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PubMed2006

SigFlux: a novel network feature to evaluate the importance of proteins in signal transduction networks.

BACKGROUND: Measuring each protein's importance in signaling networks helps to identify the crucial proteins in a cellular process, find the fragile portion of the biology system and further assist for disease therapy. However, there are relatively few methods to evaluate the importance of proteins in signaling networks. RESULTS: We developed a novel network feature to evaluate the importance of proteins in signal transduction networks, that we call SigFlux, based on the concept of minimal path sets (MPSs). An MPS is a minimal set of nodes that can perform the signal propagation from ligands to target genes or feedback loops. We define SigFlux as the number of MPSs in which each protein is involved. We applied this network feature to the large signal transduction network in the hippocampal CA1 neuron of mice. Significant correlations were simultaneously observed between SigFlux and both the essentiality and evolutionary rate of genes. Compared with another commonly used network feature, connectivity, SigFlux has similar or better ability as connectivity to reflect a protein's essentiality. Further classification according to protein function demonstrates that high SigFlux, low connectivity proteins are abundant in receptors and transcriptional factors, indicating that SigFlux candescribe the importance of proteins within the context of the entire network. CONCLUSION: SigFlux is a useful network feature in signal transduction networks that allows the prediction of the essentiality and conservation of proteins. With this novel network feature, proteins that participate in more pathways or feedback loops within a signaling network are proved far more likely to be essential and conserved during evolution than their counterparts.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Three's company: two or more unrelated receptors pair with the same ligand.

Intercellular communication relies on signal transduction mediated by extracellular ligands and their receptors. Although the ligand-receptor interaction is usually a two-player event, there are selective examples of one polypeptide ligand interacting with more than one phylogenetically unrelated receptor. Likewise, a few receptors interact with more than one polypeptide ligand, and sometimes with more than one coreceptor, likely through an interlocking of unique protein domains. Phylogenetic analyses suggest that for certain triumvirates, the matching events could have taken place at different evolutionary times. In contrast to a few polypeptide ligands interacting with more than one receptor, we found that many small nonpeptide ligands have been paired with two or more plasma membrane receptors, nuclear receptors, or channels. The observation that many small ligands are paired with more than one receptor type highlights the utilitarian use of a limited number of cellular components during metazoan evolution. These conserved ligands are ubiquitous cell metabolites likely favored by natural selection to establish novel regulatory networks. They likely possess structural features useful for designing agonistic and antagonistic drugs to target diverse receptors.

Animals↗
PubMed1981

Immunohistochemical study of the pancreatic endocrine cells of the ray, Dasyatis akajei.

The pancreatic endocrine cells of the ray, Dasyatis akajei was studied by aldehyde-fuchsin-Masson-Goldner's staining and by immunohistochemical methods. The pancreatic endocrine cells of the ray do not form islets by represent the most primitive distribution among elasmobranchs, occupying the outer layer of the double-layered duct epithelium of the pancreas. The endocrine cells showed no evidence of reaching the duct lumen, i. e., they are closed in type. By the use of immunohistochemical techniques, insulin-, glucagon-, somatostatin-and pancreatic polypeptide (PP)-like immunoreactivities were detected in the endocrine cells. The PP-positive cells could not be differentiated from the somatostatin-immunoreactive cells, although the former were smaller in number. The possible reasons for this result were discussed. The present finding supports the view that those four peptides are essential regulatory substances of the endocrine system of the pancreas at a fairy early stage of vertebrate evolution.

Animals↗
PubMed2003

Evolution and cell biology of dopamine receptors in vertebrates.

Dopamine, one of main modulatory neurotransmitters of the nervous system acts on target cells through two classes of G protein-coupled receptors, D1 and D2. The two dopamine receptor classes display different structures, interact with different regulatory partners (including heterotrimeric G proteins) and, accordingly, have independent evolutionary origins. In vertebrates, each of these receptor classes comprises several subtypes, generated by two steps of gene duplications, early in vertebrate evolution. In the D1 receptor class, the D1A, D1B, D1C and D1D subtypes, and in the D2 class, the D2, D3 and D4 receptor subtypes have been conserved in most vertebrate groups. This conservation has been driven by the acquisition, by each receptor subtype, of a small number of specific properties, which were selected for adaptive purpose in vertebrates. Among these properties, affinity for dopamine, the natural ligand, intrinsic receptor activity, and agonist-induced desensitization clearly distinguish the receptor subtypes. In addition, each dopamine receptor subtype is addressed to a specific location within neuronal networks, although detailed information is lacking for several receptor subtypes. Receptors localization at diverse subcellular places in neurons may also differ from one subtype to another, resulting in different ways of regulating cell signalisation. One challenge for future research on dopamine and its receptors would be to identify the nature of the protein partners and the molecular mechanisms involved in localizing receptors to the neuronal plasma membrane. In this respect, the evolutionary approach we have undertaken suggests that, due to gene duplications, a reasonable degree of freedom exists in the tight organisation of dopamine receptors in neurons. This "evolvability" of dopamine systems has been instrumental to adapt the vertebrate species to nearly all the possible environments.

Animals↗
PubMed1976

An ultrastructural analysis of chick embryonic skin development in vitro.

Behaviour of 6-day chick embryo thigh skin in vitro in two different nutrients was studied electron microscopically. In explants supported with chicken serum containing medium epithelium keratinized faster than and in a similar way to that in ovo, except for the absence of corpuscola cribriformia in pericytes. It did not in explants supported with chick embryo extract containing medium, but underwent a noticeable ultrastructural evolution, mainly of granular reticulum and Golgi complexes. In the two series of cultures mesenchyme presented the same ultrastructural characteristics, especially as far as collagen fibers were concerned. The above data rule out the suggested regulatory role of collagen fibers in epidermal differentiation and support a possible epidermal two-step differentiative process. They are discussed in relation to the general mechanisms implicated in skin evolution.

Animals↗
PubMed1999

Evolutionally conserved plant homologue of the Bax inhibitor-1 (BI-1) gene capable of suppressing Bax-induced cell death in yeast(1).

The plant homologue of Bax Inhibitor-1, a gene described to suppress the cell death induced by Bax gene expression in yeast, was isolated from Oryza sativa L. (rice) and Arabidopsis. The amino acid sequence of the predicted protein was well conserved in both animal and plant (45% in amino acids) and contained six or seven membrane-spanning segments. Northern blot analysis showed that OsBI-1 transcripts were present in all tissues examined. The OsBI-1 cDNA suppressed cell death induced by mammalian Bax in yeast, suggesting functional conservation of this BI-1 homologue in the plant kingdom.

Amino Acid Sequence↗
PubMed2004

Evolution and function of the sucrose-phosphate synthase gene families in wheat and other grasses.

Suc-phosphate synthase (SPS) is a key regulatory enzyme in the pathway of Suc biosynthesis and has been linked to quantitative trait loci controlling plant growth and yield. In dicotyledonous plants there are three SPS gene families: A, B, and C. Here we report the finding of five families of SPS genes in wheat (Triticum aestivum) and other monocotyledonous plants from the family Poaceae (grasses). Three of these form separate subfamilies within the previously described A, B, and C gene families, but the other two form a novel and distinctive D family, which on present evidence is only found in the Poaceae. The D-type SPS proteins lack the phosphorylation sites associated with 14-3-3 protein binding and osmotic stress activation, and the linker region between the N-terminal catalytic glucosyltransferase domain and the C-terminal Suc-phosphatase-like domain is 80 to 90 amino acid residues shorter than in the A, B, or C types. The D family appears to have arisen after the divergence of mono- and dicotyledonous plants, with a later duplication event resulting in the two D-type subfamilies. Each of the SPS gene families in wheat showed different, but overlapping, spatial and temporal expression patterns, and in most organs at least two different SPS genes are expressed. Analysis of expressed sequence tags indicated similar expression patterns to wheat for each SPS gene family in barley (Hordeum vulgare) but not in more distantly related grasses. We identified an expressed sequence tag from rice (Oryza sativa) that appears to be derived from an endogenous antisense SPS gene, and this might account for the apparently low level of expression of the related OsSPS11 sense gene, adding to the already extensive list of mechanisms for regulating the activity of SPS in plants.

Amino Acid Sequence↗
PubMed2004

Evolution of human IgH3'EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites.

The enhancer complex regulatory region at the 3' of the immunoglobulin heavy cluster (IgH3'EC) is duplicated in apes along with four constant genes and the region is highly conserved throughout humans. Both human IgH3'ECs consist of three loci high sensitive (HS) to DNAse I with enhancer activity. It is thus possible that the presence of structural divergences between the two IgH3'ECs and of relative polymorphisms correspond to functional regulatory changes. To analyse the polymorphisms of these almost identical regions, it resulted mandatory to identify the presence of divergent sequences, in order to select distinctive primers for specific PCR genomic amplifications. To this aim, we first compared the two entire IgH3'ECs in silicio, utilising the updated GenBank (GB) contigs, then we analysed the two IgH3'ECs by cloning and sequencing amplicons from independent genomes. In silicio analysis showed that several inversions, deletions and short insertions had occurred after the duplication. We analysed in detail, by sequencing specific regions, the polymorphisms occurring in enhancer HS1,2-A (which lies in IgH3'EC-1, 3' to the Calpha-1 gene) and in enhancer HS1,2-B (which lies in IgH3'EC-2, 3' to Calpha-2). Polymorphisms are due to the repetition (occurring one to four times) of a 38-bp sequence present at the 3' of the core of enhancers HS1,2. The structure of both human HS1,2 enhancers has revealed not yet described polymorphic features due to the presence of variable spacer elements separating the 38-bp repetitions and to variable external elements bordering the repetition cluster. We found that one of the external elements gave rise to a divergent allele 3 in the two clusters. The frequency of the different alleles of the two loci varies in the Italian population and allele 3 of both loci are very rare. The analysis of the Callicebus moloch, Gorilla gorilla and Pan troglodytes HS1,2 enhancers showed the transformation from the ancestral structure with the 31- to the 17-bp external element in hominids. The relevance of the polymorphisms in the HS1,2 enhancers is due to the variable number of binding sites for the transcription factors: NF-kappaB, CMYB, BSAP1/2, AP1/4, E47, MyoD and muE5 and thus to the possible influence of these variations on switch, production of Ig and on maturation of B cells.

Animals↗
PubMed2000

Recycling to remodel: evolution of dosage-compensation complexes.

In diploid species where sex determination involves heteromorphic sex chromosomes, a mechanism has evolved to compensate for gene-dosage differences in sex-linked genes between the sexes. This regulatory mechanism, which is based on chromatin remodeling, is the function of complexes that include components themselves involved in other cellular functions or with homologs that are involved in such functions. Directing these complexes to the correct chromosome in the appropriate sex relies on pioneer or novel components as well as on the presence of sequence-dependent target sites.

Animals↗
PubMed2006

Heat-shock promoters: targets for evolution by P transposable elements in Drosophila.

Transposable elements are potent agents of genomic change during evolution, but require access to chromatin for insertion-and not all genes provide equivalent access. To test whether the regulatory features of heat-shock genes render their proximal promoters especially susceptible to the insertion of transposable elements in nature, we conducted an unbiased screen of the proximal promoters of 18 heat-shock genes in 48 natural populations of Drosophila. More than 200 distinctive transposable elements had inserted into these promoters; greater than 96% are P elements. By contrast, few or no P element insertions segregate in natural populations in a "negative control" set of proximal promoters lacking the distinctive regulatory features of heat-shock genes. P element transpositions into these same genes during laboratory mutagenesis recapitulate these findings. The natural P element insertions cluster in specific sites in the promoters, with up to eight populations exhibiting P element insertions at the same position; laboratory insertions are into similar sites. By contrast, a "positive control" set of promoters resembling heat-shock promoters in regulatory features harbors few P element insertions in nature, but many insertions after experimental transposition in the laboratory. We conclude that the distinctive regulatory features that typify heat-shock genes (in Drosophila) are especially prone to mutagenesis via P elements in nature. Thus in nature, P elements create significant and distinctive variation in heat-shock genes, upon which evolutionary processes may act.

Animals↗
PubMed2000

Penicillin binding proteins, beta-lactams, and lactamases: offensives, attacks, and defensive countermeasures.

A strong outer covering of peptidoglycan (the sacculus) is essential for most bacteria. Beta-lactams have evolved billions of years ago and can block saccular growth of the organism. This led to the evolution of beta-lactamases and resistant penicillin binding proteins (PBPs). With the introduction of lactam antibiotics by the pharmaceutical industry, resistance genes in nature were laterally transferred to antibiotic-treated disease-causing organisms and additional modification of beta-lactamase genes and of the regulatory genes of the mecA region took place. However, it can be concluded that very little of either type of resistance mechanisms represents new basic evolution against the penicillin type antibiotics. In the last 60 years the resistant bacteria in the main arose by movement of genes from other organisms, from minor genetic changes, and from alteration of the regulation of synthesis.

Bacteria↗
PubMed2001

Evolutionary analyses of the human genome.

The completion of the human genome will greatly accelerate the development of a new branch of science--evolutionary genomics. We can now directly address important questions about the evolutionary history of human genes and their regulatory sequences. Computational analyses of the human genome will reveal the number of genes and repetitive elements, the extent of gene duplication and compositional heterogeneity in the human genome, and the extent of domain shuffling and domain sharing among proteins. Here we present some first glimpses of these features.

Conserved Sequence↗
PubMed1996

RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom.

Until recently, the RFX family of DNA binding proteins consisted exclusively of four mammalian members (RFX1-RFX4) characterized by a novel highly conserved DNA binding domain. Strong conservation of this DNA binding domain precluded a precise definition of the motif required for DNA binding. In addition, the biological systems in which these RFX proteins are implicated remained obscure. The recent identification of four new RFX genes has now shed light on the evolutionary conservation of the RFX family, contributed greatly to a detailed characterization of the RFX DNA binding motif, and provided clear evidence for the function of some of the RFX proteins. RFX proteins have been conserved throughout evolution in a wide variety of species, including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, mouse and man. The characteristic RFX DNA binding motif has been recruited into otherwise very divergent regulatory factors functioning in a diverse spectrum of unrelated systems, including regulation of the mitotic cell cycle in fission yeast, the control of the immune response in mammals, and infection by human hepatitis B virus.

Amino Acid Sequence↗
PubMed2001

Evolution of regeneration and fission in annelids: insights from engrailed- and orthodenticle-class gene expression.

The recent explosion of information on the role of regulatory genes in embryogenesis provides an excellent opportunity to study how these genes participate in post-embryonic developmental processes. We present a detailed comparison of regulatory gene expression during regeneration and asexual reproduction (by fission) in the segmented worm Pristina leidyi (Annelida: Oligochaeta). We isolated three genes from Pristina, one homolog of engrailed and two homologs of orthodenticle, and characterized their expression in different developmental contexts. In situ hybridization studies on worms undergoing normal growth, regeneration and fission demonstrate that in all three processes, Pl-en is expressed primarily in the developing nervous system, and Pl-Otx1 and Pl-Otx2 are expressed primarily in the anterior body wall, foregut and developing nervous system. Our data reveal extensive similarities between expression during regeneration and fission, consistent with the idea that similar developmental processes underlie these two types of development. Thus, we argue that in these annelids fission may have evolved by recruitment of regenerative processes. Furthermore, by comparing our data to existing data from leech embryos, we find evidence that embryonic processes are re-deployed during regeneration and fission.

Amino Acid Sequence↗
PubMed1999

ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has convened an expert working group which consisted of the authors of this paper and their respective committees, consulting groups and task forces. Two ICH guidances regarding genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspects of Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.' Together, these guidance documents now form the regulatory backbone for genotoxicity testing and assessment of pharmaceuticals in the European Union, Japan, and the USA. These guidances do not constitute a revolutionary new approach to genotoxicity testing and assessment, instead they are an evolution from preexisting regional guidelines, guidances and technical approaches. Both guidances describe a number of specific criteria as well as a general test philosophy in genotoxicity testing. Although these guidances were previously released within the participating regions in their respective regulatory communiqués, to ensure their wider distribution and better understanding, the texts of the guidances are reproduced here in their entirety (see Appendix A) and the background for the recommendations are described. The establishment of a standard battery for genotoxicity testing of pharmaceuticals was one of the most important issues of the harmonisation effort. This battery currently consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay, (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. A major change in testing philosophy is the acceptance of the interchangeability of testing for chromosomal aberrations in mammalian cells and the mouse lymphoma tk assay. This agreement was reached on the basis of the extensive review of databases and newly generated experimental data which are in part described in this publication. The authors are fully aware of the fact that some of the recommendations given in these ICH guidances are transient in nature and that the dynamic qualities and ongoing evolution of genetic toxicology makes necessary a continuous maintenance process that would serve to update the guidance as necessary.

Animals↗
PubMed1988

Isolation of the tachykinin, des[Ser1Pro2]scyliorhinin II from the intestine of the ray, Torpedo marmorata.

A peptide with neurokinin A-like immunoreactivity was isolated from an extract of the intestine of an elasmobranch fish, Torpedo marmorata. The primary structure of the peptide was established as Ser-Asn-Ser-Lys-Cys-Pro-Asp-Gly-Pro-Asp-Cys-Phe-Val-Gly-Leu-Met.NH2. This amino acid sequence is identical to that of residues (3-18) of scyliorhinin II previously isolated from the intestine of the common dogfish (Scyliorhinus canicula). The presence of the truncated peptide, lacking Ser-Pro, in the Torpedo gut suggests that scyliorhinin II may be a substrate for an enzyme with dipeptidylpeptidase IV-like specificity. The data support previous assertions that strong evolutionary pressure has acted within the elasmobranch subclass of chondrichthyean fish to conserve the structures of regulatory peptides.

Amino Acids↗
PubMed2005

Carotenoid biosynthetic pathway: molecular phylogenies and evolutionary behavior of crt genes in eubacteria.

Phylogenetic analysis of carotenoid biosynthetic pathway genes and their evolutionary rate variations were studied among eubacterial taxa. The gene sequences for the enzymes involved in this pathway were obtained for major phylogenetic groups of eubacteria (green sulfur bacteria, green nonsulphur bacteria, Gram-positive bacteria, proteobacteria, flavobacteria, cyanobacteria) and archeabacteria. These gene datasets were distributed under five major steps of carotenoid biosynthesis in eubacteria; isoprenoid precursor biosynthesis, phytoene synthesis, dehydrogenation of phytoene, lycopene cyclization, formation of acyclic xanthophylls, formation of cyclic xanthophylls and carotenoid biosynthesis regulation. The NJ algorithm was used on protein coding DNA sequences to deduce the evolutionary relationship for the respective crt genes among different eubacterial lineages. The rate of nonsynonymous nucleotide substitutions per nonsynonymous site (d(N)) and synonymous nucleotide substitutions per synonymous site (d(S)) were calculated for different clades of the respective phylogenetic tree for specific crt genes. The phylogenetic analysis suggests that evolutionary pattern of crt genes in eubacteria is characterized by lateral gene transfer and gene duplication events. The d(N) values indicate that carotenoid biosynthetic genes are more conserved in proteobacteria than in any other eubacterial phyla. Furthermore, of the genes involved in carotenoid biosynthesis pathway, structural genes evolve slowly than the regulatory genes in eubacteria.

Bacteria↗