[Transcriptional regulation by Ah (dioxin) receptor].
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Animals↗
Biomedical subjects
J Mimura
Publications and source records attributed to J Mimura.
Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300.
Hypoxia-inducible factor 1 alpha (HIF1alpha) and its related factor, HLF, activate expression of a group of genes such as erythropoietin in response to low oxygen. Transfection analysis using fusion genes of GAL4DBD with various fragments of the two factors delineated two transcription activation domains which are inducible in response to hypoxia and are localized in the C-terminal half. Their sequences are conserved between HLF and HIF1alpha. One is designated NAD (N-terminal activation domain), while the other is CAD (C-terminal activation domain). Immunoblot analysis revealed that NADs, which were rarely detectable at normoxia, became stabilized and accumulated at hypoxia, whereas CADs were constitutively expressed. In the mammalian two-hybrid system, CAD and NAD baits enhanced the luciferase expression from a reporter gene by co-transfection with CREB-binding protein (CBP) prey, whereas CAD, but not NAD, enhanced beta-galactosidase expression in yeast by CBP co-expression, suggesting that NAD and CAD interact with CBP/p300 by a different mechanism. Co-transfection experiments revealed that expression of Ref-1 and thioredoxin further enhanced the luciferase activity expressed by CAD, but not by NAD. Amino acid replacement in the sequences of CADs revealed a specific cysteine to be essential for their hypoxia-inducible interaction with CBP. Nuclear translocation of thioredoxin from cytoplasm was observed upon reducing O2 concentrations.
Amino Acid Sequence↗
Identification of a novel mechanism of regulation of Ah (dioxin) receptor function.
Ah receptor (AhR) is a ligand-activated transcription factor that mediates pleiotropic effects of environmental pollutants such as 2,3, 7,8-tetrachlorodibenzo-p-dioxin on host animals. In addition to induction of drug-metabolizing enzymes, the liganded AhR complex was found to activate gene expression of a factor designated AhR repressor (AhRR), which inhibits AhR function by competing with AhR for dimerizing with Arnt and binding to the XRE sequence. Thus, AhR and AhRR form a regulatory circuit in the xenobiotic signal transduction pathway and provide a novel mechanism of regulation of AhR function that may determine tissue-specific sensitivity to environmental pollutants.
Amino Acid Sequence↗
Portal venous volume flow: in vivo measurement by time-domain color-velocity imaging.
The portal venous velocity and flow volume in 39 patients (16 with liver cirrhosis, 11 with chronic hepatitis, 12 without liver disease) were measured using both color velocity imaging quantification (CVI-Q) and conventional Doppler flowmetry. The average portal venous velocity and flow volume values obtained using the two methods were similar. The correlation coefficients for the paired measurements show positive correlations (velocity: 0.73, p < 0.0001; volume: 0.50, p = 0.001). However, the coefficients of variation between the two methods were not good (velocity: 14.9%, volume: 26.4%). In conventional Doppler flowmetry, the mean velocity to maximum velocity ratio (Vmean:Vmax) is assumed to be constant (Vmean:Vmax = 0.57 in this study). However, the Vmean:Vmax ratios calculated from the flow profile in CVI-Q were 0.67 +/- 0.13 in the patients with liver cirrhosis, 0.58 +/- 0.13 in the patients with chronic hepatitis, and 0.53 +/- 0.08 in the patients without liver disease. Therefore, a measurement method that takes the blood flow profile into account, such as CVI-Q, might be useful for the quantitative measurement of the portal venous velocity and volume.
Adult↗
Relationship between asthma and gastro-oesophageal reflux: significance of endoscopic grade of reflux oesophagitis in adult asthmatics.
BACKGROUND: The association between asthma and gastro-oesophageal reflux disease (GERD) is well known. The aim of this study was to elucidate the causal relationship between reflux oesophagitis (RE) and asthma. METHODS: Seventy-two adult asthmatics were examined regarding their GERD symptoms, and each underwent an endoscopic examination. According to the Los Angeles classification, we divided the patients into three groups: group 1 (n= 52), no mucosal break; group 2 (n= 15), RE corresponding to grades A or B; group 3 (n = 5), RE corresponding to grades C or D. The asthmatics in groups 2 and 3 received anti-reflux treatment for their GERD for 8 weeks. Their morning and evening peak expiratory flow rates (PEFR), daily variability of the PEFR and daily use of an inhalation bronchodilator were compared before and after this treatment. RESULTS: The percentage of severe asthma and postprandial exacerbation of asthma in group 3 were significantly higher than those in the other two groups. In contrast, the number of eosinophiles and the serum level of immunoglobulin E in group 3 were significantly lower than those in the other two groups. After the antireflux treatment, significant improvements of both PEFR and daily use of the inhalation bronchodilator were observed only in group 3. CONCLUSIONS: The endoscopic severity of RE is associated with the characteristics of adult asthmatics and the treatment of severe RE improved the asthmatics' condition.
Adult↗
Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome.
Human Sim2 is a product of one of the genes located on human chromosome 21q22 and is a homolog of Drosophila single-minded ( sim ) which is a critical player in midline development of the central nervous system of the fly. Since Sim2 mRNA is expressed in facial, skull, palate and vertebra primordia in human and rodent embryos, features that are associated with phenotypes of Down's syndrome (DS), its trisomic state is suspected to contribute to the symptoms of DS. Here we describe that mSim2 mRNA is expressed in hippocampus and amygdala of adult mice, and that while mice overexpressing mSim2 under the control of the beta-actin promoter are viable and fertile and have superficially normal skeletal, brain and heart structures, they exhibit a moderate defect in context-dependent fear conditioning and a mild defect in the Morris water maze test. Taken together, our data show that overdosage of Sim2 may be important for the pathogenesis of Down's syndrome, especially mental retardation.
Animals↗
Colonic ulceration caused by administration of loxoprofen sodium.
A 54-year-old female with chronic headache was admitted to our hospital because of hematochezia. She had routinely taken loxoprofen sodium because of severe headache. Emergent colonoscopic examination revealed ulceration of the cecum. After administration of loxoprofen sodium was discontinued and administration of sulfasalazine was initiated, her intestinal bleeding subsided. Two months after discontinuation of loxoprofen sodium, the colonoscopic examination revealed scar formation at the site of cecal ulceration. In this case, it was conceivable that the administration of loxoprofen sodium might have induced colonic ulceration.
Anti-Inflammatory Agents, Non-Steroidal↗
Structure and expression of the mouse AhR nuclear translocator (mArnt) gene.
Aryl hydrocarbon receptor (AhR) nuclear translocator (Arnt) gene has been isolated and characterized from a mouse genomic DNA library. The gene is about 60 kilobases long and split into 22 exons. An unusual exon/intron junctional sequence was found in the 11th intron of the gene that begins with GC at its 5'-end. The exon/intron arrangement of mArnt gene differs greatly from those of the other members of the same basic-helix-loop-helix/PAS family. The gene is TATA-less and has several transcription start sites. The promoter region of the mArnt gene is GC-rich and contains a number of putative regulatory DNA sequences such as two GC-boxes, a cAMP-responsive element, E-box, AP-1 site, and CAAT-box. Deletion experiments revealed that all these DNA elements made substantial contributions to a high level of expression of the gene, except for the cAMP-responsive element. Of all, two GC-boxes displayed the most dominant enhancing effects. It was demonstrated that there exist specific factors binding to these DNA elements in the nuclear extracts of HeLa cells. Among them, Sp1 and Sp3, and CAAT-box binding factor-A were identified to bind the GC-boxes and CAAT-box, respectively. Expression of MyoD in HeLa cells stimulated the Arnt promoter activity by binding to the E-box.
Amino Acid Sequence↗
Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock.
We isolated a cDNA clone encoding a polypeptide of 626 amino acids containing basic helix-loop-helix (bHLH) and PAS domains from a mouse cDNA library of P19 cells. This protein, termed Arnt3, showed the highest similarity to Arnt and Arnt2 in the bHLH and PAS regions. Arnt3 mRNA was expressed in brain, skeletal muscle, 13.5-day embryos, and P19 cells treated with retinoic acid. The partner PAS proteins of Arnt3 were searched for by the two-hybrid system in yeast, and HIF-1 alpha, HLF, and Clock among various bHLH/PAS proteins were found. Gel mobility shift analysis using nuclear extracts from 293T cells cotransfected with Arnt3 and HIF-1 alpha (or HLF) expression plasmids revealed that these complexes specifically bound the hypoxia-response element (HRE). Coexpression of Arnt3 and HIF-1 alpha (or HLF) in Arnt-deficient c4 cells enhanced transcription of a reporter gene driven by the HRE sequences. We also showed that Arnt3 contained an activation domain at the C-terminal region and a repression domain between the PAS-A and PAS-B regions.
ARNTL Transcription Factors↗
cDNA cloning and predicted primary structure of scallop sarcoplasmic reticulum Ca(2+)-ATPase.
Sarcoplasmic reticulum (SR) Ca(2+)-ATPase of the scallop cross-striated adductor muscle was purified with deoxycholate and digested with lysyl endopeptidase for sequencing of the digested fragments. Overlapping cDNA clones of the ATPase were isolated by screening the cDNA library with an RT-PCR product as a hybridization probe, which encodes the partial amino acid sequence of the ATPase. The predicted amino acid sequence of the ATPase contained all the partial sequences determined with the proteolytic fragments and consisted of the 993 residues with approximately 70% overall sequence similarity to those of the SR ATPases from rabbit fast-twitch and slow-twitch muscles. An outline of the structure of the scallop ATPase molecule is predicted to mainly consist of ten transmembrane and five 'stalk' domains with two large cytoplasmic regions as observed with the rabbit ATPase molecules. The sequence relationship between scallop and other sarco/endoplasmic reticulum-type Ca(2+)-ATPases is discussed.
Amino Acid Sequence↗
"cDNA cloning and predicted primary structure of scalllop sarcoplasmic reticulum Ca(2+)-ATPase" [Comp Biochem Physiol 119B(1998)777-785].
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Amino Acid Sequence↗
Power Doppler imaging of hepatic tumours: differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma.
We evaluated the usefulness of power Doppler imaging in the differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma. Forty-seven patients with hepatocellular carcinoma and 18 patients with metastatic adenocarcinoma were evaluated using power Doppler imaging. The colour signals of hepatic tumours were graded as follows: 1, colour signals only in the marginal area; 2, small dot or dotted line colour signals within the tumours; 3, continuous solid line colour signals within the tumours. The grade 3 colour signals were classified in the following three patterns; winding line pattern, stretched line pattern and mixed pattern. The colour signals of hepatocellular carcinoma were grade 1 in seven patients, grade 2 in 11 and grade 3 in 29. The colour signals of metastatic adenocarcinoma were grade 1 in three patients and grade 3 in 15. Of the 29 hepatocellular carcinoma patients with a grade 3 signal, 26 patients had winding line patterns and three had mixed patterns. Of the 15 metastatic adenocarcinoma patients with a grade 3 signal, 12 patients had stretched line patterns and three had mixed patterns. In conclusion, power Doppler imaging is useful in the differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma to evaluate the colour signal pattern within the tumour.
Adenocarcinoma↗
Transient protein-losing enteropathy associated with cytomegalovirus infection in a noncompromised host: a case report.
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Adult↗
Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor.
BACKGROUND: The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand-activated transcription factor that is considered to mediate pleiotropic biological responses such as teratogenesis, tumour promotion, epithelial hyperplasia and the induction of drug-metabolizing enzymes to environmental contaminants usually represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In contrast to the role of AhR in the regulatory mechanism of xenobiotic-metabolizing enzymes, there is no direct proof that the AhR is involved in the teratogenic effects of TCDD. RESULTS: To gain insight into the physiological and teratogenic role of the AhR, we have used gene targeting in mice to disrupt the murine Ahr gene by homologous recombination. Ahr-null mice were viable and fertile and were apparently normal at birth, but displayed a slightly slower growth rate than wild-type mice for the first few weeks of life. When pregnant dams were administered with TCDD by gavage, at a dose of 40 microg/kg body weight at gestation day 12.5, none of the Ahr-null mutant foetuses were sensitive to the teratogenic effects of TCDD, although almost all wild-type foetuses suffered from cleft palate and hydronephrosis. In heterozygous Ahr+/- genotypes, nearly all foetuses suffered from hydronephrosis in response to TCDD treatment, while haplo-insufficiency was observed in the incidence of cleft palate. CONCLUSION: These results clearly show that the AhR is involved in the malformation of the palate and kidney in mouse embryos caused by TCDD and suggests that the mechanism of its involvement differs between the cleft palate and hydronephrosis.
Animals↗
cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt).
We isolated mouse cDNA clones (Arnt2) that are highly similar to but distinct from the aryl hydrocarbon receptor (AhR) nuclear translocator (Arnt). The composite cDNA covered a 2,443-bp sequence consisting of a putative 2,136-bp open reading frame encoding a polypeptide of 712 amino acids. The predicted Arnt2 polypeptide carries a characteristic basic helix-loop-helix (bHLH)/PAS motif in its N-terminal region with close similarity (81% identity) to that of mouse Arnt and has an overall sequence identity of 57% with Arnt. Biochemical properties and interaction of Arnt2 with other bHLH/PAS proteins were investigated by coimmunoprecipitation assays, gel mobility shift assays, and the yeast two-hybrid system. Arnt2 interacted with AhR and mouse Sim as efficiently as Arnt, and the Arnt2-AhR complex recognized and bound specifically the xenobiotic responsive element (XRE) sequence. Expression of Arnt2 successfully rescued XRE-driven reporter gene activity in the Arnt-defective c4 mutant of Hepa-1 cells. RNA blot analysis revealed that expression of Arnt2 mRNA was restricted to the brains and kidneys of adult mice, while Arnt mRNA was expressed ubiquitously. In addition, whole-mount in situ hybridization of 9.5-day mouse embryos showed that Arnt2 mRNA was expressed in the dorsal neural tube and branchial arch 1, while Arnt transcripts were detected broadly in various tissues of mesodermal and endodermal origins. These results suggest that Arnt2 may play different roles from Arnt both in adult mice and in developing embryos. Finally, sequence comparison of the currently known bHLH/PAS proteins indicates a division into two phylogenetic groups: the Arnt group, containing Arnt, Arnt2, and Per, and the AhR group, consisting of AhR, Sim, and Hif-1alpha.
Amino Acid Sequence↗
Polymorphic forms of the Ah receptor and induction of the CYP1A1 gene.
Induction of cytochrome P4501A1 (CYP1A1) by certain xenobiotics is mediated by the Ah receptor/Arnt complex. The present knowledge about the molecular process of induction is summarized with special attention to our recent work on characterization of the polymorphic forms of the Ah receptor.
Cloning, Molecular↗
Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.
The genetic difference in the susceptibility of mice to environmental toxicities induced by dioxin and related chemicals is governed by polymorphism of the arylhydrocarbon receptor (AhR) (Poland, A., and Knutson, C. (1982) Annu. Rev. Pharmacol. Toxicol. 22, 517-554). cDNA cloning of AhR cDNA from responder (C57BL/6) and non-responder (DBA/2J) mice allowed us to analyze the structure and function of these AhRs. Both of the AhRs, which were expressed in COS-7 cells transfected with their expression plasmids, showed a clear 9 S complex with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD) in a linear glycerol gradient centrifugation, consistent with the result of the endogenously expressed AhR in Hepa-1 cells. This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically. Scatchard plot analysis revealed that the dissociation constant (Kd) of C57BL AhR for TCDD is 0.27 nM, while that of DBA AhR is elevated up to six times that high. Chimeric plasmids between the two cDNAs and site-directed mutagenesis revealed two critical alterations responsible for the reduced ligand binding activity: an Ala375 to Val alteration and an elongated carboxyl-terminal sequence due to a T to C mutation at the first letter of the termination codon of C57BL AhR. Two variants with reduced and intermediate ligand binding activity were also found in human AhRs with amino acid alterations equivalent to those of the DBA AhR. Importance of the amino acid at position 381 of human AhR (equivalent to position 375 of mouse AhR) in the ligand binding was confirmed by the fact that the mutation of Val381 to Asp completely abolished the ligand binding activity of human AhR.
Amino Acid Sequence↗
A complete structure of the mouse Ah receptor gene.
A complete sequence of the Ah receptor gene was cloned from a mouse genomic library by using the Ah receptor cDNA as a probe. The Ah receptor gene is 37.5 kb long and is split into 11 exons by 10 introns. Sequence analysis of the 5' flanking region of the Ah receptor gene reveals that there is neither a TATA box nor a CAAT box in the promoter region. Instead, this gene has a few GC boxes and other enhancer elements in the 5' upstream flanking region. Southern blot analysis indicated that the Ah receptor gene is a unique gene.
Animals↗