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PubMed1985

A novel form of ectopic human chorionic gonadotrophin beta-subunit in the serum of a woman with epidermoid cancer.

A novel form of free human chorionic gonadotrophin beta-subunit (hCG beta) was found in serum from ElBre, a woman with epidermoid carcinoma of unknown origin. ElBre hCG beta was larger than standard (pregnancy urine) hCG beta when analysed by gel chromatography (apparent molecular weight 54 000 vs 44 000). This size difference appeared to be due to a larger carboxyterminal extension (CTE) of ElBre hCG beta since thermolysin cleavage of the CTE from standard hCG beta and Elbre hCG beta yielded core products of the same size. Oligosaccharides, O-linked to serine or threonine, were present in ElBre hCG beta, presumably on its CTE as judged by the complete binding of desialylated ElBre hCG beta to immobilized peanut agglutinin (this lectin is specific for terminal galactose linked beta 1----3 to N-acetylgalactosamine, a disaccharide exposed after desialylation of the O-linked oligosaccharides of standard hCG beta). ElBre hCG beta, however, was incompletely recognized by antisera specific for the CTE of standard hCG beta, especially the carbohydrate-sensitive antiserum R141. The O-linked oligosaccharides of standard hCG beta are heterogeneous in size; 13% are of the largest (hexasaccharide) form. In contrast, over 50% of the O-linked oligosaccharides in hCG beta from the JAr choriocarcinoma cell line are hexasaccharides. Like desialylated ElBre hCG beta, desialylated JAr hCG beta bound completely to peanut agglutinin, but was incompletely recognized by antisera to the hCG beta-CTE. Furthermore, JAr hCG beta was intermediate in size between standard hCG beta and ElBre hCG beta when analysed by gel chromatography (apparent molecular weight 49 000).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell↗

PubMed1995

The neuropsychiatric aspects of boxing.

OBJECTIVE: To review the neuropsychiatry of boxing. METHOD: This update considers the clinical, neuropsychological, diagnostic, neurobiological, and management aspects of boxing-related brain injury. RESULTS: Professional boxers with multiple bouts and repeated head blows are prone to chronic traumatic encephalopathy (CTE). Repeated head blows produce rotational acceleration of the brain, diffuse axonal injury, and other neuropathological features. CTE includes motor changes such as tremor, dysarthria, and parkinsonism; cognitive changes such as mental slowing and memory deficits; and psychiatric changes such as explosive behavior, morbid jealousy, pathological intoxication, and paranoia. Screening with neuropsychological tests and neuroimaging may help predict those boxers at risk for CTE. CONCLUSIONS: Boxing results in a spectrum of CTE ranging from mild, nonprogressive motor changes to dementia pugilistica. Recent emphasis on safety in the ring, rehabilitation techniques, and other interventions do not eliminate the risk for CTE. For this reason, there is an active movement to ban boxing.

Athletic Injuries↗

PubMed2000

[Chemical composition of Creole cattle meat].

Proximal composition was determined in meat's Creole cattle (CGBC). For this purpose, four raw cuts of CGBC were analyzed: buttock, flank, loin blade steak, and shoulder blade steak. The mentioned names of the meat cuts come from the National Meat Bureau from the Republic of Argentina. These cuts were taken from an experimental lot of Creole cattle (n = 11) in Jujuy province. Comparisons were made with data extracted from Argentine Table of Food Composition, edited by National Nutrition Institute, Buenos Aires, Argentina (1942). The results show that the level of protein is slightly inferior (in the case of CGBC varies between 18.44 +/- 0.30 and 21.06 +/- 0.11 g/100 g, while in the CTE varies between 20 and 23.8 g/100 g). The content of lipids in the cuts without visible fat is variable (1.06 +/- 0.01 to 2.74 +/- 0.61 g/100 g in the cuts of CGBC and 1.4 to 8.4 for the cuts of CTE). The content of minerals is similar (Fe 2.26 +/- 0.18 to 2.35 +/- 0.23 mg/100 g in CGBC, while in the CTE varies between 3.15 and 3.46 mg/100 g; Phosphorous varies between 142 +/- 10 and 170 +/- 11 mg/100 g in CGBC and 186 to 213 mg/100 g in CTE). These outcomes allow to affirm that the quality of CGBC beef is very similar to CTE beef with regard to principal nutrients.

Analysis of Variance↗

PubMed1997

Secondary structure and mutational analysis of the Mason-Pfizer monkey virus RNA constitutive transport element.

The Mason-Pfizer monkey virus (MPMV) genome contains a cis-acting element that serves to facilitate nucleocytoplasmic export of intron-containing RNA. This element, known as the constitutive transport element (CTE), has been mapped to a 154-nt region close to the 3' end of the MPMV genome. The CTE contains a degenerate direct repeat of approximately 70 nt. We have probed the secondary structure of the CTE using double-strand- and single-strand-specific ribonucleases and chemical modification agents. A mutational analysis was also performed to confirm critical features of the CTE structure, as well as to identify regions that contain sequence-specific information required for function. Our results indicate that the CTE forms a long stem structure that contains a 9-nt terminal hairpin loop as well as two identical 16-nt inner loops. The inner loop sequences are rotated 180 degrees relative to each other within the structure. The mutational analysis shows that primary sequences in the loop regions are important for function, suggesting that they may contain binding sites for cellular proteins involved in RNA export. Interestingly, sequences with significant homology to the inner loop regions are found in the genomes of spumaviruses and mouse intracisternal A particles.

Base Sequence↗

PubMedDate not supplied

Isoflurane increases the anaerobic metabolites of halothane.

The effect of isoflurane on the anaerobic metabolism of halothane to chlorodifluoroethene (CDE) and chlorotrifluoroethane (CTE) was studied with microsomes of guinea pig liver by gas chromatography. The reaction mixture used to measure the end products of anaerobic metabolism consisted of a microsomal suspension, 3 mM NADPH, halothane and isoflurane (except in control groups) in 0.1 M potassium phosphate buffer solution (pH 7.4). The Km values for CDE formation were 601.61 +/- 266.91, 254.22 +/- 86.58, 257.92 +/- 129.11, 268.55 +/- 125.66 and 319.22 +/- 86.76 microM (mean +/- SD, n = 5) at 0 mM (0%), 0.12 mM (0.26%), 0.29 mM (0.64%), 0.58 mM (1.30%) and 1.16 mM (2.59%) isoflurane, respectively. The Km values for CTE formation were 1204.74 +/- 551.64, 553.75 +/- 177.89, 521.14 +/- 249.77, 560.67 +/- 229.61 and 711.05 +/- 317.13 microM (n = 5) at 0 mM (0%), 0.12 mM (0.26%), 0.29 mM (0.64%), 0.58 mM (1.30%) and 1.16 mM (2.59%) isoflurane, respectively. In contrast, the Vmax values for CDE and CTE formation at these isoflurane concentrations were not significantly different than in the control groups. In this study the production of CDE and CTE was significantly (P < 0.05) increased by isoflurane, at concentrations up to 0.58 mM (1.30%).

Anaerobiosis↗

PubMed2000

Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors.

We present a systematic comparison of three modules that enhance expression from retroviral gene transfer vectors at a posttranscriptional level: (i) splice signals (SS) that create an intron in the 5' untranslated region; (ii) constitutive RNA transport elements (CTE), originally discovered in D-type retroviruses; and (iii) the posttranscriptional regulatory element of woodchuck hepatitis virus (WPRE). Here we show that enhancement of expression depends not only on the specific element, but also on the gene of interest, implying context-dependent activity of the RNA elements. Interestingly, different results were obtained for genes that normally require or do not require such control elements. Expression of the HIV-1 gag-protease gene, which normally depends on the viral export factor Rev, was strongly enhanced by an oligomeric CTE, while WPRE had only a marginal effect. On the other hand, both CTE and WPRE compensated for the lack of an intron in the expression of human beta-globin. In this case, the strongest stimulation of RNA production was observed when functional SS were combined with the WPRE. Both CTE and, in particular, WPRE also enhanced expression of cDNAs that do not normally require any such element (green fluorescent protein, human multidrug resistance-1). In this study, functional SS and WPRE acted in an additive manner, resulting in a 10-fold higher level of expression. Our results indicate that the described modules act on different levels of RNA processing, transport, and translation and that the correct choice of a posttranscriptional enhancer configuration depends on the type of cDNA to be expressed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Rev/RRE-independent Mason-Pfizer monkey virus constitutive transport element-dependent propagation of SIVmac239 vectors using a single round of replication assay.

In a step toward creating live-attenuated or DNA subunit vaccines for AIDS, the replication of simian immunodeficiency virus (SIV) was studied independently of the Rev and RRE (Rev-responsive element) regulatory system, over a single round. To accomplish this, the env gene of an SIV vector was made defective by the insertion of a SV40 promoter/enhancer hygromycin B phosphotransferase gene cassette. Using this vector as the backbone, molecular clones of SIV were generated that contained a mutated Rev, Rev(-), a deleted RRE, RRE(-), or both, Rev(-)RRE(-). It has been shown recently that human immunodeficiency virus type 1 (HIV-1) Rev and RRE functions can be replaced in vitro by a cis-acting sequence, constitutive transport element (CTE), from simian type D retroviruses. To determine whether such a cis-acting element from Mason-Pfizer monkey virus (MPMV) would substitute for SIV Rev and RRE functions, the MPMV CTE was inserted either into the Nef ORF or at the junction of vpx and vpr of our Rev(-), RRE(-), and Rev(-)RRE(-) SIV molecular clones. Cell-free viral stocks harvested from Cos cells following transfections of these molecular clones revealed that these stocks were infectious over a single round of replication; however, their replication was attenuated 16-fold compared to that of wild-type virus. In addition, our experiments revealed that CTE functions in a position-dependent manner such that its insertion at the junction of vpx and vpr attenuated SIV replication 8- to 12-fold compared to the attenuation observed when it was inserted in the nef region. Our results demonstrate that MPMV CTE is capable of substituting for SIV Rev and RRE functions, resulting in an attenuated ability to produce infectious virus.

Animals↗

PubMed2001

Nucleocytoplasmic RNA transport in retroviral replication.

Retroviral replication is highly dependent on post-transcriptional regulation because a single primary transcript directs synthesis of many viral proteins. The identification and characterization of two post-transcriptional regulatory systems (Rev/RRE and CTE) revealed the efficient use of cellular transport pathways by retroviruses to achieve production of infectious progeny virus. The Rev/RRE system of HIV-1 consists of the viral Rev protein which binds to its target sequence on incompletely spliced RNAs and channels these into the CRM1-dependent export pathway, which is normally used for export of cellular proteins and RNAs (U snRNAs and 5 S rRNA). The CTE, on the other hand, directly recruits the cellular mRNA export receptor TAP to the viral RNA. Both systems have in common that they recruit a key player of a specific cellular export pathway and this recruitment appears to out-compete the respective cellular target molecules. The fact that CTE can functionally substitute for Rev/RRE, yielding a replication-competent virus, indicates that very short sequence elements are sufficient for post-transcriptional control. The presence of short dominant export signals could relieve the selective pressure on the remainder of the genome to maintain a sequence that is easily exported. The resultant increase in permitted sequence space may increase the potential for immune escape, thereby providing a selective advantage for the virus. Replication of the CTE-dependent HIV-1 variant is significantly impaired compared with the wild-type virus. Considering that post-transcriptional control in the case of HIV is also used to provide a temporal switch from the early phase of regulatory protein expression to the late phase of virion production, one may suggest that the CRM1 export pathway is advantageous for the rapid delivery of large amounts of cargo (i.e. HIV RNA). This would be in accordance with its normal function because CRM1 has been shown to direct the nuclear export of cellular regulatory proteins which must be accomplished rapidly as well. In summary, retroviruses have evolved fascinating ways to deal with their cellular environment and to make use of cellular transport pathways, allowing nuclear export of intron-containing RNAs which are normally restricted to the nucleus. Specific signals on the viral RNAs recruit key factors of cellular export, thus bypassing these restrictions and ensuring efficient viral replication.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2007

A microscale device for measuring emissions from materials for indoor use.

Emission test chambers or cells are used to determine organic vapour emissions from construction products under controlled conditions. Polymeric car trim component emissions are typically evaluated using direct thermal desorption/extraction. The Microchamber/Thermal Extractor (mu-CTE, Markes International) was developed to provide both a complementary tool for rapid screening of volatile organic compound (VOC) emissions--suitable for industrial quality control--and a means for thermal extraction of larger, more representative samples of car trim components. To determine the degree of correlation between conventional emission test methods and the microchamber, experiments were carried out under different conditions of temperature, air change rate and sample conditioning time. Good quantitative and qualitative correlation was obtained for measurements at ambient temperature. Moreover, it was shown that ambient-temperature emissions data collected using the mu-CTE as rapidly as possible--i.e. with minimal or no sample conditioning time--nevertheless provided a reliable guide as to how well that material would perform in subsequent 3-day chamber tests of VOC emissions. The parameters found to have the greatest influence on data correlation for experiments carried out at elevated temperatures were the sample mass (for bulk emissions testing) and the conditioning time. The results also showed that, within the constraints of inherent sample homogeneity, the mu-CTE gave reproducible emissions data, despite its small sample size/capacity relative to that of conventional chambers. Preliminary results of modelling the air flow within a microchamber using computational fluid dynamics showed a high degree of turbulent flow and two potential areas of still air which could cause sink effects. However, the experimental data reported here and in previous studies showed enhanced recovery of semivolatile components from the mu-CTE relative to a recovery from a 1 m(3) conventional chamber. This indicates that if these areas of relatively still air are present within the microchamber, they do not appear to be significant in practice.

Journal Article↗

PubMed2002

Immunohistochemical localization of acyl-CoA hydrolase/thioesterase multigene family members to rat epithelia.

Acyl-CoA hydrolases cleave acyl-CoA thioesters to free fatty acids and coenzyme A. The potency of these enzymes may serve to modulate cellular levels of acyl-CoAs to affect various cellular functions, including lipid metabolism. In this study, we investigated the tissue distribution of this multigene family of enzymes, focusing on cytosolic (CTE-I) and mitochondrial acyl-CoA thioesterases (MTE-I) in adult rats, using an anti-CTE-I antibody which recognizes both the isoforms. Western blotting detected them mainly in organs closely related to fatty acid oxidation, of which kidney contained the highest levels of both enzymes. Immunohistochemistry localized the enzymes primarily in the proximal tubules, where a large energy demand is expected and fatty acids represent a major fuel, correlating well with the intrarenal distribution of peroxisomal beta-oxidation. In situ hybridization suggested colocalization of CTE-I and MTE-I in the kidney. The immunoreactivity was also found in various epithelial tissues in the body, including Harderian gland and sebaceous gland. These results demonstrated the distribution of CTE-I and MTE-I in a wide variety of rat tissues, primarily characterized by an epithelial localization, being consistent with their involvement in fatty acid metabolism.

Adipose Tissue, Brown↗

PubMed1985

Formation of bacterial mutagens from the reaction of chewing tobacco with nitrite.

Using the Salmonella/microsome assay system, the mutagenicity of chewing tobacco extracts (CTE) treated with and without sodium nitrite under acidic conditions was examined. Mutagenic activity was found only for nitrite-treated CTE in both tester strains, TA98 and TA100, and was independent of metabolic activation. Formation of mutagenic substances from CTE by nitrite was dependent on acidic pHs (the highest at pH 2) and could be inhibited by ascorbate. The mutagenic potency of CTE plus nitrite was proportional to the content of nitroso compounds generated in the reaction mixture, indicating that the nitrosation process was involved. The possible in vivo nitrosation and the potential health effect are discussed.

Animals↗

PubMed2005

Impairment in clock-time estimation following right hemisphere ischemic damage.

In order to assess clock-time estimation (CTE), we asked "what time is it in your opinion?" to 48 recent stroke in-patients, 21 with right (RH), 27 with left hemispheric (LH) lesions, and to 20 control in-patients without brain lesions (C). Errors were measured in terms of the number of minutes by which the estimated clock-time was later (advance errors) or earlier (delay errors) than the real clock-time. CTE was considered pathological when exceeding the mean advance or delay errors observed in control patients plus 2.5 standard deviations. The estimation of the duration of a short psychological interview was also assessed. CTE, and not duration estimation, was disturbed in patients. RH patients made significantly more pathological advance errors than LH patients (43% vs. 12%). This study points out the RH dominance for CTE in stroke patients.

Adult↗

PubMed2003

Hepatic induction of mitochondrial and cytosolic acyl-coenzyme a hydrolases/thioesterases in rats under conditions of diabetes and fasting.

Acyl-coenzyme A (CoA) hydrolases/thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoA thioesters to free fatty acids and CoA-SH. The potency of these enzymes may serve to modulate intracellular concentrations of acyl-CoAs, free fatty acids, and CoA to affect various cellular functions, including lipid metabolism. In this study, we investigated the effect of diabetes and fasting on the protein levels of mitochondrial (MTE-I) and cytosolic acyl-CoA thioesterases (CTE-I), multigene family members of this class of enzymes, in adult rat liver. Rats were treated with alloxan to induce diabetes or fasted for 72 hours. Western blot analysis with the liver homogenates revealed 2.8-fold and 3.8-fold increases in MTE-I and 8.5-fold and 9.2-fold increases in CTE-I under the diabetic and fasting conditions, respectively, compared with the control in which the level of MTE-I was 4.3-fold higher than CTE-I. Serum level of free fatty acids was elevated 5-fold and 2.5-fold in diabetic and fasted rats, respectively. These results confirm the adaptive induction of MTE-I and CTE-I in response to fatty acid overload in the liver, being consistent with their auxiliary role in fatty acid degradation.

Animals↗

PubMed2001

Analysis of the S(2) subsite specificities of the recombinant cysteine proteinases CPB of Leishmania mexicana, and cruzain of Trypanosoma cruzi, using fluorescent substrates containing non-natural basic amino acids.

We have explored the specificity of the S(2) subsite of recombinant cysteine proteinases from Leishmania mexicana (CPB2.8 Delta CTE) and from Trypanosoma cruzi (cruzain) employing a series of fluorogenic substrates based on the peptide Bz-F-R-MCA, in which Bz is the benzoyl group and the Phe residue has been substituted for by Arg, His and non-natural basic amino acids that combine a basic group with an aromatic or hydrophobic group at the side chain: 4-aminomethyl-phenylalanine (Amf), 4-guanidine phenylalanine (Gnf), 4-aminomethyl-N-isopropyl-phenylalanine (Iaf), 3-pyridyl-alanine (Pya), 4-piperidinyl-alanine (Ppa), 4-aminomethyl-cyclohexyl-alanine (Ama), and 4-aminocyclohexyl-alanine (Aca). Bz-F-R-MCA was hydrolyzed well by CPB2.8 Delta CTE and cruzain, but all the substitutions of Phe resulted in less susceptible substrates for the two enzymes. CPB2.8 Delta CTE has a restricted specificity to hydrophobic side chains as with cathepsin L. However, the peptides with the residues Amf and Ama presented higher affinity to CPB2.8 Delta CTE, and the latter was an inhibitor of the enzyme. Although, cruzain accepts basic as well as hydrophobic residues at the S(2) subsite, it is more restrictive than cathepsin B and no inhibitor was found amongst the examined peptides.

Amino Acids, Basic↗

PubMed2002

An element in the 3' untranslated region of human LINE-1 retrotransposon mRNA binds NXF1(TAP) and can function as a nuclear export element.

Export of unspliced mRNA to the cytoplasm is required for the replication of all retroviruses. In simian type D retroviruses, the RNA export is mediated by the constitutive transport element (CTE) that binds the cellular nuclear export factor 1, NXF1(TAP). To search for potential cellular RNA substrates for NXF1, we have set up an in vitro selection procedure, using an RNA library expressed from total human genomic DNA. A sequence that was isolated most frequently as independent clones exhibits extensive homology to the 3' untranslated region of expressed LINE1 (L1) retrotransposons. This region, termed L1-NXF1 binding element (L1-NBE) bears no structural resemblance to the viral CTE, but binds NXF1 as strongly as CTE, based on gel mobility shift competition assays. A deletion analysis of the NXF1 protein reveals that CTE and L1-NBE have different, but overlapping, binding domains on NXF1. Placed in an intron, L1-NBE is capable of mediating nuclear export of lariat RNA species in Xenopus laevis oocytes and of an unspliced HIV-1 derived RNA in human 293 cells, suggesting that it may function as a nuclear export element for the intronless L1 mRNA.

3' Untranslated Regions↗

PubMed1985

Isolation and characterization of chicken thymic electrolectin.

We have detected the presence of a beta-D-galactoside-binding lectin (electrolectin) in extracts of the thymus of adult chickens. This lectin was purified by affinity chromatography on a lactosyl-Sepharose column to yield 1.4 mg of pure protein from 230 g of thymus. The chicken thymic electrolectin (CTE) has an Mr of 15 300 when analysed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and of 30 000 when analysed by gel filtration. The amino acid composition of CTE is similar to that of other electrolectins purified from human and rat lung. CTE cross-reacts immunologically, but is not identical, with electrolectins from electric-eel electric organ and from chick-embryo pectoral muscle. CTE agglutinates chicken thymocytes but does not appear to promote their mitosis.

Amino Acids↗

PubMed2001

S1 subsite specificity of a recombinant cysteine proteinase, CPB, of Leishmania mexicana compared with cruzain, human cathepsin L and papain using substrates containing non-natural basic amino acids.

We have explored the substrate specificity of a recombinant cysteine proteinase of Leishmania mexicana (CPB2.8 Delta CTE) in order to obtain data that will enable us to design specific inhibitors of the enzyme. Previously we have shown that the enzyme has high activity towards substrates with a basic group at the P1 position [Hilaire, P.M.S., Alves, L.C., Sanderson, S.J., Mottram, J.C., Juliano, M.A., Juliano, L., Coombs, G.H. & Meldal M. (2000) Chem. Biochem. 1, 115--122], but we have also observed high affinity for peptides with hydrophobic residues at this position. In order to have substrates containing both features, we synthesized one series of internally quenched fluorogenic peptides derived from the sequence ortho-amino-benzoyl-FRSRQ-N-[2,4-dinitrophenyl]-ethylenediamine, and substituted the Arg at the P1 position with the following non-natural basic amino acids: 4-aminomethyl-phenylalanine (Amf), 4-guanidine-phenylalanine (Gnf), 4-aminomethyl-N-isopropyl-phenylalanine (Iaf), 3-pyridyl-alanine (Pya), 4-piperidinyl-alanine (Ppa), 4-aminomethyl-cyclohexyl-alanine (Ama), and 4-aminocyclohexyl-alanine (Aca). For comparison, the series derived from ortho-amino-benzoyl-FRSRQ-N-[2,4-dinitrophenyl]-ethylenediamine was also assayed with cruzain (the major cysteine proteinase of Trypanosoma cruzi), human cathepsin L and papain. The peptides ortho-amino-benzoyl-FAmfSRQ-N-[2,4-dinitrophenyl]-ethylenediamine (k(cat)/K(m) = 12,000 mM(-1) x s(-1)) and ortho-amino-benzoyl-FIafSRQ-N-[2,4-dinitrophenyl]-ethylenediamine (k(cat)/K(m) = 27,000 mM(-1) x s(-1)) were the best substrates for CPB2.8 Delta CTE. In contrast, ortho-amino-benzoyl-FAmaSRQ-N-[2,4-dinitrophenyl]-ethylenediamine and ortho-amino-benzoyl-FAcaSRQ-N-[2,4-dinitrophenyl]-ethylenediamine were very resistant and inhibited this enzyme with K(i) values of 23 nM and 30 nM, respectively. Cruzain hydrolyzed quite well the substrates in this series with Amf, Ppa and Aca, whereas the peptide with Ama was resistant and inhibited cruzain with a K(i) of 40 nM. Human cathepsin L presented an activity on these peptides very similar to that of CPB2.8 Delta CTE and papain hydrolyzed all the peptides with high efficiency. In conclusion, we have demonstrated that CPB2.8 Delta CTE has more restricted specificity at the S1 subsite and it seems possible to design efficient inhibitors with amino acids such as Ama or Aca at the P(1) position.

Animals↗

PubMed1998

A carboxyl-terminal extension of the zinc finger domain contributes to the specificity and polarity of peroxisome proliferator-activated receptor DNA binding.

Heterodimers of the peroxisome proliferator-activated receptors (PPAR) and the retinoid X receptors (RXR) recognize response elements (PPREs) that exhibit the consensus sequence 5'-A(A/T)CT(A/G)GGNCAAAG(G/T)TCA-3'. The consensus PPRE includes both a 5'-extension and a direct repeat (DR1) comprised of two canonical core recognition sequences (underlined) for nuclear receptor zinc fingers separated by a single nucleotide spacer. The extended binding site recognized by PPARs is very similar to sites that bind monomers of the nuclear receptors Rev-ErbA and ROR suggesting that the latter could bind to PPREs and affect gene transcription. However, Rev-ErbA and ROR bind weakly to naturally occurring PPREs relative to the consensus binding site, and significant effects on PPARalpha transactivation of a CYP4A6-Z reporter were not observed. In contrast, PPAR/RXR heterodimers bind to a DR2 element containing the conserved 5'-extended sequence that is recognized by dimers of RORalpha or Rev-ErbA. PPARalpha/RXRalpha positively regulate transcription from this element, and co-expression of Rev-ErbA blocks this effect. The nuclear receptors NGFI-B and ROR utilize a carboxyl-terminal extension (CTE) of the zinc finger DNA binding domain in their interactions with the 5'-extension of a single zinc finger-binding site. DNA binding domains (DBD) of PPARs alpha, delta, and gamma that contain the zinc finger motif and a CTE display binding to core recognition sequences that is dependent on the 5'-extended sequence found in PPREs. Unlike DBDs of other nuclear receptors that form heterodimers with RXR, the PPAR-DBDs did not exhibit cooperative binding with the DBD of RXR and exhibit the opposite polarity for binding to the direct repeat motif. In contrast to the corresponding DBD of RXR, the PPAR-DBDs bind as monomers to a single extended binding site as well as to the consensus PPRE. A chimera linking the zinc finger domain of RXRalpha to the CTE from PPARalpha bound to a single extended binding site indicating a functional role for the CTE of PPARs in extended binding site recognition.

Amino Acid Sequence↗