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Results for “regulatory evolution”

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PubMed1999

Phylogenetic analysis of L4-mediated autogenous control of the S10 ribosomal protein operon.

We investigated the regulation of the S10 ribosomal protein (r-protein) operon among members of the gamma subdivision of the proteobacteria, which includes Escherichia coli. In E. coli, this 11-gene operon is autogenously controlled by r-protein L4. This regulation requires specific determinants within the untranslated leader of the mRNA. Secondary structure analysis of the S10 leaders of five enterobacteria (Salmonella typhimurium, Citrobacter freundii, Yersinia enterocolitica, Serratia marcescens, and Morganella morganii) and two nonenteric members of the gamma subdivision (Haemophilus influenzae and Vibrio cholerae) shows that these foreign leaders share significant structural homology with the E. coli leader, particularly in the region which is critical for L4-mediated autogenous control in E. coli. Moreover, these heterologous leaders produce a regulatory response to L4 oversynthesis in E. coli. Our results suggest that an E. coli-like L4-mediated regulatory mechanism may operate in all of these species. However, the mechanism is not universally conserved among the gamma subdivision members, since at least one, Pseudomonas aeruginosa, does not contain the required S10 leader features, and its leader cannot provide the signals for regulation by L4 in E. coli. We speculate that L4-mediated autogenous control developed during the evolution of the gamma branch of proteobacteria.

Base Sequence↗

PubMed1999

Expression cloning and characterization of PREB (prolactin regulatory element binding), a novel WD motif DNA-binding protein with a capacity to regulate prolactin promoter activity.

Previous studies have implied that a transcription factor(s) other than Pit-1 is involved in homeostatic regulation of PRL promoter activity via Pit-1-binding elements. One such element, 1P, was employed to clone from a rat pituitary cDNA expression library a novel 417-amino acid WD protein, designated PREB (PRL regulatory element binding) protein. PREB contains two PQ-rich potential transactivation domains, but no apparent DNA-binding motif, and exhibits sequence-specific binding to site 1P, to a site nonidentical to that for Pit-1. The PREB gene (or a related gene) is conserved, as an apparently single copy, in rat, human, fly, and yeast. A single approximately 1.9-kb PREB transcript accumulates in GH3 rat pituitary cells, to levels similar to Pit-1 mRNA. PREB transcripts were detected in all human tissues examined, but the observation of tissue-specific multiple transcript patterns suggests the possibility of tissue-specific alternative splicing. RT-PCR analysis of human brain tumor RNA samples suggested region-specific expression of PREB transcripts in brain. Western and immunocytochemical analysis implied that PREB accumulates specifically in GH3 cell nuclei. Transient transfection employing PREB-negative C6 rat glial cells showed that PREB is as active as, and additive with, Pit-1 in transactivation of a PRL promoter construct, and that PREB, but not Pit-1, can mediate transcriptional activation by protein kinase A (PKA). Expression in GH3 cells of a GAL4-PREB fusion protein both strongly transactivated a 5XGAL indicator construct and yielded a further stimulation of expression of this construct by coexpressed PKA, implying that PREB can mediate both basal and PKA-stimulated transcriptional responses in pituitary cells. These observations imply that PREB will prove to play a significant transcriptional regulatory role, both in the pituitary and in other organs in which transcripts of its gene are expressed.

Amino Acid Sequence↗

PubMed2003

Subpopulations of equine infectious anemia virus Rev coexist in vivo and differ in phenotype.

Lentiviruses exist in vivo as a population of related, nonidentical genotypes, commonly referred to as quasispecies. The quasispecies structure is characteristic of complex adaptive systems and contributes to the high rate of evolution in lentiviruses that confounds efforts to develop effective vaccines and antiviral therapies. Here, we describe analyses of genetic data from longitudinal studies of genetic variation in a lentivirus regulatory protein, Rev, over the course of disease in ponies experimentally infected with equine infectious anemia virus. As observed with other lentivirus data, the Rev variants exhibited a quasispecies character. Phylogenetic and partition analyses suggested that the Rev quasispecies comprised two distinct subpopulations that coexisted during infection. One subpopulation appeared to accumulate changes in a linear, time-dependent manner, while the other evolved radially from a common variant. Over time, the two subpopulations cycled in predominance coincident with changes in the disease state, suggesting that the two groups differed in selective advantage. Transient expression assays indicated the two populations differed significantly in Rev nuclear export activity. Chimeric proviral clones containing Rev genotypes representative of each population differed in rate and overall level of virus replication in vitro. The coexistence of genetically distinct viral subpopulations that differ in phenotype provides great adaptability to environmental changes within the infected host. A quasispecies model with multiple subpopulations may provide additional insight into the nature of lentivirus reservoirs and the evolution of antigenic and drug-resistant variants.

Amino Acid Sequence↗

PubMed1997

Evolution of plasminogen-related growth factors (HGF/SF and HGF1/MSP).

HGF/SF and HGF1/MSP define a novel growth factor family whose members share the domain structure and the proteolytic process of activation of the blood proteinase precursor plasminogen. The amino acid and RNA sequences of HGF/SF and HGF1/MSP, the intron-exon organization of their genes and the predicted 3D structure of individual domains indicate that HGF/SF and HGF1/MSP evolved along with plasminogen and other members of the kringle-serine proteinase (KSP) superfamily from an ancestral gene that contained a single copy of the kringle domain, a serine proteinase domain and an activation peptide connecting the two domains. A series of intragenic duplications of the kringle domain, gene duplications, exon shuffling and deletions is responsible for the genes currently present in mammals, avians and amphibians. Plasminogen, HGF/SF and HGF1/MSP represent paradigmatic examples of the modern, multi-domain proteins typically associated with vertebrate organisms and illustrate a novel evolutionary pathway that led to the emergence of molecules with growth regulatory activity from proteolytic enzymes.

Amino Acid Sequence↗

PubMed2006

Different words, same meaning: understanding the languages of the genome.

There is undeniable value in using sequence comparison to identify putative regulatory sequences. However, a recent report has demonstrated that not all regulatory sequences are evolutionarily conserved. Cis-acting sequences around the RET gene, conserved in mammals but not in fish, are able to reproduce patterns of RET expression in zebrafish embryos. It is as yet unclear whether these sequences are 'below the radar' of current sequence alignment tools or whether their functional homology is not sequence based.

Animals↗

PubMed2003

Behavior of the hobo transposable element with regard to TPE repeats in transgenic lines of Drosophila melanogaster.

The hobo transposable element of Drosophila melanogaster is known to induce a hybrid dysgenesis syndrome. Moreover it displays a polymorphism of a microsatellite in its coding region: TPE repeats. In European populations, surveys of the distribution of hobo elements with regard to TPE repeats revealed that the 5TPE element is distributed along a frequency gradient, and it is even more frequent than the 3TPE element in Western populations. This suggests that the invasive ability of the hobo elements could be related to the number of TPE repeats they contain. To test this hypothesis we monitored the evolution of 16 lines derived from five initial independent transgenic lines bearing the 3TPE element and/or the 5TPE element. Four lines bearing 5TPE elements and four bearing 3TPE elements were used as a noncompetitive genetic background to compare the evolution of the 5TPE element to that of the 3TPE element. Eight lines bearing both elements provided a competitive genetic context to study potential interactions between these two elements. We studied genetic and molecular aspects of the first 20 generations. At the molecular level, we showed that the 5TPE element is able to spread within the genome at least as efficiently as the 3TPE element. Surprisingly, at the genetic level we found that the 5TPE element is less active than the 3TPE element, and moreover may be able to regulate the activity of the 3TPE element. Our findings suggest that the invasive potential of the 5TPE element could be due not only to its intrinsic transposition capacity but also to a regulatory potential.

Animals↗

PubMed1991

Time-course development of differentiated hepatocarcinoma and lung metastasis in transgenic mice.

A precise targeting of the SV40 T early region expression in the liver of transgenic mice was obtained using 700 bp of the antithrombin III regulatory sequences to control oncogene expression. In the strain expressing the highest level of large T antigen (Tag), the incidence of hepatocarcinoma was 100%. The evolution was reproducible and characterized by a marked cytolysis occurring as early as 4 weeks, when no morphological and histological modifications were visible, a preneoplastic state marked by a progression from hyperplasia to proliferative nodules composed of highly differentiated cells exhibiting a high Tag expression, which elicited tumor formation in nude mice and could proliferate in vitro, and hepatocellular carcinoma associated, in 10% of the cases, with lung metastasis. These transgenic mice constituted a useful model for therapeutic assays and fundamental studies on carcinogenesis.

Animals↗

PubMed1997

Dynamical behavior of a neural network with periodical external inputs.

Localized neural populations in different brain areas can undergo periodical external influence. To study this situation we consider the well known model by Wilson and Cowan (1972). It describes the evolution of two interconnected neuronal subpopulations of excitatory and inhibitory neurons correspondingly. Besides, it could be considered as a model of an abstract self-regulatory system. We describe and reveal underlying mechanisms of two regimes of forced oscillations in the model. In the first one the system acts as a phase comparator, demonstrating high sensitivity to a value of a phase shift between inputs to excitatory and inhibitory neurons. In the second regime it acts similar to a low pass filter: amplitudes of forced oscillations of the both components are not small and almost constant for low frequencies of the external input to the excitatory subpopulation. But they decrease significantly when the frequency becomes rather high. For simplified versions of the model analytical estimates for corresponding ranges of parameters are derived. It is shown that they are in good agreement with the results of computer simulations.

Animals↗

PubMed2000

Coevolution of transcriptional and allosteric regulation at the chorismate metabolic branch point of Saccharomyces cerevisiae.

Control of transcription and enzyme activities are two interwoven regulatory systems essential for the function of a metabolic node. Saccharomyces cerevisiae strains differing in enzyme activities at the chorismate branch point of aromatic amino acid biosynthesis were constructed by recombinant DNA technology. Expression of an allosterically unregulated, constitutively activated chorismate mutase encoded by the ARO7(T226I) (ARO7(c)) allele depleted the chorismate pool. The resulting tryptophan limitation caused growth defects, which could be counteracted only by transcriptional induction of TRP2 encoding the competing enzyme anthranilate synthase. ARO7 expression is not transcriptionally regulated by amino acids. Transcriptional activation of the ARO7(c) allele led to stronger growth retardation upon tryptophan limitation. The same effect was achieved by removing the competing enzyme anthranilate synthase, which is encoded by the TRP2 gene, from the transcriptional control. The allelic situation of ARO7(c) being under general control instead of TRP2 resulted in severe growth defects when cells were starved for tryptophan. In conclusion, the specific regulatory pattern acting on enzymatic activities at the first metabolic node of aromatic amino acid biosynthesis is necessary to maintain proper flux distribution. Therefore, the evolution of the sophisticated allosteric regulation of yeast chorismate mutase requires as prerequisite (i) that the encoding ARO7 gene is not transcriptionally regulated, whereas (ii) the transcription of the competing feedback-regulated anthranilate synthase-encoding gene is controlled by availability of amino acids.

Alleles↗

PubMed2000

Searching for the prototypic eye genetic network: Sine oculis is essential for eye regeneration in planarians.

We have identified a sine oculis gene in the planarian Girardia tigrina (Platyhelminthes; Turbellaria; Tricladida). The planarian sine oculis gene (Gtso) encodes a protein with a sine oculis (Six) domain and a homeodomain that shares significant sequence similarity with so proteins assigned to the Six-2 gene family. Gtso is expressed as a single transcript in both regenerating and fully developed eyes. Whole-mount in situ hybridization studies show exclusive expression in photoreceptor cells. Loss of function of Gtso by RNA interference during planarian regeneration inhibits eye regeneration completely. Gtso is also essential for maintenance of the differentiated state of photoreceptor cells. These results, combined with the previously demonstrated expression of Pax-6 in planarian eyes, suggest that the same basic gene regulatory circuit required for eye development in Drosophila and mouse is used in the prototypic eye spots of platyhelminthes and, therefore, is truly conserved during evolution.

Amino Acid Sequence↗

PubMed1998

Multifunctional lens crystallins and corneal enzymes. More than meets the eye.

The abundant water-soluble proteins, called crystallins, of the transparent, refractive eye lens have been recruited from metabolic enzymes and stress-protective proteins by a process called "gene sharing." Many crystallins are also present at lower concentration in nonocular tissues where they have nonrefractive roles. The complex expression pattern of the mouse alpha B-crystallin/small heat shock protein gene is developmentally controlled at the transcriptional level by a combinatorial use of shared and lens-specific regulatory elements. A number of crystallin genes, including that for alpha B-crystallin, are activated by Pax-6, a conserved transcription factor for eye evolution. Aldehyde dehydrogenase class 3 and transketolase are metabolic enzymes comprising extremely high proportions of the water-soluble proteins of the cornea and may have structural as well as enzymatic roles, reminiscent of lens enzyme-crystallins. Inductive processes appear to be important for the corneal-preferred expression of these enzymes. The use of the same protein for entirely different functions by a gene-sharing mechanism may be a general strategy based on evolutionary tinkering at the level of gene regulation.

Animals↗

PubMed2006

Evolution of immunity and host chromosome integration site of P2-like coliphages.

The amount and distribution of variation in the genomic region containing the genes in the lytic-lysogenic genetic switch and the sequence that determines the integration site into the host chromosome were analyzed for 38 P2-like phages from Escherichia coli. The genetic switch consists of two convergent mutually exclusive promoters, Pe and Pc, and two repressors, C and Cox. The immunity repressor C blocks the early Pe promoter, leading to the establishment of lysogeny. The Cox repressor blocks expression of Pc, allowing lytic growth. Phylogenetic analyses showed that the C and Cox proteins were distributed into seven distinct classes. The phylogenetic relationship differed between the two proteins, and we showed that homologous recombination plays a major role in creating alterations in the genetic switch, leading to new immunity classes. Analyses of the host integration site for these phages resulted in the discovery of a previously unknown site, and there were at least four regular integration sites. Interestingly, we found no case where phages of the same immunity class had different host attachment sites. The evolution of immunity and integration sites is complex, since it involves interactions both between the phages themselves and between phages and hosts, and often, both regulatory proteins and target DNA must change.

Amino Acid Sequence↗

PubMed1985

Secreted mouse prolactin (PRL) and stored ovine PRL. II. Role of amides in receptor binding and immunoreactivity.

Native PRL and des-amido forms 1, 2, and 3 were tested for their individual immunochemical and receptor-binding abilities. The results show that deamidation of either secreted mouse PRL or stored ovine PRL alters their binding in a radioreceptor assay. For each accumulated deamidation there was a statistically significant (P less than 0.05) decrease in the binding potency of either stored ovine PRL or secreted mouse PRL to a cell membrane receptor preparation. RIAs indicated that there was a statistically significant (P less than 0.05) decrease in PRL's immunopotency toward polyclonal antisera only when select residues deamidated. This study suggests that all the asn/gln residues which deamidate in order to make des-amido forms 1, 2, and 3 constitute part of the receptor-binding domains of both secreted and stored PRLs, while only a fraction of those same residues form portions of PRL's antigenic sites. Thus PRL's receptor-binding surface is separated from its antigenic sites, with only partial overlap being indicated. Our data also indicate that there are no major structural differences in the receptor-binding domains of secreted and stored PRLs. We also see that the receptor-binding domain of PRL has been highly conserved throughout evolution. Since the binding affinity of PRL to a membrane-bound receptor can be altered through deamidation, we view the process as a plausible regulatory mechanism for controlling the quantitative action of PRL at a given target organ.

Animals↗

PubMed2006

Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module.

We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members; MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.

Animals↗

PubMed2003

The use of hydrodynamic vortex separators and screening systems to improve water quality.

The paper reviews the evolution of Hydrodynamic Vortex Separators (HDVS) in the context of application as high rate rotary flow separators for achieving water quality improvements to meet with regulatory requirements in Europe and North America. The types of HDVS and their application for the control of wet-weather discharges such as combined sewer overflows (CSOs), sanitary sewer overflows (SSOs) and stormwater are outlined and a number of myths surrounding their use, dispelled. Reference is made to outputs of peer reviewed comprehensive monitoring, evaluation and demonstration projects on pilot and full-scale installations to demonstrate the efficacy and extensive track record of these systems. Recent developments and innovations in HDVS technologies are discussed, focusing on their combined use as solids liquid separators, contact vessels for wastewater disinfection, the incorporation of self-cleansing screening devices for the control of aesthetic pollutants (e.g. floatables) and the use of computational modelling for optimisation.

Disinfectants↗

PubMed1992

[The general functional characteristics of endogenous regulatory oligopeptides].

A number of physicochemical factors of the endogenous regulatory oligopeptides are considered to be the basis of their general functional properties as indicated by the phenomena of cascade regulation, morphogenesis, behaviour and biological evolution. Functional characteristics and chemical features of classical transmitters and, probably, other endogenous substances allow to consider them as the integrity of endogenous molecular regulators.

Animals↗

PubMed1990

Analysis of autosomal dosage compensation involving the alcohol dehydrogenase locus in Drosophila melanogaster.

An example of autosomal dosage compensation involving the expression of the alcohol dehydrogenase (Adh) locus is described. Flies trisomic for a quarter of the length of the left arm of chromosome two, including Adh, have diploid levels of enzyme activity and alcohol dehydrogenase messenger RNA. Subdivision of the compensating trisomic into smaller ones revealed a region that exerts an inverse regulatory effect on alcohol dehydrogenase activity and messenger RNA levels and a smaller region surrounding the structural gene that exhibits a direct gene dosage response. The two opposing effects are of sufficient magnitude that they cancel when simultaneously present resulting in the observed compensation in the larger aneuploid. An Adh promoter-white structural gene fusion construct is affected by the inverse regulatory region indicating that the effect is mediated through the Adh promoter sequences. The role of autosomal dosage compensation in understanding aneuploid syndromes and karyotype evolution in Drosophila species is discussed.

Alcohol Dehydrogenase↗

PubMed1989

Chemical risk assessment: a review.

People are exposed to a staggering assortment of chemicals and foreign substances. Potential health risks accompany these exposures. Intelligent, informed decisions are needed on which risks can and should be reduced, eliminated, or simply ignored. Therefore, a method of determining the attendant human health risks involved in chemical exposure is necessary. This need has resulted in the evolution of the risk assessment process which was developed to aid in identifying, characterizing and quantifying risks. Risk assessment today is an essential component of regulatory decision-making. In the context of chemical exposure, risk assessment is an evaluation of the risk in human exposure to chemicals in the environment. Quantitative risk assessment (QRA) is the use of experimental laboratory data and/or human epidemiological data in a process to derive a quantitative value for the estimate of the probability of harm occurring to exposed human populations. It is a sophisticated process involving an array of techniques that can be used to identify potential risks to human health. There are 4 components involved in the formalized risk assessment process--hazard identification, toxicity assessment, exposure assessment and risk characterization. These 4 steps collectively address each of 6 key areas identified as essential in characterizing a risk situation involving a chemical exposure. The process of risk estimation involves uncertainties because there are always gaps in knowledge or a lack in understanding mechanisms. These crucial gaps in knowledge are filled when extrapolations, models or assumptions are used. The uncertainties inherent in the risk assessment process are the basis of arguments against the use of the process. Many of these sources of uncertainty inherent in the risk assessment process are examined herein. These include, but are not limited to, modeling methods, understanding mechanisms and pharmacodynamics, exposure data, assumptions and extrapolations. Some new techniques and approaches being applied to the risk assessment process are examined. These include improved models for extrapolating data and quantifying risks, improved laboratory techniques for investigating pharmacodynamic and mechanistic pathways and advancements in quality and application of epidemiological data. The actual concept of uncertainty is being examined and attempts are being made to directly address, quantify and manage uncertainty.

Animals↗