeation rates between enantiomers and their racemates do not have to be related to stereoselective interactions, since they may also be explained by differences in physicochemical properties. The study also showed that there was no difference in the permeation enhancement ability between the (R)-(-) and (S)-(+) isomers of 6-aminohexanoic acid 2-octylester (the ERs were 2.72+/-0.42 and 2.79+/-0.60 for (R) and (S) enantiomers, respectively), suggesting that the enhancing properties of the compounds are not dependent on their spatial arrangement. Although stereoselective interactions between an enhancer and stratum corneum components may exist, they seem not to be important for the enhancer action.

Aged↗

PubMedDate not supplied

Patterns of peripheral enhancement in breast masses: correlation of findings on contrast medium enhanced MRI with histologic features and tumor angiogenesis.

PURPOSE: Our goal was to review patterns of peripheral enhancement on contrast-enhanced MRI of the breast and to correlate radiologic findings with pathologic features. METHOD: We reviewed the MR images of 124 consecutive women with breast lesions. Peripheral enhancement was identified in 35 (32 malignant, 3 benign) lesions. MRI findings were correlated with pathologic features including microvessel density and distribution determined histologically. RESULTS: Early peripheral enhancement with centripetal progression was seen in invasive carcinomas with a high peripheral and a low central microvessel density, associated with fibrosis and/or necrosis (n = 18; 15 with central fibrosis, 2 with fibrosis and necrosis, and 1 with necrosis alone). Early peripheral enhancement with minimal or no change in enhancement was seen in both malignant (n = 10) and benign (n = 3) lesions. Delayed peripheral enhancement with centrifugal progression was seen in carcinomas that had an expansive growth pattern and a high marginal vessel density with or without a vascularized rim of connective tissue (n = 4). CONCLUSION: Early peripheral enhancement with centripetal progression appears to be fairly specific for carcinomas, whereas early enhancement with minimal or no centripetal progression, although more common in malignant tumors, may be seen in some benign lesions as well.

Adult↗

PubMed2003

Cirrhosis or chronic hepatitis: evaluation of small (<or=2-cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging.

PURPOSE: To evaluate the frequency and clinical importance of small (<or=2 cm) early-enhancing hepatic lesions in cirrhotic liver disease with serial multiphasic contrast material-enhanced dynamic magnetic resonance (MR) imaging. MATERIALS AND METHODS: The study population included 208 patients with cirrhosis (n = 162) or chronic hepatitis (n = 46) who underwent dynamic contrast-enhanced MR imaging at least twice during the clinical course, with at least a 12-month interval between the initial and latest MR examinations. Initial images were evaluated for the presence and shape of small (<or=2 cm) early-enhancing hepatic lesions at arterial-phase contrast-enhanced MR imaging. If a small early- enhancing lesion was seen on the initial image, the latest follow-up image was reviewed to assess the serial changes in the features of a specific lesion. RESULTS: One hundred fifty-eight small early-enhancing lesions were detected in 75 (36%) of the 208 patients on the initial MR images. Of those 158 lesions, 104 were round or oval, 30 wedge-shaped, 18 geographic (irregularly shaped), and six triangular. Among the 104 round or oval lesions, 54 (52%) disappeared or decreased in size on the latest MR images and were considered definite pseudolesions. Twenty-nine (28%) of the 104 round or oval lesions were classified as hepatocellular carcinoma (HCC) on the basis of their interval growth or pathologic confirmation. The remaining 21 (20%) lesions were stable in size and appearance and considered probable pseudolesions. For the other three shapes, 73% of wedge-shaped, 78% of geographic, and 67% of triangular lesions disappeared or decreased in size. CONCLUSION: Small early-enhancing hepatic lesions in patients with cirrhosis usually showed no interval growth or disappeared during serial contrast-enhanced dynamic MR imaging. Even though these lesions are round or oval, they may more frequently be pseudolesions than HCCs.

Adult↗

PubMed2004

Contrast-enhanced sonographic appearance of hepatocellular carcinoma in patients with cirrhosis: comparison with contrast-enhanced helical CT appearance.

OBJECTIVE: We sought to investigate the efficacy of contrast-enhanced sonography using a second-generation contrast agent for the evaluation of hepatocellular carcinoma in patients with cirrhosis by comparing the results to those obtained with contrast-enhanced helical CT. SUBJECTS AND METHODS: Between October 2002 and March 2003, 74 patients with cirrhosis (60 men and 14 women; age range, 47-80 years; mean age, 67 years) who had a single nodule of hepatocellular carcinoma were selected to be studied from a cohort of 437 patients with cirrhosis. The size range of the 74 nodules was 9-65 mm (mean, 28.2 mm). Twenty-eight (38%) were 20 mm smaller (range, 9-20 mm; mean, 16.6 mm), and 46 (62%) were larger than 20 mm (range, 21-65 mm; mean, 35.2 mm). Contrast-enhanced sonography was performed at a low mechanical index after IV administration of the contrast agent SonoVue. CT scans were obtained in all patients. The enhancement pattern related to tumor hypervascularity was analyzed. The chi-square test was used for statistical analysis. RESULTS: For the 28 hepatocellular carcinomas 20 mm or smaller, contrast-enhanced sonography showed 15 (53.6%) as hypervascular and 10 (35.7%) as avascular; three (10.7%) carcinomas were missed. On CT, 12 (42.9%) of the 28 hepatocellular carcinomas appeared hypervascular, 13 (46.4%) appeared hypovascular, and three (10.7%) were missed. For the 46 hepatocellular carcinomas larger than 20 mm, contrast-enhanced sonography showed 42 (91.3%) as hypervascular and four (8.7%) as avascular. On CT, 35 (76.1%) hepatocellular carcinomas appeared hypervascular, eight (17.4%) appeared hypovascular, and three (6.5%) were missed. Differences between CT appearance of hepatocellular carcinomas and contrast-enhanced sonographic appearance of the carcinomas were not statistically significant. Concordance between contrast-enhanced sonographic and CT appearances was observed in 61 (82.4%) of 74 cases. CONCLUSION: Contrast-enhanced sonography is similar to CT for detecting hepatocellular carcinoma hypervascularity. It could be complementary to conventional unenhanced sonography for evaluation of liver nodules.

Aged↗

PubMed1993

[MRI enhancement of the facial nerve with Gd-DTPA--second report--investigation of enhanced nerve portions in patients with facial palsy].

We performed enhanced MRI using Gd-DTPA in 84 patients with facial palsy. After assessing enhancement of the normal facial nerve, we examined enhancement in patients with Bell's palsy and Ramsay Hunt syndrome. The following results were obtained. 1. In 95% of patients with Bell's palsy, enhancement was obtained in the distal IAC and labyrinthine portions. In 72%, enhancement was significant from the distal IAC portion through the vertical portion. In some of the patients who underwent enhanced MRI twice, increased signal intensity was observed in distal portions such as the vertical portion. 2. In many cases with Ramsay Hunt syndrome, enhancement was seen extensively in the IAC portion through the vertical portion. In the subjects with internal auditory symptoms such as vertigo and tinnitus, enhancement of the IAC portion was seen not only in the facial nerve but also in the vestibular and the cochlear nerves. These results suggest that the vascular permeability of lesions in Bell's palsy may be increased from the distal IAC portion to the vertical portion. Judging from the present findings with Ramsay Hunt syndrome, symptoms related to the enhanced portions suggest that accompanying internal auditory symptoms occur due to inflammation of the IAC portions of cochlear and vestibular nerves.

Adult↗

PubMed1987

The enhancement of the immune response by pain stimulation in mice. I. The enhancement effect on PFC production via sympathetic nervous system in vivo and in vitro.

Effects of catecholamines and osmotical and physical stimuli on the induction of anti-sheep red blood cells (SRBC) plaque-forming cells (PFC) were investigated in (C57BL/6 X BALB/c)F1 mice in vivo and in vitro. The anti-SRBC PFC from mice immunized with 5 X 10(7) SRBC was markedly increased by daily s.c. injections of epinephrine. The enhancement of PFC by epinephrine was completely blocked by preadministration with propranolol and hexamethonium, but not with phentolamine. The PFC was increased by osmotic and physical stimuli given once a day for 4 days after immunization with SRBC. The enhancement of PFC by these stimuli was completely blocked by preadministration with propranolol and hexamethonium. The enhancement of PFC by physical stimuli was observed in nonimmunized mice when spleen cells from stimulated mice were cultured with SRBC in vitro. In normal mice, the enhancement of PFC was observed 2 hr after one physical stimulation. However, spleen cells from mice given two physical stimuli did not show the enhancement of PFC after treatment with anti-Thy-1.2 antibody and complement, nor after removal of nonadherent cells. Next, the serum obtained from mice 30 to 60 min after a physical stimulation enhanced PFC of normal mice spleen cells in vitro, but the enhancement was abolished by the addition of propranolol. The enhancement of anti-SRBC PFC by s.c. injection of epinephrine suggested that the autonomic nervous system, especially the sympathetic nervous system, was activated by a local stimulus effect of the injection. This enhancement of anti-SRBC PFC appear to be due to the activation of antigen non-specific helper T lymphocytes by the beta-actin of endogenous catecholamines from the adrenal gland.

Animals↗

PubMed1997

Synaptic enhancement and enhanced excitability in presynaptic and postsynaptic neurons in the conditioned stimulus pathway of Hermissenda.

Identified type A photoreceptors of Hermissenda express differential effects of classical conditioning. Lateral type A photoreceptors exhibit an increase in excitability to both the conditioned stimulus (CS; light) and extrinsic current. In contrast, medial type A photoreceptors do not express enhanced excitability, but do show enhancement of the medial B to medial A synaptic connection. Therefore, both enhanced excitability and changes in synaptic strength may contribute to long-term plasticity underlying classical conditioning. The activation of protein kinase C (PKC) is involved in the induction of enhanced excitability of identified type B photoreceptors produced by one-trial conditioning and the expression of enhanced excitability in B photoreceptors after multitrial classical conditioning. We have examined a possible role for persistent kinase activity in the expression of enhanced excitability in lateral type A photoreceptors and enhancement of the medial B to medial type A synaptic connection after classical conditioning. Injection of the PKC inhibitor peptide PKC(19-36) into medial type B photoreceptors of conditioned animals did not significantly change the amplitude of medial A IPSPs elicited by single spikes in the medial B photoreceptor. Injections of PKC(19-36) into medial B photoreceptors of pseudorandom controls also did not significantly change the amplitude of IPSPs recorded from the medial A photoreceptor. In contrast, spikes elicited by extrinsic current in lateral type A photoreceptors of conditioned animals were significantly reduced in frequency after intracellular injection of PKC(19-36) as compared with pseudorandom controls. Injection of the noninhibitory analog peptide [glu27]PKC(19-36) did not affect excitability. Thus, enhanced excitability in the lateral A photoreceptor of conditioned animals seems to be influenced, in part, by a constitutively active kinase or a persistent kinase activator, whereas synaptic enhancement of the connection between the medial B and medial A photoreceptors of conditioned animals may involve a different mechanism.

Action Potentials↗

PubMed1997

The potent enhancer activity of the polycythemic strain of spleen focus-forming virus in hematopoietic cells is governed by a binding site for Sp1 in the upstream control region and by a unique enhancer core motif, creating an exclusive target for PEBP/CBF.

The polycythemic strain of the spleen focus-forming virus (SFFVp) contains the most potent murine retroviral enhancer configuration known so far for gene expression in myeloerythroid hematopoietic cells. In the present study, we mapped two crucial elements responsible for the high activity of the SFFVp enhancer to an altered upstream control region (UCR) containing a GC-rich motif (5'-GGGCGGG-3') and to a unique enhancer core (5'-TGCGGTC-3'). Acquisition of these motifs accounts for half of the activity of the complete retroviral enhancer in hematopoietic cells, irrespective of the developmental stage or lineage. Furthermore, the UCR motif contains the major determinant for the enhancer activity of SFFVp in embryonic stem (ES) cells. Using electrophoretic mobility shift assays, we show that the UCR of SFFVp, but not of Friend murine leukemia virus, is targeted by the ubiquitous transcriptional activator, Sp1. The core motif of SFFVp creates a specific and high-affinity target for polyomavirus enhancer binding protein/core binding factor (PEBP/CBF) and excludes access of CAAT/enhancer binding protein. Cotransfection experiments with ES cells imply that PEBP/CBF cooperates with the neighboring element, LVb (the only conserved Ets consensus in the SFFVp enhancer), and that the Sp1 motif in the UCR stimulates transactivation through the Ets-PEBP interaction. Putative secondary structures of the retroviral enhancers are proposed based on these data.

Animals↗

PubMed2001

Atypically enhancing hepatic cavernous hemangiomas: high-spatial-resolution gadolinium-enhanced triphasic dynamic gradient-recalled-echo imaging findings.

We retrospectively investigated the appearance and frequency of atypically enhancing cavernous hemangiomas with high-spatial-resolution (512x224 matrix) gadolinium-enhanced triphasic dynamic gradient-recalled-echo (GRE) MR images. Images of 132 hepatic cavernous hemangiomas (ranging in size from 4 to 72 mm; mean size 17.2 mm) in 95 patients (42 men and 53 women; age range 25-85 years; mean age 54 years) were retrospectively reviewed by two independent radiologists. Forty (30%) of 132 lesions atypically enhanced. Smaller hemangiomas (< or =15 mm) more frequently (29%) showed early entire enhancement with or without arterio-portal shunting in the hepatic arterial-dominant phase ( p<0.001); most of them showed hyperintense complete fill-in in the equilibrium phase and were readily characterized. "Bright dot" or minimal peripheral enhancement in the equilibrium phase was seen in a small number of lesions (6% each). With T2-weighted images, 130 (98%) lesions showed moderately to very high signal intensity and only 2 (2%) with minimal peripheral enhancement showed hyperintensity of slight degree. The high-spatial-resolution dynamic GRE images clearly revealed minute enhancement characteristics of hemangiomas. Although moderately to very high signal intensity with T2-weighted MR images is informative for the diagnosis of most cavernous hemangiomas, when a lesion shows minimal peripheral enhancement in the equilibrium phase and hyperintensity of slight degree with T2-weighted images, further follow-up or biopsy may be warranted to discriminate hypovascular metastases.

Adult↗

PubMed2006

Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadolinium comparators.

RATIONALE AND OBJECTIVES: Gadobenate dimeglumine (Gd-BOPTA) possesses a two-fold higher T1 relaxivity compared to other available gadolinium contrast agents. The study was conducted to evaluate the benefits of this increased relaxivity for MR imaging of intracranial enhancing brain lesions. MATERIALS AND METHODS: Forty-five patients (31 males, 14 females) with suspected glioma or cerebral metastases were evaluated. Patients received Gd-BOPTA and either Gd-DTPA (n = 23) or Gd-DOTA (n = 22) in fully randomized order at 0.1 mmol/kg body weight and at a flow rate of 2 ml/s. The second agent was administered 1-14 days after the first agent. Images were acquired precontrast (T1wSE, T2wFSE sequences) and at sequential postcontrast time-points (T1wSE sequences at 0, 2, 4, 6, and 8 and 15 min and a T1wSE-MT sequence at 12 min) at 1.0 or 1.5 T using a head coil. Determination of contrast enhancement was performed quantitatively (lesion-to-brain ratio, contrast-to-noise ratio, and percent enhancement) and qualitatively (border delineation, internal morphology, contrast enhancement, and diagnostic preference) by two independent, fully blinded readers. RESULTS: Images from 43/45 patients were available for quantitative assessment. After correction for precontrast values, significantly greater lesion-to-brain ratio (P < .003), contrast-to-noise ratio (P < .03), and percent enhancement (P < .0001) was noted by both readers for Gd-BOPTA-enhanced images at all time-points from 2 min postcontrast. Qualitative assessment of all patients similarly revealed significant preference for Gd-BOPTA for lesion border delineation (P < .004), lesion internal morphology (P < .008), contrast enhancement (P < .0001), and diagnostic preference (P < .0005). CONCLUSIONS: The greater T1 relaxivity of Gd-BOPTA permits improved visualization of intracranial enhancing lesions compared to conventional gadolinium agents.

Adult↗

PubMed2000

The Mu enhancer is functionally asymmetric both in cis and in trans. Topological selectivity of Mu transposition is enhancer-independent.

Mu DNA transposition from a negatively supercoiled DNA substrate requires interaction of an enhancer element with the left (attL) and right (attR) ends of Mu. The orientation of the L and R ends with respect to each other (inverted) and with respect to the enhancer is normally inviolate. We show that when the enhancer is provided in trans as a linear fragment, the head to head orientation of the L/R ends is still required. Each functional half of the linear enhancer maintains the same "cross-wise" interaction with the subsites L1 and R1, when present in cis or in trans. In reactions catalyzed by an enhancer-independent variant of the Mu transposase, the need for negative supercoiling of the substrate and the inverted orientation of L and R ends is not relaxed. These results show that the orientation specificity of the enhancer is not determined by its topological linkage to the Mu ends. There is a functional asymmetry inherent to the enhancer. Furthermore, the enhancer does not directly impose topological constraints on the transposition reaction or specify the reactive orientation of the Mu ends.

Bacteriophage mu↗

PubMed2006

Enhancer blocking by chicken beta-globin 5'-HS4: role of enhancer strength and insulator nucleosome depletion.

The 5'-HS4 chicken beta-globin insulator functions as a positional enhancer blocker on chromatinized episomes in human cells, blocking the HS2 enhancer of the human beta-globin locus control region from activating a downstream epsilon-globin gene. 5'-HS4 interrupted formation of a domain of histone H3 and H4 acetylation encompassing the 6-kb minilocus and inhibited transfer of RNA polymerase from the enhancer to the gene promoter. We found that the enhancer blocking phenotype was amplified when the insulated locus contained a weakened HS2 enhancer in which clustered point mutations eliminated interaction of the transcription factor GATA-1. The GATA-1 mutation compromised recruitment of histone acetyltransferases and RNA polymerase II to HS2. Enhancer blocking correlated with a significant depletion of nucleosomes in the core region of the insulator as revealed by micrococcal nuclease and DNase I digestion studies. Nucleosome depletion at 5'-HS4 was dependent on interaction of the insulator protein CCCTC-binding factor (CTCF) and was required for enhancer blocking. These findings provide evidence that a domain of active chromatin is formed by spreading from an enhancer to a target gene and can be blocked by a nucleosome-free gap in an insulator.

Animals↗

PubMed1989

Two closely spaced promoters are equally activated by a remote enhancer: evidence against a scanning model for enhancer action.

To explain the activation of transcription by a remote enhancer, two models are most often considered, namely looping and scanning. A scanning model, also referred to as 'polymerase entry site' model predicts that for two adjacent promoters the one proximal to an enhancer would be preferentially activated. Preferential activation of the proximal promoter in a tandem promoter arrangement has been found before in several laboratories, including our own, but for technical reasons the data were inconclusive with regards to the enhancer mechanism. In the work presented here, we readdress the question of preferential promoter activation by an enhancer using a more clearly defined system. Two identical promoters were kept closeby in a divergent, or directly repeated orientation. The SV40 enhancer was placed at a great distance on one or the other side of the two promoters, to see whether the enhancer position influenced the relative efficiency of the two promoters in transfected cells. Our finding that the promoter usage is virtually unaffected by the enhancer position does not favor a scanning model, but is compatible with a looping model of enhancer action.

Animals↗

PubMed1995

Enhancer-independent variants of phage Mu transposase: enhancer-specific stimulation of catalytic activity by a partner transposase.

Assembly of the functional tetrameric form of phage Mu transposase (A protein) requires specific interactions between the Mu A monomer and its cognate sequences at the ends of the Mu genome (attL and attR) as well as those internal to it (the enhancer element). We describe here deletion variants of Mu A that show enhancer-independence in the assembly of the strand cleavage complex. These deletions remove the amino-terminal region of Mu A required for its interactions with the enhancer elements. The basal enhancer-independent activity of the variant proteins can be stimulated by a partner variant harboring an intact enhancer-binding domain. By exploiting the identical att-binding, and nonidentical enhancer-binding specificities of Mu A and D108 A (transposase of the Mu related phage D108), we show that the stimulation of activity is enhancer-specific. Taken together, these results suggest that the domain of Mu A that includes the enhancer-interacting region may exert negative as well as positive modulatory effects on the strand cleavage reaction. We discuss the implications of these results in the framework of a recent model for the assembly of shared active sites within the Mu A tetramer.

Attachment Sites, Microbiological↗

PubMed1989

Identification of a novel constitutive enhancer element and an associated binding protein: implications for human papillomavirus type 11 enhancer regulation.

The human papillomavirus type 11 enhancer, when linked to the minimal simian virus 40 early promoter, has been dissected into two domains in monkey kidney CV-1 cells, one being constitutive (designated CEI) and the other inducible by trans-acting E2 proteins encoded by homologous and heterologous papillomaviruses (H. Hirochika, T.R. Broker, and L.T. Chow, J. Virol. 61:2599-2606, 1987; H. Hirochika, R. Hirochika, T.R. Broker, and L.T. Chow, Genes Dev. 2:54-67, 1988). We have demonstrated that the natural promoter regulated by this enhancer is located immediately upstream of the E6 open reading frame (the E6 promoter). We have mapped the cap site to nucleotide 99 by RNase protection. We further demonstrate a second constitutive enhancer element, CEII, which is required for transcription from the E6 promoter in the human cervical carcinoma cell lines C-33A and HeLa but not in CV-1 cells. By deletion mapping, we have localized this cell type-specific domain to 71 base pairs by using chloramphenicol acetyltransferase assays. Deletion of either CEI or CEII dramatically decreased the constitutive activity of the enhancer and the E6 promoter, whereas multimerization of either domain in the absence of the other could independently restore expression. Furthermore, when either of these elements was deleted, the full-length E2 protein of human papillomavirus type 11 abolished the remaining basal E6 promoter activity, demonstrating for the first time that the enhancer-activating E2 protein of human papillomaviruses can also function as a transcriptional repressor for the homologous E6 viral promoter. The presence of multiple copies of each element in tandem overcomes the repression by the E2 protein. The effects of CEII are at the level of transcription, without changing the cap site. By gel shift assay, we have shown that a protein present in nuclear extracts of C-33A and HeLa cervical carcinoma cells binds to the newly identified constitutive element II. This protein did not bind the simian virus 40 enhancer, nor did it bind to the enhancer region of many other papillomaviruses tested. UV cross-linking experiments revealed major 44-kilodalton and minor 34-kilodalton proteins that bound specifically to CEII. These two proteins are either related or bind to CEII with high cooperativity. We conclude that transcriptional activities directed by the enhancer and E6 promoter reflect an intricate balance among viral and cellular factors. We present a model on the regulation of the E6 promoter by host and viral transcription factors.

Animals↗

PubMed2001

Matrix attachment region-dependent function of the immunoglobulin mu enhancer involves histone acetylation at a distance without changes in enhancer occupancy.

Nuclear matrix attachment regions (MARs), which flank the immunoglobulin mu heavy-chain enhancer on either side, are required for the activation of the distal variable-region (V(H)) promoter in transgenic mice. Previously, we have shown that the MARs extend a local domain of chromatin accessibility at the mu enhancer to more distal sites. In this report, we examine the influence of MARs on the formation of a nucleoprotein complex at the enhancer and on the acetylation of histones, which have both been implicated in contributing to chromatin accessibility. By in vivo footprint analysis of transgenic mu gene constructs, we show that the occupancy of factor-binding sites at the mu enhancer is similar in transcriptionally active wild-type and transcriptionally inactive DeltaMAR genes. Chromatin immunoprecipitation experiments indicate, however, that the acetylation of histones at enhancer-distal nucleosomes is enhanced 10-fold in the presence of MARs, whereas the levels of histone acetylation at enhancer-proximal nucleosomes are similar for wild-type and DeltaMAR genes. Taken together, these data indicate that the function of MARs in mediating long-range chromatin accessibility and transcriptional activation of the V(H) promoter involves the generation of an extended domain of histone acetylation, independent of changes in the occupancy of the mu enhancer.

Acetylation↗