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PubMed2003

The parathyroid hormone mRNA 3'-untranslated region AU-rich element is an unstructured functional element.

Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally by hypocalcemia and hypophosphatemia. This regulation is dependent upon binding of protective trans-acting factors to a specific element in the PTH mRNA 3'-untranslated region (UTR). We have previously demonstrated that a 63-nucleotide (nt) AU-rich PTH mRNA element is sufficient to confer regulation of RNA stability by calcium and phosphate in an in vitro degradation assay (IVDA). The 63-nt element consists of a core 26-nt minimal binding sequence and flanking regions. We have now studied the functionality of this element in HEK293 cells using reporter genes and showed that it destabilizes mRNAs for green fluorescent protein (GFP) and growth hormone, similar to its effect in the IVDA. To understand how the cis-element functions as an instability element, we have analyzed its structure by RNase H, primer extension, and computer modeling. The results indicate that the PTH mRNA 3'-UTR and in particular the region of the cis-element are dominated by significant open regions with little folded base pairing. Mutation analysis of the 26-nt core element demonstrated the importance of defined nucleotides for protein-RNA binding. In the GFP reporter system, the same mutations that prevented binding were also ineffective in destabilizing GFP mRNA in HEK293 cells. This is the first study of an AU-rich element that relates function to structure. The PTH mRNA 3'-UTR cis-acting element is an open region that utilizes the distinct sequence pattern to determine mRNA stability by its interaction with trans-acting factors.

3' Untranslated Regions↗
PubMed2004

Predicting rules on organization of cis-regulatory elements, taking the order of elements into account.

MOTIVATION: In eukaryotes, rules regarding organization of cis-regulatory elements are complex. They sometimes govern multiple kinds of elements and positional restrictions on elements. RESULTS: We propose a method for detecting rules, by which the order of elements is restricted. The order restriction is expressed as element patterns. We extract all the element patterns that occur in promoter regions of at least the specified number of genes. Then, we find significant patterns based on the expression similarity of genes with promoter regions containing each of the extracted patterns. When we applied our method to Saccharomyces cerevisiae, we detected significant patterns overlooked by previous methods, thus demonstrating the utility of our method for analyses of eukaryotic gene regulation. We also suggest that several types of element organization exist: (i) those in which only the order of elements is important, (ii) order and distance both are important and (iii) only the combination of elements is important. AVAILABILITY: The program for extracting element patterns is available upon request.

Algorithms↗
PubMed1989

The rat albumin promoter: cooperation with upstream elements is required when binding of APF/HNF1 to the proximal element is partially impaired by mutation or bacterial methylation.

We have characterized in the accompanying paper (P. Herbomel, A. Rollier, F. Tronche, M.-O. Ott, M. Yaniv, and M. C. Weiss, Mol. Cell. Biol. 9:4750-4758, 1989) six different elements in the albumin promoter. One of them, the proximal element (PE), is the binding site for a strictly liver specific factor, APF/HNF1. This binding site contains a bacterial DAM DNA methylase methylation target sequence which, when methylated, decreases the affinity of the protein for this element. When the different albumin promoter constructions were prepared in an Escherichia coli deoxyadenosine methylase-negative strain, the respective contributions of the elements to the overall promoter activity were strikingly different. An intact proximal element plus the TATA box gave almost full transcriptional activity in transient transfection experiments and only in differentiated hepatoma cells of line H4II, whereas the distal elements (distal element III [DEIII], the NF1-binding site DEII, and the E/CBP-binding site DEI) had become essentially dispensable. Mutations affecting the CCAAT box showed only a two- to threefold decrease. When PE was methylated, mutated, or replaced by the homologous element from the alpha-fetoprotein gene, activity in the context of the short promoter (PE plus the TATA box) was abolished. However, activity was restored in the presence of the upstream elements, showing that cooperation with factors binding to the CCAAT box and distal elements favors the functional interaction of the liver-specific APF/HNF1 factor with lower-affinity binding sites.

Albumins↗
PubMed1999

DNA-protein interactions between mammalian nuclear proteins and a GCC-element included in a composite cis-acting element of mouse ribosomal protein L32 promoter.

DNA-protein complex formation between the sequence GC(GCC)4 (GCC-element) of mouse ribosomal protein L32 (rpL32) promoter and nuclear proteins of mouse and human cells has been studied using gel retardation and South-Western blotting methods. The rpL32 promoter fragment (-24.+11) was able to form specific complexes with mouse and human nuclear proteins mainly due to the presence of the GCC-element (-19.-6). DNA-protein complex patterns exhibited marked tissue-specificity. Three nuclear polypeptides of approximately 18, 28, and 50 kD that bind to the rpL32 promoter region (-24.+11) have been detected in HeLa cells by ligand blotting. At least one of them (18 kD) interacted with the GCC-element directly. The same fragment of the promoter interacted only with one nuclear polypeptide (28-31 kD) from human fibroblasts. DNA-protein complex formation between the investigated rpL32 promoter fragment containing the GCC-element and human fibroblast nuclear proteins is Zn2+-dependent. The method of functional titration (in vivo competition in the CAT-test) revealed that the GCC-element within the rpL32 promoter functions as a positive cis-acting transcriptional element in NIH 3T3 cells. Thus, our data characterize the sequence GC(GCC)4 as a functionally active cis-element included as a component in the more complex (composite) cis-element of mouse rpL32 promoter exhibiting tissue-specific properties. In various mammalian cell types the GCC-element can interact with various nuclear proteins, and the mode of these interactions can be determined by its relative position to other cis-elements in the regulatory sites of the genome.

3T3 Cells↗
PubMed1992

A regulatory element that mediates co-operation between a PEA3-AP-1 element and an AP-1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells.

We have characterized a transcriptional enhancer of the human urokinase-type plasminogen activator (uPA) gene and found a regulatory element required for co-operation between a PEA3--AP-1 element and an AP-1 site in the enhancer. We designated this regulatory element co-operation mediator (COM). Both the PEA3--AP-1 element, the AP-1 site and the COM are required for efficient phorbol ester induction of transcription from the uPA promoter in the HepG2 hepatoma cell line. We show that the COM is also required for co-operation between the PEA3--AP-1 element and a glucocorticoid response element, both in the presence or absence of TPA, indicating that the COM is generally capable of mediating synergism between inducible enhancer elements. The COM contains multiple overlapping binding sites for nuclear proteins, designated uPA enhancer factors 1-4 (UEF-1-4). We have identified putative binding sites for UEF-1, -2 and -3. The UEF-1 and -3 sites in the uPA enhancer are highly conserved between species. We demonstrate the binding of UEF-3 to the NIP element, a previously characterized regulatory element in the human interleukin-3 and stromelysin promoters, suggesting that this factor plays a role in regulation of a variety of genes.

Base Sequence↗
PubMed1991

Identification and structural characterization of further DNA elements in the potato and pepper genomes homologous to the transposable element-like insertion Tst1.

The molecular cloning and nucleotide sequence of elements from potato and pepper that are related to the recently identified Tst1 element are described. Sequence analysis reveals considerable conservation of sequences internal to both the Tst1 element and two of the related elements identified here. In six potato clones analysed, the 11 bp inverted repeat first identified in the Tst1 element is conserved. Several of the elements are flanked by an 8 bp direct repeat. DNA fragments which were amplified from several pepper genomes by polymerase chain reaction (PCR) amplification using the inverted repeat as sequence primers also display considerable conservation of sequences internal to the Tst1 element. These data further support the possibility that Tst1 is a non-autonomous transposable element and that Tst1 might be the first example of a transposable element which occurs in several genera of solanaceous plants.

Base Sequence↗
PubMed1991

A major factor contributing to the high degree of unexplained variability of some elements concentrations in biological tissue: 27 elements in 5 organs of the mussel Mytilus as a model.

It has long been known that a high degree of "unexplained" residual variability can occur in the concentrations of some elements in some biological tissues. Until now, no reasons have been found for the presence of such high levels of variability. The present study describes a factor which can adequately explain this phenomenon. It was found that elements which are stored primarily in an insoluble form showed much higher degrees of variability than those stored in a soluble form. Elements found primarily in an insoluble form are often isolated from cellular metabolism including any regulatory processes and may build up to high levels in some individuals. The groups of elements showing the highest levels of residual variability were the heavy metals, lanthanides and actinides. These groups tended to be stored primarily in an insoluble form as determined by subcellular fractionation. The groups of elements showing the lowest levels of residual variability were the alkali metals and non-metals which were found to occur primarily in a soluble form in mussel tissue. The elements of the kidney generally had higher levels of residual variability than those of any other organ probably because of the kidney's ability to store high concentrations of elements in insoluble granules. A study of the behavior of aluminum in the digestive gland suggests that elements associated with insoluble granules of sediment passing through the gut could contribute to the residual variability of these elements. The highest levels of residual variability were observed for zinc, silver and lead in the kidney while the lowest for rubidium in the gills.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

The ICESt1 element of Streptococcus thermophilus belongs to a large family of integrative and conjugative elements that exchange modules and change their specificity of integration.

The 34,734-bp element ICESt1 from Streptococcus thermophilus CNRZ368 is site-specifically integrated into the 3(') end of the gene fda. ICESt1 encodes integrative functions and putative transfer functions. Six proteins of the putative conjugative system of ICESt1 are related to those encoded by the conjugative transposon Tn916 from Enterococcus faecalis. A comparison of these proteins with those encoded by the complete or partial genome sequences of various low G+C bacteria including Bacillus subtilis, Clostridium difficile, E. faecalis, Listeria monocytogenes, Staphylococcus aureus, and Streptococcus mutans revealed the presence of numerous putative site-specific integrative conjugative elements and/or conjugative transposons within these genomes. Sequence comparisons revealed that these elements possess a modular structure and that exchanges of unrelated or distantly related modules and genes have occurred between these elements, and also plasmids and prophages. These exchanges have probably led to modifications in the site specificity of integration of these elements. Therefore, a distinction between low specificity integrative conjugative elements (i.e., conjugative transposons) and site-specific integrative conjugative elements does not appear to be relevant. We propose to call all the conjugative elements that excise by site-specific recombination and integrate by recombination between a specific site of a circular intermediate and another site, "Integrative and Conjugative Elements" (ICEs), irrespective of the integration specificity.

Base Composition↗
PubMed2002

Ultraviolet B (UVB) induction of the c-fos promoter is mediated by phospho-cAMP response element binding protein (CREB) binding to CRE and c-fos activator protein 1 site (FAP1) cis elements.

The ultraviolet B (UVB) portion (280-320 nm) of the ultraviolet spectrum has been shown to contribute to the development of non-melanoma skin cancer in humans. Research in the human keratinocyte cell line, HaCaT, revealed that UVB irradiation caused the upregulation of the transcription factor activator protein-1 (AP-1). The AP-1 complex formed in UVB-irradiated HaCaT cells is specifically composed of c-fos and Jun D. c-Fos expression was induced in a manner that correlated with the UVB-induced activation of AP-1. To investigate how c-fos expression is regulated by UVB irradiation, the role of each of four cis elements within the c-fos promoter was evaluated. Clustered point mutations at the sis inducible element (SIE), serum response element (SRE), c-fos AP-1 site (FAP1), or cyclic AMP response elements (CRE) significantly inhibited UVB induction of the c-fos promoter. This indicated that all four cis elements are required for maximum promoter activity. The CRE and FAP1 elements were the two most active cis elements that mediate the UVB transactivation of c-fos. Homodimers of phosphorylated cAMP response element binding protein (CREB) were induced by UVB irradiation to bind to each of these elements. Therefore, CREB may function as an important regulatory protein in the UVB-induced expression of c-fos.

Binding Sites↗
PubMed1992

The distribution of transposable elements within and between chromosomes in a population of Drosophila melanogaster. I. Element frequencies and distribution.

Data were collected on the distribution of nine families of transposable elements among second and third chromosomes isolated from a natural population of Drosophila melanogaster, by means of in situ hybridization of element probes to polytene chromosomes. It was found that the copy numbers per chromosome in the distal sections of the chromosome arms followed a Poisson distribution. Elements appeared to be distributed randomly along the distal sections of the chromosome arms. There was no evidence for linkage disequilibrium in the distal sections of the chromosomes, but some significant disequilibrium was detected in proximal regions. There were many significant correlations between different element families with respect to the identity of the sites that were occupied in the sample. There were also significant correlations between families with respect to sites at which elements achieved relatively high frequencies. Element frequencies per chromosome band were generally low in the distal sections, but were higher proximally. These results are discussed in the light of models of the population dynamics of transposable elements. It is concluded that they provide strong evidence for the operation of a force or forces opposing transpositional increase in copy number. The data suggest that the rate of transposition per element per generation is of the order of 10(-4), for the elements included in this study.

Animals↗
PubMed1999

The effectiveness of element downsizing on a three-dimensional finite element model of bone trabeculae in implant biomechanics.

More validity of finite element analysis in implant biomechanics requires element downsizing. However, excess downsizing needs computer memory and calculation time. To investigate the effectiveness of element downsizing on the construction of a three-dimensional finite element bone trabeculae model, with different element sizes (600, 300, 150 and 75 microm) models were constructed and stress induced by vertical 10 N loading was analysed. The difference in von Mises stress values between the models with 600 and 300 microm element sizes was larger than that between 300 and 150 microm. On the other hand, no clear difference of stress values was detected among the models with 300, 150 and 75 microm element sizes. Downsizing of elements from 600 to 300 microm is suggested to be effective in the construction of a three-dimensional finite element bone trabeculae model for possible saving of computer memory and calculation time in the laboratory.

Biomechanical Phenomena↗
PubMed1989

The heritable activation of cryptic Suppressor-mutator elements by an active element.

A weakly active maize Suppressor-mutator (Spm-omega) element is able to heritably activate cryptic Spm elements in the maize genome. The spontaneous activation frequency, which is 1-5 x 10(-5) in the present genetic background, increases by about 100-fold in the presence of an Spm-omega and remains an order of magnitude above the background level a generation after removal of the activating Spm-omega. Sectorial somatic reactivation of cryptic elements can be detected phenotypically in kernels. Selection of such kernels constitutes an efficient selection for plants with reactivated Spm elements. Analysis of the reactivation process reveals that it is gradual and proceeds through genetically metastable intermediates that exhibit different patterns of element expression during plant development. Newly reactivated elements tend to return to an inactive form. However, the probability that an element will remain in a heritably active state increases when the element is maintained in the presence of an active Spm element for several generations.

Alleles↗
PubMed2001

The mutant phenotype associated with P-element alleles of the vestigial locus in Drosophila melanogaster may be caused by a readthrough transcript initiated at the P-element promoter.

We report here the isolation of a new P-element-induced allele of the vestigial locus vg(2a33), the molecular characterization of which allows us to propose a unifying explanation of the phenotypes of the large number of vestigial P-element alleles that now exists. The first P-element allele of vestigial to be isolated was vg(21), which results in a very weak mutant wing phenotype that is suppressed in the P cytotype. By destabilizing vg(2a33) in a dysgenic cross, we isolated the vg(2a33) allele, which exhibits a moderate mutant wing phenotype and is not suppressed by the P cytotype. The new allele is characterized by a 46-bp deletion that removes the 3'-proximal copy of the 11-bp internal repeat from the P element of vg(21). To understand how this subtle difference between the two alleles leads to a rather pronounced difference in their phenotypes, we mapped both the vg and P-element transcription units present in wild type and mutants. Using both 5'-RACE and S1 protection, we found that P-element transcription is initiated 19 bp farther upstream than previously thought. Using primer extension, the start of vg transcription was determined to lie 435 bp upstream of the longest cDNA recovered to date and upstream of the P-element insertion site. Our discovery that the P element is situated within the first vg exon has prompted a reassessment of the large body of genetic data on a series of alleles derived from vg(21). Our current hypothesis to explain the degree of variation in the mutant phenotypes and their response to the P repressor invokes a critical RNA secondary structure in the vg transcript, the formation of which is hindered by a readthrough transcript initiated at the P-element promoter.

Alleles↗
PubMed2002

Regulation of P-element transposase activity in Drosophila melanogaster by hobo transgenes that contain KP elements.

Fusions between the Drosophila hsp70 promoter and three different incomplete P elements, KP, SP, and BP1, were inserted into the Drosophila genome by means of hobo transformation vectors and the resulting transgenic stocks were tested for repression of P-element transposase activity. Only the H(hsp/KP) transgenes repressed transposase activity, and the degree of repression was comparable to that of a naturally occurring KP element. The KP transgenes repressed transposase activity both with and without heat-shock treatments. Both the KP element and H(hsp/KP) transgenes repressed the transposase activity encoded by the modified P element in the P(ry(+), Delta2-3)99B transgene more effectively than that encoded by the complete P element in the H(hsp/CP)2 transgene even though the P(ry(+), Delta2-3)99B transgene was the stronger transposase source. Repression of both transposase sources appeared to be due to a zygotic effect of the KP element or transgene. There was no evidence for repression by a strictly maternal effect; nor was there any evidence for enhancement of KP repression by the joint maternal transmission of H(hsp/KP) and H(hsp/CP) transgenes. These results are consistent with the idea that KP-mediated repression of P-element activity involves a KP-repressor polypeptide that is not maternally transmitted and that KP-mediated repression is not strengthened by the 66-kD repressor produced by complete P elements through alternate splicing of their RNA.

Animals↗
PubMed1989

Trace element absorption in infants as a foundation to setting upper limits for trace elements in infant formulas.

The bioavailability of the trace elements iron, zinc, copper and manganese from human milk is high compared to cow's milk and infant formulas. This high bioavailability may be explained by the presence of lactoferrin in human milk, which may facilitate iron and manganese uptake via an intestinal receptor for this protein. High concentrations of ascorbate and citrate may also facilitate uptake of trace elements from human milk and milk formulas, while a high concentration of casein in cow's milk and cow's milk formulas may limit trace element absorption from these diets. Trace element absorption from soy formula is low, mostly due to the presence of phytate but possibly also due to some protein fraction. Trace elements sharing absorptive pathways compete for uptake, and imbalances in the ratios between trace elements (Fe/Zn, Zn/Cu, Fe/Mn) in formulas may impair trace element absorption. These factors need to be taken into consideration when setting upper limits for trace elements in formulas. With our present knowledge, an upper limit for iron of 14 mg/l, for zinc, 12 mg/l, copper, 1.2 mg/l, and manganese, 0.6 mg/l are suggested. The capacity of infants to homeostatically adapt to varying intakes of trace elements needs to be further evaluated.

Female↗
PubMed1995

Characterization of a glucocorticoid responsive element and identification of an AT-rich element that regulate the link protein gene.

The cartilage matrix is composed of characteristic components including type II collagen, aggrecan and link protein. In this paper, we report two DNA elements that regulate the link protein gene. Using transient transfection assays with link protein gene constructs in chondrocytes, chloramphenicol acetyl transferase (CAT) assays were used to measure the transcriptional activity of the link protein gene. Previously, we identified an enhancer-like activity within the first intron of the gene. In this paper, we report an active 34 bp (+1390 to +1424) fragment within this region that contains a glucocorticoid-like response element (GRE). Both deletion of, and site-specific mutations within this sequence motif reduced the dexamethasone-inducible activity. The GRE-like sequence from the rat link protein gene, or the homologous sequence from the human link protein gene were included in vectors containing the thymidine kinase promoter linked to the CAT gene (tkCAT). Both human and rat elements transferred the ability to respond to dexamethasone and hydrocortisone with a > 10-fold induction. Deletions through the promoter from -923 to -900 identified a second site required for both glucocorticoid and serum responsiveness. A four base substitution at this site resulted in a loss of serum responsiveness. This region contains an AT-rich element, similar to the AT-rich elements involved in homeotic protein regulation of the growth hormone gene and the muscle creatine kinase gene. Southwestern analysis using oligonucleotides containing the AT-rich element from the link protein gene or the muscle creatine kinase gene, identified a 32 kDa protein band from nuclear extracts of chick chondrocytes. Using these AT-rich oligonucleotides in band-shift analyses, nuclear extracts of chick sternal muscle, rat chondrosarcoma and chick sternal chondrocytes each showed formation of different complexes suggesting cell specificity. AT-rich elements have been identified as binding sites for homeodomain-containing proteins and can contribute to gene regulation by serum response factors. The identification of an AT-rich element in the link protein gene suggests similar functions for this element.

Animals↗
PubMed2002

The as-1 promoter element is an oxidative stress-responsive element and salicylic acid activates it via oxidative species.

The activation sequence-1 (as-1)-like element found in the promoter of some glutathione S-transferase (GST) genes, has been previously described as a salicylic acid (SA)- and auxin-responsive element. In this paper, we tested the hypothesis that the activating effect of SA on the as-1 element is mediated by oxidative species. Supporting this hypothesis, our results show that the antioxidants dimethylthiourea (DMTU) and 3-t-butyl-4-hydroxy-anizole (BHA) inhibit the SA-induced transcription of genes controlled by as-1 elements in tobacco (Nicotiana tabacum) plants [i.e. GNT35 gene coding for a GST and (as-1)(4)/beta-glucuronidase (GUS) reporter transgene]. DMTU and BHA also inhibit SA-activated as-1-binding activity in nuclear extracts. Further support for the hypothesis that the as-1 element is activated by oxidative species comes from our result showing that light potentiates the SA-induced activation of the as-1 element. Furthermore, methyl viologen, a known oxidative stress inducer in plants, also activates the as-1 element. Increasing H(2)O(2) levels by incubation with H(2)O(2) or with the catalase inhibitor 3-amino-1,2,5-triazole does not activate the (as-1)(4)/GUS gene. On the contrary, 3-amino-1,2,5-triazole inhibits the activating effect of SA on the (as-1)(4)/GUS gene. These results suggest that oxidative species other than H(2)O(2) mediate the activation of the as-1 element by SA. Our results also suggest that even though the as-1 binding activity is stimulated by oxidative species, this is not sufficient for the transactivation of genes controlled by this element. The complex interplay between SA and reactive oxygen species in the transcriptional activation of defense genes is discussed.

Amitrole↗
PubMed2001

Formation of chromosomal tandem arrays of the SXT element and R391, two conjugative chromosomally integrating elements that share an attachment site.

The SXT element, a conjugative, self-transmissible, integrating element (a constin) originally derived from a Vibrio cholerae O139 isolate from India, and IncJ element R391, originally derived from a South African Providencia rettgeri isolate, were found to be genetically and functionally related. Both of these constins integrate site specifically into the Escherichia coli chromosome at an identical attachment site within the 5' end of prfC. They encode nearly identical integrases, which are required for chromosomal integration, excision, and extrachromosomal circularization of these elements, and they have similar tra genes. Therefore, these closely related constins have virtually identical mechanisms for chromosomal integration and dissemination. The presence of either element in a recipient cell did not significantly reduce its ability to acquire the other element, indicating that R391 and SXT do not encode surface exclusion determinants. In cells harboring both elements, SXT and R391 were integrated in tandem fashion on the chromosome, and homologous recombination appeared to play little or no role in the formation of these arrays. Interference between R391 and SXT was detected by measuring the frequency of loss of an unselected resident element upon introduction of a second selected element. In these assays, R391 was found to have a stronger effect on SXT stability than vice versa. The level of expression and/or activity of the donor and recipient integrases may play a role in the interference between these two related constins.

Chromosomes, Bacterial↗