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PubMed1990

Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution.

The DNA sequence motif ATTTGCAT (octamer) or its inverse complement has been identified as an evolutionarily conserved element in the promoter region of immunoglobulin genes. Two major DNA-binding proteins that bind in a sequence-specific manner to the octamer DNA sequence have been identified in mammalian species--a ubiquitously expressed protein (Oct-1) and a lymphoid-specific protein (Oct-2). During characterization of the promoter region of the chicken immunoglobulin light chain gene, we identified two homologous octamer-binding proteins in chicken B cells. When the cloning of the human gene for Oct-2 revealed it to be a member of a distinct family of homeobox genes, we sought to determine if the human Oct-2 cDNA could be used to identify homologous chicken homeobox genes. Using a human Oct-2 homeobox-specific DNA probe, we were able to identify 6-10 homeobox-containing genes in the chicken genome, demonstrating that the Oct-2-related subfamily of homeobox genes exists in avian species. Low-stringency screening of a chicken embryonic cDNA library allowed us to clone one of these genes. DNA sequence analysis revealed it to be the chicken homologue of the human Oct-1 gene. The predicted protein sequence of the chicken Oct-1 gene demonstrated that the gene for Oct-1 has been highly conserved during vertebrate evolution with an overall 96% amino acid sequence identity between the chicken and human proteins. The previously described POU domain (termed POU for its presence in the Pit-1, Oct-1/Oct-2, and Unc-86 genes) and homeobox domain are 100% conserved between the two protein products. Together, our data show that the POU-containing subfamily of homeobox genes have been highly conserved during vertebrate evolution, apparently as a result of selection for their DNA-binding and transcriptional regulatory properties.

Amino Acid Sequence↗

PubMed1989

Role of growth factors in inflammation and repair.

Mononuclear cells generate a variety of hormone-like proteins termed growth factors that are instrumental in the evolution and resolution of inflammatory reactions. Many of these growth regulatory molecules have multifunctional properties. For example, the mononuclear cell-derived growth factors, platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-beta), are potent leukocyte chemoattractants. In addition, TGF-beta, a product of platelets, T lymphocytes, and monocytes, appears to induce the transcription of other monocyte-derived growth hormone genes. In this regard, picomolar concentrations of TGF-beta stimulate peripheral blood monocytes to transcribe the genes for PDGF (c-sis), basic fibroblast growth factor (FGF), interleukin 1 (IL-1), and tumor necrosis factor (TNF). Furthermore, levels of mRNA for TGF-beta, which is constitutively expressed in resting monocytes, are also increased by exogenous TGF-beta. Each of these monocyte products exhibits a plethora of biological activities on other cell types. T lymphocytes, in response to antigen, contribute to this network by secreting growth factors and lymphokines that regulate monocyte growth factor production.

Growth Substances↗

PubMed1998

Origin of Metazoa: sponges as living fossils.

The phylogenetic position of the phylum Porifera (sponges) is at the base of the kingdom Metazoa. During the past few years not only rDNA sequences but--and this was a major advance--even cDNAs/genes have been isolated and characterized from sponges, especially from the marine demosponge Geodia cydonium, which code for proteins. The analyses of their deduced amino acid sequences allowed a molecular biological approach to solve the problem of monophyly of Metazoa. Molecules of the extracellular matrix/basal lamina, with the integrin receptor, fibronectin, and galectin as prominent examples, cell-surface receptors (tyrosine kinase receptor), elements of sensory systems (crystallin, metabotropic glutamate receptor), and homologs/modules of an immune system (immunoglobulin like molecules, scavenger receptor cysteine-rich, and short consensus repeats, rhesus system) classify the Porifera as true Metazoa. As living fossils, provided with simple, primordial molecules allowing cell-cell and cell-matrix adhesion as well as processes of signal transduction as known in a more complex manner from higher Metazoa, they also show peculiarities not known in other metazoan phyla. Tissues of sponges are rich in telomerase activity, suggesting a high plasticity in the determination of cell lineages. It is concluded that molecular biological studies with sponges as model will not only help to understand the evolution of Protoctista to Metazoa but also the complex, hierarchial regulatory network of cells in higher Metazoa.

Amino Acid Sequence↗

PubMed2001

The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology.

The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) together with the intermediate zone of the medullary reticular formation (IRZ) are pivotal relay stations within central autonomic regulatory feedback systems. This study was undertaken to investigate the evolution of the Alzheimer's disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and classified the cortical Alzheimer-related cytoskeletal anomalies according to an established staging system (neurofibrillary tangle/neuropil threads [NFT/NT] stages I-VI). The lesions were visualized either with the antibody AT8, which is immunospecific for the abnormally phosphorylated form of the cytoskeletal protein tau, or with a modified Gallyas silver iodide stain. The MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB in stage II, whereby bothstages correspond to the preclinical phase of Alzheimer's disease (AD). In stages III-IV (incipient AD), the MPB and SPP are severely affected. In all of the stage III-IV cases, the lesions in the LPB and IRZ are well developed. In stages V and VI (clinical phase of AD), the MPB and SPP are filled with the abnormal intraneuronal material. At stages V-VI, the LPB is moderately involved and the IRZ shows severe damage. The pathogenesis of the AD-related cytoskeletal lesions in the nuclei of the pontine parabrachial region and in the IRZ conforms with the cortical NFT/NT staging sequence I-VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conceivable that autonomic mechanisms progressively deteriorate with advancing cortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.

Aged↗

PubMed2005

Structural conservation of the salivary gland-specific slalom gene in the blowfly Lucilia sericata.

Glycosylation and sulfation are two of the essential post-translational modifications of proteins. The slalom gene encodes a 3'-phosphoadenosine 5'-phosphosulfate transporter, a conserved protein found in organisms as diverse as plants and humans and required for sulfation of proteins. In Drosophila, slalom is exclusively expressed in salivary glands, which is unexpected, taken into account the general function for sulfation of proteins. In this paper, we present a detailed description of the slalom gene in a large insect, the blowfly Lucilia sericata. Our data demonstrate that the slalom gene structure, the protein and the expression pattern are highly conserved between Lucilia and Drosophila. Lucilia slalom promoter analysis, using transgenic Drosophila, demonstrates that the Lucilia slalom promoter can faithfully mimic the expression pattern of both Lucilia and Drosophila slalom in salivary glands. Taken together, these data show the structure and the transcriptional cis-regulatory elements of the slalom gene to be unchanged during evolution, despite the 100 million years of divergence between the two insects. Moreover, it suggests that the salivary gland-specific expression of slalom bears an important and conserved function for sulfation of specific macromolecules.

Amino Acid Sequence↗

PubMed2006

Comparative analysis of the risk-handling procedures for gene technology applications in medical and plant science.

In this paper we analyse how the risks associated with research on transgenic plants are regulated in Sweden. The paper outlines the way in which pilot projects in the plant sciences are overseen in Sweden, and discusses the international and national background to the current regulatory system. The historical, and hitherto unexplored, reasons for the evolution of current administrative and legislative procedures in plant science are of particular interest. Specifically, we discuss similarities and differences in the regulation of medicine and plant science, and we examine the tendency towards dichotomizing risk--focusing on social/ethical risks in medicine and biological risks in plant science. The context of this article is the Synpraxia research project, an inter-disciplinary program combining expertise in sciences and the humanities.

Biomedical Technology↗

PubMed2004

Hormonal regulation of the fish gastrointestinal tract.

The gastrointestinal tracts (GIT) of fish and other vertebrates are challenged with a diversity of functional demands caused by changes and differences in dietary inputs and environmental conditions. This contribution reviews how hormonal regulation plays an essential role in modulating the GIT functions of fish to match changes in functional demands. Exemplary is how hormones produced by the GIT, the associated organs (e.g., pancreas), and other sources (e.g., hypothalamus, adrenal cortex, thyroid, gonads) modulate the digestive processes (motility, secretion, and nutrient absorption) in response to dietary inputs. Hormones regulate the other GIT functions of osmoregulation (secretion and absorption of electrolytes and water), immunity, endocrine secretions, metabolism, and the elimination of toxic metabolites and environmental contaminants to match changes in environmental conditions and physiological states. Although the regulatory molecules and associated signaling pathways have been conserved during evolution of the vertebrate GIT, the specific responses often vary among fish with different feeding habits and from different environments, and can differ from those described for mammals.

Animals↗

PubMed1996

Palliative medicine and the medical oncologist. Defining the purview of care.

The fusion of palliative medicine and medical oncology, in practice and in education, can provide a better standard of patient care, reduce the risk of oncologist burnout, and increase the likelihood of patient family and physician satisfaction. There need be no gulf between these disciplines, and only together do they represent truly comprehensive cancer care. The realization of this fusion will require the participation of individual clinicians, program directors, and the policy makers for cancer centers, professional organizations, and the health care regulatory authorities. It is a logical next step in the evolution of medical oncology.

Hospice Care↗

PubMed2000

The ced-8 gene controls the timing of programmed cell deaths in C. elegans.

Loss-of-function mutations in the gene ced-8 lead to the late appearance of cell corpses during embryonic development in C. elegans. ced-8 functions downstream of or in parallel to-the regulatory cell death gene ced-9 and may function as a cell death effector downstream of the caspase encoded by the programmed cell death killer gene ced-3. In ced-8 mutants, embryonic programmed cell death probably initiates normally but proceeds slowly. ced-8 encodes a transmembrane protein that appears to be localized to the plasma membrane. The CED-8 protein is similar to human XK, a putative membrane transport protein implicated in McLeod Syndrome, a form of hereditary neuroacanthocytosis.

Alleles↗

PubMed1998

Sequence analysis of the 5'-flanking region of the gene encoding human HOXA-7.

We have isolated and characterized the immediate 5'-flanking region (886 bp) of the gene encoding human HOXA-7. When the total sequence was compared with those of mice, 93% of the 3' 518 bp (nt 370-886) sequences were identical, in which the 245 bases just preceding the AUG initiator codon (nt 614) was as highly conserved as in the coding region (nt 614-886). Sequences further upstream (nt 1-370) by comparison were highly diverged. In the 245 bp region, 8 stop and 3 initiation (including the initiator) codons were located, and a 50-aa long presumptive polypeptide was encoded. Nucleotide sequence analysis revealed three Sp1 and one AP2 binding sites, as well as one CAAT box. However, there was no consensus sequence for a TATA box in the 5' flanking region. One RARE repeat, one krox20 and three Hox-PBC binding sites were detected. Since many of the factor recognition sites were located in the immediate 5' flanking sequences of a highly-conserved region, it might be speculated that a regulatory mechanism for Hox gene expression is conserved throughout the evolution and one possible mechanism could be at the post-translational level.

5' Untranslated Regions↗

PubMed2003

Glutamine synthetase from the marine cyanobacteria Prochlorococcus spp: characterization, phylogeny and response to nutrient limitation.

The regulation of glutamine synthetase (EC 6.3.1.2) from Prochlorococcus was previously shown to exhibit unusual features: it is not upregulated by nitrogen starvation and it is not inactivated by darkness (El Alaoui et al. (2001) Appl Environ Microbiol 67: 2202-2207). These are probably caused by adaptations to oligotrophic environments, as confirmed in this work by the marked decrease in the enzymatic activity when cultures were subjected to iron or phosphorus starvation. In order to further understand the adaptive features of ammonium assimilation in this cyanobacterium, glutamine synthetase was purified from two Prochlorococcus strains: PCC 9511 (high-light adapted) and SS120 (low-light adapted). We obtained approximately 100-fold purified samples of glutamine synthetase electrophoretically homogeneous, with a yield of approximately 30%. The estimated molecular mass of the subunits was roughly the same for both strains: 48.3 kDa. The apparent Km constants for the biosynthetic activity were 0.30 mM for ammonium, 1.29 mM for glutamate and 1.35 mM for ATP; the optimum pH was 8.0. Optimal temperature was surprisingly high (55 degrees C). Phylogenetic analysis of glnA from three Prochlorococcus strains (MED4, MIT9313 and SS120) showed they group closely with marine Synechococcus isolates, in good agreement with other studies based on 16 S RNA sequences. All of our results suggest that the structure and kinetics of glutamine synthetase in Prochlorococcus have not been significantly modified during the evolution within the cyanobacterial radiation, in sharp contrast with its regulatory properties.

Adenosine Triphosphate↗

PubMed2004

'Gotta pick a megabase or two': in silico routes to gene regulation.

A number of vertebrate genome sequences are now available in draft or high-quality form. By comparing genomes from related species, conserved elements that are located outside the coding regions can be identified, many of which represent regulatory elements. The design of the sequence comparisons, taking into account the extent of the evolutionary divergence, is crucial to the outcome. Clearly, investigations of these conserved regulatory elements are important in understanding mechanisms underlying both vertebrate evolution and human disease.

Animals↗

PubMed1999

Structure-function analysis of an evolutionary conserved protein, DAP3, which mediates TNF-alpha- and Fas-induced cell death.

A novel approach to the isolation of positive mediators of programmed cell death, based on random inactivation of genes by expression of anti sense RNAs, was employed to identify mediators of interferon-gamma-induced apoptosis. One of the several genes identified is DAP3, which codes for a 46 kDa protein with a potential nucleotide-binding motif. Structure-function studies of the protein indicate that the intact full-length protein is required for its ability to induce apoptosis when overexpressed. The N-terminal 230 amino acids, on the other hand, act in a dominant-negative fashion. Both of these functions are dependent on the integrity of the nucleotide binding motif. Expression of anti-sense DAP3 RNA and of the dominant interfering form of DAP3 both protected cells from apoptosis induced by activation of Fas and tumor necrosis factor alpha (TNF-alpha) receptors. Thus, DAP3 is implicated as a positive mediator of these death-inducing stimuli. It functions downstream of the receptor signaling complex and its death promoting effects depend on caspase activity. In the nematode Caenorhabditis elegans, a potential homolog of DAP3 showing 35% identity and 64% similarity to the human protein was isolated. Overexpression of the nematode DAP3 cDNA in mammalian cells induced cell death, indicating that the protein is conserved at the functional level as well as the structural level.

Amino Acid Sequence↗

PubMed2006

Global similarity and local divergence in human and mouse gene co-expression networks.

BACKGROUND: A genome-wide comparative analysis of human and mouse gene expression patterns was performed in order to evaluate the evolutionary divergence of mammalian gene expression. Tissue-specific expression profiles were analyzed for 9,105 human-mouse orthologous gene pairs across 28 tissues. Expression profiles were resolved into species-specific coexpression networks, and the topological properties of the networks were compared between species. RESULTS: At the global level, the topological properties of the human and mouse gene coexpression networks are, essentially, identical. For instance, both networks have topologies with small-world and scale-free properties as well as closely similar average node degrees, clustering coefficients, and path lengths. However, the human and mouse coexpression networks are highly divergent at the local level: only a small fraction (<10%) of coexpressed gene pair relationships are conserved between the two species. A series of controls for experimental and biological variance show that most of this divergence does not result from experimental noise. We further show that, while the expression divergence between species is genuinely rapid, expression does not evolve free from selective (functional) constraint. Indeed, the coexpression networks analyzed here are demonstrably functionally coherent as indicated by the functional similarity of coexpressed gene pairs, and this pattern is most pronounced in the conserved human-mouse intersection network. Numerous dense network clusters show evidence of dedicated functions, such as spermatogenesis and immune response, that are clearly consistent with the coherence of the expression patterns of their constituent gene members. CONCLUSION: The dissonance between global versus local network divergence suggests that the interspecies similarity of the global network properties is of limited biological significance, at best, and that the biologically relevant aspects of the architectures of gene coexpression are specific and particular, rather than universal. Nevertheless, there is substantial evolutionary conservation of the local network structure which is compatible with the notion that gene coexpression networks are subject to purifying selection.

Animals↗

PubMed2005

Mechanisms regulating melatonin synthesis in the mammalian pineal organ.

The day/night rhythm in melatonin production is a characteristic feature in vertebrate physiology. This hormonal signal reliably reflects the environmental light conditions and is independent of behavioral aspects. In all mammalian species, melatonin production is regulated by norepinephrine, which is released from sympathetic nerve fibers exclusively at night. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A. This pathway is crucial for regulation of the penultimate enzyme in melatonin biosynthesis, the arylalkylamine N-acetyltransferase (AANAT); cAMP/protein kinase A may, however, act in different ways. In ungulates and primates, pinealocytes constantly synthesize AANAT protein from continually available Aanat mRNA. During the day-in the absence of noradrenergic stimulation-the protein is immediately destroyed by proteasomal proteolysis. At nighttime, elevated cAMP levels cause phosphorylation of AANAT by protein kinase A. This posttranslational modification leads to interaction of phosphorylated AANAT with regulatory 14-3-3 proteins, which protect AANAT from degradation. Increases in AANAT protein are paralleled by increases in enzyme activity. Stimulation of the cAMP/protein kinase A pathway may also activate pineal gene expression. In rodents, transcriptional activation of the Aanat gene is the primary mechanism for the induction of melatonin biosynthesis and results in marked day/night fluctuations in Aanat mRNA. It involves protein kinase A-dependent phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB) and binding of phosphorylated CREB in the promoter region of the Aanat gene. In conclusion, a common neuroendocrine principle, the nocturnal rise in melatonin, is controlled by strikingly diverse regulatory mechanisms. This diversity has emerged in the course of evolution and reflects the high adaptive plasticity of the melatonin-generating pineal organ.

Animals↗

PubMed2025

Evolution of primate T-cell leukemia virus type 1 accessory genes and functional divergence of its antisense proteins.

Human T-cell leukemia virus type 1 (HTLV-1) is derived from simian T-cell leukemia virus type 1 (STLV-1), and together they form a broader category known as primate T-cell leukemia virus type 1 (PTLV-1). PTLV-1 encodes multiple proteins from overlapping open reading frames (ORFs) in the pX region. This study aims to characterize the conservation of these proteins in different PTLV-1 subtypes and their role in pathogenesis. For the first time, we report the full-length proviral sequence of an STLV-1 strain isolated from chimpanzee and African green monkey. Phylogenetic analysis reveals high conservation of the accessory proteins p12, p30, and p13 in the HTLV-1a subtype. Conversely, some African PTLV-1 subtypes exhibit loss of ORFs for p12 or p13. For Asian subtypes, simian strains often lack p12, p13, or p30 proteins, whereas human strains retain the ORFs of p30 and p13 but not p12. To assess the infectivity of a simian strain of PTLV-1 lacking ORFs for p12, p13, and p30, we constructed a molecular clone from a naturally infected Japanese macaque (Mfu: Macaca fuscata) and compared it with HTLV-1a. Using a reporter assay and ELISA, we found similar infectivity to Jurkat T cells; however, STLV-1 Mfu exhibited impaired infectivity in the monocytic cell line THP-1. Additionally, despite the conservation of the HTLV-1/STLV-1 bZIP factor (HBZ/SBZ) ORFs, HBZ/SBZ proteins derived from HTLV-1a and African PTLV-1 subtypes induce significantly higher activation of the TGF-β/Smad signaling pathway than those from Asian subtypes. Collectively, our findings suggest that the acquisition of the accessory proteins by PTLV-1 subtypes potentially confers an advantageous adaptation of PTLV-1 during infection in apes, including humans. Moreover, among PTLV-1 strains, HBZ/SBZ had varying degrees of activity on the TGF-β/Smad pathway; this fact underscores the complex interplay between viral proteins and host signaling pathways, possibly influencing the viral pathogenicity in different species.

Animals↗

PubMed1999

[MALT-type non-Hodgkin's lymphoma: advances in biopsy diagnosis and pathogenesis].

Malignant Non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue display unique morphological and biological features. Unlike the situation in nodal lymphomas, they almost invariably arise from defined and recognisable precursor lesions, such as chronic infections or autoimmune diseases. From the diagnostic point of view, efforts have been undertaken to define (1) the minimal requirements for the unequivocal diagnosis of MALT-type lymphoma, (2) the regression stages after Helicobacter pylori eradication, and (3) to establish a grading system for the respective lesions. Of importance, it must be emphasized that in most cases the biopsy received in first-line is not enough in establishing a correct diagnosis with regard to biological and therapeutic implications. In particular, the accurate estimation of the biological aggressiveness of the tumour will in most cases require extensive rebiopsies. As in nodal tumours, the genetic constitution of low grade MALT-type lymphomas is more and more revealed. While data on the importance of numerical aberrations are conflicting, certain structural aberrations, such as the t(1;14) and the t(11;18), have been unequivocally linked to MALT-type lymphomas. Preliminary data suggest that these aberrations may target the apoptotic pathway. Their recognition may herald the evolution of new tumour features, such as independence from outer regulatory influences, obviously in early stages determined by the microenvironment and might be closely related to the site of tumour development and hence be a feature of the primary inflammatory disorder.

Biopsy↗

PubMed1992

METASIM: object-oriented modelling of cell regulation.

Enzymatic processes and substances are modelled as distinct objects, belonging to a limited number of classes. A set of class definitions in C++ is presented that constitutes an object-oriented programming platform. The latter supports 'biological' data types and functions and facilitates simulation of metabolic and regulatory pathways in living cells. To compute the time-evolution, Euler or Runge-Kutta methods are used, though the latter method compromises a strict object-oriented philosophy. As an example, histone gene expression during embryogenesis of Xenopus laevis is modelled. This object-oriented programming system forms a modelling 'language' which is readily understood by both biochemists and programmers. It allows biological problems to be programmed more easily and correctly and brings the program closer to the biological reality, hence making it more meaningful to bioscientists. Moreover, it can readily be extended to new models by class derivation.

Cells↗