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PubMed2003

Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs.

Protein kinases regulate a number of critical events in mitosis and meiosis. A study of the evolution of kinases involved in cell cycle control (CCC) might shed light on the evolution of the eukaryotic cell cycle. In particular, applying quantitative phylogenetic methods to key CCC kinases could provide information on the relative timing of gene duplication events. To investigate the evolution of CCC kinases, we constructed phylogenetic trees for the CDC28 family and performed statistical tests of the tree topology. This family includes the cyclin-dependent kinases (CDKs), which are key regulators of the eukaryotic cell cycle, as well as other CCC kinases. We found that CDKs and, in particular, the principal cell cycle regulator Cdc28p, branch off the phylogenetic tree at a late stage, after several other kinases involved in either mitosis or meiosis regulation. On the basis of this tree topology, it is proposed that, at early stages of evolution, the eukaryotic cell cycle was not controlled by CDKs and that only a subset of extant kinases, notably the DNA damage checkpoint kinase Chk1p, were in place. During subsequent evolution, a series of duplications of kinase genes occurred, gradually adding more kinases to the CCC system, the CDKs being among the last major additions.

Animals↗

PubMed1990

Zn2+ regulation of ornithine transcarbamoylase. I. Mechanism of action.

Ornithine transcarbamoylase catalyzes the formation of L-citrulline from carbamoyl phosphate and L-ornithine. The anabolic enzyme from Escherichia coli is composed of three identical subunits and resembles, in both primary and quaternary structures, the catalytic unit of aspartate transcarbamoylase. However, ornithine transcarbamoylase has no regulatory subunits. Although this enzyme does not bind its substrates co-operatively, fluorescence spectroscopic experiments show that zinc adds allosterically to the free enzyme. The metal binding process is dictated by deprotonation of an enzymic group with a pKa less than 7. The saturation binding curve of the metal ion is sigmoidal and yields a Hill coefficient of 1.6 at pH 8.5 and 25 degrees C. In the absence of substrates, zinc further promotes a slow enzyme isomerization, which occurs with a first-order rate constant of 7 min-1; thus, the metal is a slow, tight-binding inhibitor. The isomerized enzyme is inactive and contains three zinc ions. When the enzyme is first bound with carbamoyl phosphate, steady-state kinetic assays reveal that zinc again binds co-operatively to the binary enzyme complex, with a Hill coefficient of 1.5, but the metal ion now behaves simply as a classical, reversible inhibitor; it is competitive against L-ornithine, non-competitive against carbamoyl phosphate, and induces no enzyme isomerization. However, as a result of the competition between zinc and L-ornithine for the same site on the enzyme, the L-ornithine saturation curve becomes sigmoidal. Displacement of the allosteric zinc from the enzyme by L-ornithine is the cause of co-operative addition of this substrate. The combined results suggest that zinc regulates ornithine transcarbamoylase via two routes: (1) as an allosteric cofactor of the substrate-bound enzyme in mediating site-site interactions; and (2) as a slow, tight-binding inhibitor of the free enzyme in inducing inactivation. The concentration of zinc that is effective for action is in the micromolar range. The finding that E. coli ornithine transcarbamoylase can be induced to express co-operativity in binding its substrates has recently been confirmed by site-directed mutagenesis experiments. When the active site residue Arg106 is altered to a glycine, the resultant mutant enzyme exhibits both homotropic and heterotropic interactions towards its substrates. In view of the quaternary structure of holoenzyme aspartate transcarbamoylase, the "silent" co-operativity of ornithine transcarbamoylase is of particular interest in the study of evolution of complex, regulatory proteins.

Edetic Acid↗

PubMed2004

Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters.

Primate genomes contain a very large number of short interspersed GC-rich repeats of the Alu family, which are abundant in introns and intergenic spacers but also present in 5' flanking regions of genes enriched in binding motifs (BMs) for transcription factors and frequently containing CpG islands. Here we studied whether CpG islands located in promoters of human genes overlap with Alu repeats and with clusters of BMs for the zinc-finger transcription factors Sp1, estrogen receptor alpha, and YY1. The presence of estrogen-response elements in Alu was shown earlier and here we confirm the presence in the consensus Alu sequence of the binding sites for Sp1 and YY1. Analyzing >5000 promoters from the two databases we found that Alu sequences are underrepresented in promoters compared to introns and that approximately 4% of CpG islands located within the -1000 to +200 segments of human promoters overlap with Alu repeats. Although this fraction was found to be lower for proximal segments of promoters (-500 to +100), our results indicate that a significant number (>1000) of all human genes may be controlled by Alu-associated CpG islands. Analysis of clustering of potential BMs for the indicated transcription factors within some promoters also suggests that the Alu family contributed to the evolution of transcription cis-regulatory modules in the human genome. It is important that among Alu sequences overlapping with CpG islands in promoters a large fraction of members of the old Alu subfamilies is found, suggesting extensive retroposon-assisted regulatory genome evolution during the divergence of the primates.

5' Flanking Region↗

PubMed1996

Antigenic variation in trypanosomes: secrets surface slowly.

Among pathogenic micro-organisms that evade the mammalian immune responses. Trypanosoma brucei has developed the most elaborate capacity for antigenic variation. Trypanosomes branched early during eukaryotic evolution. They are characterized by many aberrations, ranging from the unusual compartmentation of metabolic pathways to the heresy of RNA editing. The ubiquitous phenomenon of glycosylphosphatidylinositol-anchoring of eukaryotic plasma membrane proteins and RNA trans-splicing (trypanosome genes contain no introns), which adds an identical leader sequence to all trypanosome mRNAs, were first defined during studies of antigenic variation. Genetic transformation of trypanosomes and the high efficiency of gene targeting provide new opportunities to investigate the regulation of antigenic variation. There is every reason to expect trypanosomes to provide further surprises and insights into the evolution of genetic regulatory mechanisms.

Animals↗

PubMed2004

Lamprey contractile protein genes mark different populations of skeletal muscles during development.

Agnathan lampreys retain ancestral characteristics of vertebrates in the morphology of skeletal muscles derived from two mesodermal regions: trunk myotomes and unsegmented head mesoderm. During lamprey development, some populations of myoblasts migrate via pathways that differ from those of gnathostomes. To investigate the evolution of skeletal muscle differentiation in vertebrates, we characterize multiple contractile protein genes expressed in the muscle cells of the Japanese lamprey, Lethenteron japonicum. Lamprey actin gene LjMA2, and myosin heavy chain (MyHC) genes LjMyHC1 and LjMyHC2 are all expressed in the developing skeletal muscle cells of early embryos. However, LjMyHC1 and LjMyHC2 are expressed only in cells originating from myotomes, while LjMA2 is expressed in both myotomal and head musculature. Thus, in lampreys, myotomes and head mesoderm differ in the use of genes encoding contractile protein isoforms. Phylogenetic tree analyses including lamprey MyHCs suggest that the variety of muscle MyHC isoforms in different skeletal muscles may correspond to the morphological complexity of skeletal muscles of different vertebrate species. Another lamprey actin gene LjMA1 is likely to be the first smooth muscle actin gene isolated from non-tetrapods. We conclude that, in vertebrate evolution, the different regulatory systems for striated and smooth muscle-specific genes may have been established before the agnathan/gnathostome divergence.

Actins↗

PubMed1996

Cases of ancient mobile element DNA insertions that now affect gene regulation.

There is no doubt that mobile elements are a major source of mutation and that in many cases insertions cause changes in the expression of genes, but a question remains open. What has the long-term effect of these processes been? The data collected here show that in many eukaryotes, segments of repetitive DNA (mobile elements) that have been inserted in the past in regions of many eukaryote genes have been preserved by selection and now affect the transcriptional control of these specific genes. At least five of the examples are considered to be solid cases demonstrating this history. There are a number of significant but less compelling sets of evidence that support the concept that the insertion of mobile elements in gene regions could be a major source of regulatory variation in evolution.

Amylases↗

PubMed1978

Chirality and stereochemical recognition in DNA-phytohormone interactions: a model approach.

Space-filling molecular models of selected phytohormones and DNA, employed as described herein, illustrate possible in vivo stereochemical recognition between nucleic acids and intercalated phytohormones. In this regard, the absolute chirality of certain phytohormones, and that of DNA may be essential for the recognition process. It is speculated further that the specific interactions shown by molecular models have significance in the evolution of plant regulatory mechanisms.

DNA↗

PubMed2006

The fractional contributions of elementary modes to the metabolism of Escherichia coli and their estimation from reaction entropies.

The metabolism of a cell can be viewed as a weighted sum of elementary modes. Due to the multiplicity of modes the identification of the individual weights represents a non-trivial problem. To enable the determination of weighting factors we have identified and implemented two gene deletions in combination with defined growth conditions that limit the metabolism from 4374 original elementary modes to 24 elementary modes for a non-PHB synthesizing control and 40 modes for a PHB synthesizing strain. These remaining modes can be further grouped into five families that have the same overall stoichiometry. Thus, the complexity of the problem is significantly reduced, and weighting factors for each family of modes could be determined from the measurement of accumulation rates of metabolites. Moreover, it is shown that individual weights are inversely correlated with the entropy generated by the operation of the used pathways defined in elementary modes. This suggests that evolution developed cellular regulatory patterns that permit diversity of pathways while favoring efficient pathways with low entropy generation. Furthermore, such correlation provides a rational way of estimating metabolic fluxes based on the thermodynamic properties of elementary modes. This is demonstrated with an example in which experimentally determined, intracellular fluxes are shown to be highly correlated with fluxes computed based on elementary modes and reaction entropies. The analysis suggests that the set of elementary modes can be interpreted analogous to a metabolic ensemble of quantum states of a macroscopic system.

Anaerobiosis↗

PubMedDate not supplied

Quality and functionality of excipients.

The quality of medicines depends not only on the active principles and production processes, but also the performance of the excipients. The traditional concept of the excipient as any component other than the active substance has undergone a substantial evolution from an 'inert' and cheap vehicle to an essential constituent of the formulation. The rapid evolution of scientific, regulatory and economic factors, the introduction of delivery systems and the advance in biopharmaceutics have led to a new interest in the role and functionality of the excipients. More than one thousand raw materials are available from a multitude of sources and are used today in the pharmaceutical industry. Their chemical structures vary from small molecules to complex natural or synthetic polymeric mixtures. Excipients are now chosen to perform a variety of functions to guarantee the stability and bioavailability of the drug substance from the drug product and its manufacturability on a production scale. Beyond the dosage form necessities, excipients are required to perform important and specific technological functions, particularly in the case of solid dosage forms. As a consequence, their characterisation must go beyond the simple tests for identity, purity and strength as prescribed in general by the Pharmacopoeia monographs. With the exception of the Textbook of Pharmaceutical Excipients, not many reference sources describing the physical mechanical characteristics of the powders for a specific role are available. Full physical characterisation of solid materials is now made possible with the help of high resolution analytical techniques on the molecular, particulate and bulk levels. This systematic approach is necessary to guarantee the behaviour of the excipient during the formulation and production phases. Some examples have been chosen in this mini-review in an effort to highlight the emerging trends in the development of 'tailor-made' materials. Three main approaches are followed by the industry: physical or minor chemical manipulation of materials already known, combination of two or more marketed excipients in order to reduce unwanted defects and, finally, preparation of new chemical entities with huge investments for the toxicity studies. Excipient harmonisation, standardised functionality tests, preformulation data bases and expert systems will contribute to change the conventional trial-and-error formulation approach into a far more scientific and technological development.

Chemistry, Pharmaceutical↗

PubMed1997

Mobile elements inserted in the distant past have taken on important functions.

Current evidence on the long-term evolutionary effect of insertion of sequence elements is reviewed. There are three criteria for inclusion of an example: (i) the element was inserted far in the past and thus the event is not a transient mutation; (ii) the element is a member of a large group of similar sequences; (iii) the element now serves a useful function. There are 21 examples from Drosophila, sea urchin, human and mouse genomes that meet these criteria. Taken together, these examples show that the insertion of sequence elements in the genome has been a significant source of regulatory variation in evolution.

Animals↗

PubMed2003

Differential mesodermal expression of two amphioxus MyoD family members (AmphiMRF1 and AmphiMRF2).

To explore the evolution of myogenic regulatory factors in chordates, we isolated two MyoD family genes (AmphiMRF1 and AmphiMRF2) from amphioxus. AmphiMRF1 is first expressed at the late gastrula in the paraxial mesoderm. As the first somites form, expression is restricted to their myotomal region. In the early larva, expression is strongest in the most anterior and most posterior somites. AmphiMRF2 transcription begins at mid/late gastrula in the paraxial mesoderm, but never spreads into its most anterior region. Through much of the neurula stage, AmphiMRF2 expression is strong in the myotomal region of all somites except the most anterior pair; by late neurula expression is downregulated except in the most posterior somites forming just rostral to the tail bud. These two MRF genes of amphioxus have partly overlapping patterns of mesodermal expression and evidently duplicated independent of the diversification of the vertebrate MRF family.

Animals↗

PubMed2001

Deletion of a coordinate regulator of type 2 cytokine expression in mice.

Mechanisms that underlie the patterning of cytokine expression in T helper (T(H)) cell subsets remain incompletely defined. An evolutionarily conserved approximately 400-bp noncoding sequence in the intergenic region between the genes Il4 and Il13, designated conserved noncoding sequence 1 (CNS-1), was deleted in mice. The capacity to develop T(H)2 cells was compromised in vitro and in vivo in the absence of CNS-1. Despite the profound effect in T cells, mast cells from CNS-1(-/-) mice maintained their capacity to produce interleukin 4. A T cell-specific element critical for the optimal expression of type 2 cytokines may represent the evolution of a regulatory sequence exploited by adaptive immunity.

Animals↗

PubMed1996

Regulation and conservation of the heat-shock transcription factor sigma32.

Heat shock and other stresses induce a set of genes encoding molecular chaperones and proteases through increase in the level of transcription factor sigma32 in Escherichia coli. Some of the cis- and trans-acting factors involved in the control of synthesis (translation), degradation and activity of sigma32 have been identified and characterized. These studies contribute to our understanding of early events of the heat-shock response, including modes of interaction between chaperones and sigma32. Besides, analysis of sigma32 homologues from diverse bacteria reveals new insights into evolution of the regulatory mechanisms.

Amino Acid Sequence↗

PubMed1991

A copper-thiolate polynuclear cluster in the ACE1 transcription factor.

ACE1 is the transcriptional activator of the metallothionein (CUP1 locus) gene in Saccharomyces cerevisiae. Previous data had implicated the N-terminal domain of ACE1 as responsible for the Cu-dependent specific DNA binding. An expression system in Escherichia coli was constructed to enable the isolation of an ACE1 domain containing the DNA and Cu-binding regions. Here we report the purification and characterization of the Cu-ACE1 truncated molecule. Spectroscopic techniques showed that ACE1 contains an unusual type of DNA binding structure that is based on a polynuclear Cu(I)-cysteinyl thiolate cluster. The cluster consists of six or seven Cu(I) ions coordinated to cysteinyl thiolates in a trigonal geometry distorted from planarity. The Cu(I)-cysteine cluster of Cu-ACE1 exhibits structural properties analogous to the Cu(I)-thiolate polynuclear cluster in yeast Cu-metallothionein itself, suggesting an unusual mechanism for the evolution of this regulatory factor. The Cu cluster organizes and stabilizes the conformation of the N-terminal domain of ACE1 for specific DNA binding.

Amino Acid Sequence↗

PubMed1996

DNA sequence insertion and evolutionary variation in gene regulation.

Current evidence on the long-term evolutionary effect of insertion of sequence elements into gene regions is reviewed, restricted to cases where a sequence derived from a past insertion participates in the regulation of expression of a useful gene. Ten such examples in eukaryotes demonstrate that segments of repetitive DNA or mobile elements have been inserted in the past in gene regions, have been preserved, sometimes modified by selection, and now affect control of transcription of the adjacent gene. Included are only examples in which transcription control was modified by the insert. Several cases in which merely transcription initiation occurred in the insert were set aside. Two of the examples involved the long terminal repeats of mammalian endogenous retroviruses. Another two examples were control of transcription by repeated sequence inserts in sea urchin genomes. There are now six published examples in which Alu sequences were inserted long ago into human gene regions, were modified, and now are central in control/enhancement of transcription. The number of published examples of Alu sequences affecting gene control has grown threefold in the last year and is likely to continue growing. Taken together, all of these examples show that the insertion of sequence elements in the genome has been a significant source of regulatory variation in evolution.

Animals↗

PubMedDate not supplied

Glutaredoxin: role in reversible protein s-glutathionylation and regulation of redox signal transduction and protein translocation.

Reversible posttranslational modifications on specific amino acid residues can efficiently regulate protein functions. O-Phosphorylation is the prototype and analogue to the rapidly emerging mechanism of regulation known as S-glutathionylation. The latter is being recognized as a potentially widespread form of modulation of the activities of redox-sensitive thiol proteins, especially those involved in signal transduction pathways and translocation. The abundance of reduced glutathione in cells and the ready conversion of sulfenic acids and S-nitroso derivatives to S-glutathione mixed disulfides support the notion that reversible S-glutathionylation is likely to be the preponderant mode of redox signal transduction. The glutaredoxin enzyme has served as a focal point and important tool for evolution of this regulatory mechanism because of its characterization as a specific and efficient catalyst of protein-SSG de-glutathionylation (akin to phosphatases). Identification of specific mechanisms and enzyme(s) that catalyze formation of protein-SSG intermediates, however, is largely unknown and represents a prime objective for furthering understanding of this evolving mechanism of cellular regulation. Several proteomic approaches, including the use of cysteine-reactive fluorescent and radiolabel probes, have been developed to detect arrays of proteins whose cysteine residues are modified in response to oxidants, thus identifying them as potential interconvertible proteins to be regulated by redox signaling (glutathionylation). Specific criteria were used to evaluate current data on cellular regulation via S-glutathionylation. Among many proteins under consideration, actin, protein tyrosine phosphatase-1B, and Ras stand out as the best current examples for establishing this regulatory mechanism.

Animals↗

PubMed1987

Regulatory and structural genes for lysozymes of mice.

The molecular and genetic basis of large differences in the concentration of P lysozyme in the small intestine has been investigated by crossing inbred strains of two species of house mouse (genus Mus). The concentration of P in domesticus is about 130-fold higher than in castaneus. An autosomal genetic element determining the concentration of P has been identified and named the P lysozyme regulator, Lzp-r. The level of P in interspecific hybrids (domesticus X castaneus) as well as in certain classes of backcross progeny is intermediate relative to parental levels, which shows that the two alleles of Lzp-r are inherited additively. There are two forms of P lysozyme in the intestine of the interspecific hybrid--one having the heat stability of domesticus P, the other being more stable and presumably the product of the castaneus P locus. These two forms occur in equal amounts, and it appears that Lzp-r acts in trans. The linkage of Lzp-r to three structural genes (Lzp-s, Lzm-sl, and Lzm-s2), one specifying P lysozyme and two specifying M lysozymes, was shown by electrophoretic analysis of backcrosses involving domesticus and castaneus and also domesticus and spretus. The role of regulatory mutations in evolution is discussed in light of these results.

Aging↗

PubMed1994

Structural organization of the mouse glycophorin A gene.

The human glycophorin gene has been extensively studied, but information on the homologous gene from other species has been unavailable. Here, we determined the structural organization of mouse glycophorin A gene and compared it with the human gene. The mouse glycophorin gene is a single copy gene while in humans, there are two highly related genes (A and B) that were generated by homologous recombination. Chromosomal mapping indicated that the mouse gene is located in the central region of the mouse chromosome 8, which is syntenic with human chromosomes 4q28-31 where the human glycophorin A gene has been mapped. The mouse gene consists of 8 exons, while the human gene consists of 7 exons and the length of each exon is quite short except for the last exon. The last 4 exons showed extensive homology between the mouse and human genes but divergence in the 5'-exons of the two genes was high. The results suggest that glycophorin genes of mouse and human may have been generated from the same ancestor, but diverged greatly during evolution. The upstream regulatory region of the mouse gene consists of multiple motifs for DNA binding factors that may be required for its erythroid-specific expression.

Animals↗