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PubMed2003

Previtamin D3 with a trans-fused decalin CD-ring has pronounced genomic activity.

Deletion of C19 in the structure of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] does not substantially alter the biological potency but prevents the conversion between the vitamin and the previtamin form. Hence, this modification allows the study of locked previtamin and vitamin forms. The locked 19-nor-1,25(OH)2-previtamin D3 analog (19-nor-previtamin D) had a low biological activity and was a rather weak activator of the genomic signal transduction pathway. 19-Nor-trans-decalin-1,25(OH)2-vitamin D3 (19-nor-TD-vitamin D), characterized by the presence of a trans-fused decalin CD-ring system, was 10-fold more potent than the parent compound and was a potent activator of the genomic signal transduction pathway. Surprisingly, the previtamin, 19-nor-trans-decalin-1,25(OH)2-previtamin D3 (19-nor-TD-previtamin D), was as potent as 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation and represents the first previtamin structure with pronounced vitamin D-like activity. Furthermore, this compound interacted as efficiently as 1,25(OH)2D3 with the vitamin D receptor (VDR), retinoid X receptor (RXR), coactivators, and DNA, which illustrated its potent ability to activate the genomic signal transduction pathway. Analysis of the transactivation potency of 12 VDR point mutants after stimulation with 19-nor-TD-previtamin D revealed that this analog used the same contact points within the receptor as did 1,25(OH)2D3. This could be confirmed by modeling analysis of this compound in the ligand binding pocket of VDR. In conclusion, a previtamin D3 analog is presented with genomic activities equivalent to 1,25(OH)2D3.

Amino Acid Substitution↗

PubMed2003

Xeroderma pigmentosum group C protein possesses a high affinity binding site to human centrin 2 and calmodulin.

Human centrin 2 (HsCen2), a member of the EF-hand superfamily of Ca2+-binding proteins, is commonly associated with centrosome-related structures. The protein is organized in two domains, each containing two EF-hand motifs, but only the C-terminal half exhibits Ca2+ sensor properties. A significant fraction of HsCen2 is localized in the nucleus, where it was recently found associated with the xeroderma pigmentosum group C protein (XPC), a component of the nuclear excision repair pathway. Analysis of the XPC sequence (940 residues), using a calmodulin target recognition software, enabled us to predict two putative binding sites. The binding properties of the two corresponding peptides were investigated by isothermal titration calorimetry. Only one of the peptides (P1-XPC) interacts strongly (Ka = 2.2 x 10(8) m-1, stoichiometry 1:1) with HsCen2 in a Ca2+-dependent manner. This peptide also binds, with a similar affinity (Ka = 1.1 x 10(8) m-1) to a C-terminal construct of HsCen2, indicating that the interaction with the integral protein is mainly the result of the contribution of the C-terminal half. The second peptide (P2-XPC) failed to show any detectable binding either to HsCen2 or to its C-terminal lobe. The two peptides interact with different affinities and mechanisms with calmodulin. Circular dichroism and nuclear magnetic resonance were used to structurally characterize the complex formed by the C-terminal domain of HsCen2 with P1-XPC.

Amino Acid Sequence↗

PubMed2002

Describing biological protein interactions in terms of protein states and state transitions: the LiveDIP database.

Biological protein-protein interactions differ from the more general class of physical interactions; in a biological interaction, both proteins must be in their proper states (e.g. covalently modified state, conformational state, cellular location state, etc.). Also in every biological interaction, one or both interacting molecules undergo a transition to a new state. This regulation of protein states through protein-protein interactions underlies many dynamic biological processes inside cells. Therefore, understanding biological interactions requires information on protein states. Toward this goal, DIP (the Database of Interacting Proteins) has been expanded to LiveDIP, which describes protein interactions by protein states and state transitions. This additional level of characterization permits a more complete picture of the protein-protein interaction networks and is crucial to an integrated understanding of genome-scale biology. The search tools provided by LiveDIP, Pathfinder, and Batch Search allow users to assemble biological pathways from all the protein-protein interactions collated from the scientific literature in LiveDIP. Tools have also been developed to integrate the protein-protein interaction networks of LiveDIP with large scale genomic data such as microarray data. An example of these tools applied to analyzing the pheromone response pathway in yeast suggests that the pathway functions in the context of a complex protein-protein interaction network. Seven of the eleven proteins involved in signal transduction are under negative or positive regulation of up to five other proteins through biological protein-protein interactions. During pheromone response, the mRNA expression levels of these signaling proteins exhibit different time course profiles. There is no simple correlation between changes in transcription levels and the signal intensity. This points to the importance of proteomic studies to understand how cells modulate and integrate signals. Integrating large scale, yeast two-hybrid data with mRNA expression data suggests biological interactions that may participate in pheromone response. These examples illustrate how LiveDIP provides data and tools for biological pathway discovery and pathway analysis.

Databases, Protein↗

PubMed1998

Enhanced glycosylation and sulfation of secretory proteoglycans is coupled to the expression of a basic secretory protein.

We have used coexpression of a salivary basic proline-rich protein (PRP) along with a proline-rich proteoglycan (PRPg) in pituitary AtT-20 cells to examine the regulation of glycosaminoglycan (GAG) biosynthesis and the storage of these secretory products for regulated secretion. The basic PRP caused a dose-dependent increase in sulfation of PRPg and also increased the extent to which PRPg polypeptide backbones are modified by a GAG chain. The sulfation of an endogenous proteoglycan was similarly increased in the presence of basic PRP; however, other sulfated secretory products of AtT-20 cells were unaffected. These results imply that enzymes functioning in elongation and sulfation of proteoglycans are coordinately regulated and that their activities respond to a change in the milieu of the intracellular transport pathway. Analysis of the regulated secretion of both the basic PRP and PRPg has indicated that while the presence of the GAG chain improves the storage of PRPg, the presence of PRPg does not increase the storage of basic PRP. Therefore, sulfation of GAGs does not appear to be a primary factor in regulated secretory sorting.

Animals↗

PubMed2002

Positional cloning of rice semidwarfing gene, sd-1: rice "green revolution gene" encodes a mutant enzyme involved in gibberellin synthesis.

A rice semidwarfing gene, sd-1, known as the "green revolution gene," was isolated by positional cloning and revealed to encode gibberellin 20-oxidase, the key enzyme in the gibberellin biosynthesis pathway. Analysis of 3477 segregants using several PCR-based marker technologies, including cleaved amplified polymorphic sequence, derived-CAPS, and single nucleotide polymorphisms revealed 1 ORF in a 6-kb candidate interval. Normal-type rice cultivars have an identical sequence in this region, consisting of 3 exons (558, 318, and 291 bp) and 2 introns (105 and 1471 bp). Dee-Geo-Woo-Gen-type sd-1 mutants have a 383-bp deletion from the genome (278-bp deletion from the expressed sequence), from the middle of exon 1 to upstream of exon 2, including a 105-bp intron, resulting in a frame-shift that produces a termination codon after the deletion site. The radiation-induced sd-1 mutant Calrose 76 has a 1-bp substitution in exon 2, causing an amino acid substitution (Leu [CTC] to Phe [TTC]). Expression analysis suggests the existence of at least one more locus of gibberellin 20-oxidase which may prevent severe dwarfism from developing in sd-1 mutants.

Amino Acid Sequence↗

PubMed1998

The MEP2 ammonium permease regulates pseudohyphal differentiation in Saccharomyces cerevisiae.

In response to nitrogen starvation, diploid cells of the budding yeast Saccharomyces cerevisiae differentiate into a filamentous, pseudohyphal growth form. This dimorphic transition is regulated by the Galpha protein GPA2, by RAS2, and by elements of the pheromone-responsive MAP kinase cascade, yet the mechanisms by which nitrogen starvation is sensed remain unclear. We have found that MEP2, a high affinity ammonium permease, is required for pseudohyphal differentiation in response to ammonium limitation. In contrast, MEP1 and MEP3, which are lower affinity ammonium permeases, are not required for filamentous growth. Deltamep2 mutant strains had no defects in growth rates or ammonium uptake, even at limiting ammonium concentrations. The pseudohyphal defect of Deltamep2/Deltamep2 strains was suppressed by dominant active GPA2 or RAS2 mutations and by addition of exogenous cAMP, but was not suppressed by activated alleles of the MAP kinase pathway. Analysis of MEP1/MEP2 hybrid proteins identified a small intracellular loop of MEP2 involved in the pseudohyphal regulatory function. In addition, mutations in GLN3, URE2 and NPR1, which abrogate MEP2 expression or stability, also conferred pseudohyphal growth defects. We propose that MEP2 is an ammonium sensor, generating a signal to regulate filamentous growth in response to ammonium starvation.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1998

Characterization of mat A-2, mat A-3 and deltamatA mating-type mutants of Neurospora crassa.

The mating-type locus of Neurospora crassa regulates mating identity and entry into the sexual cycle. The mat A idiomorph encodes three genes, mat A-1, mat A-2, and mat A-3. Mutations in mat A-1 result in strains that have lost mating identity and vegetative incompatibility with mat a strains. A strain containing mutations in both mat A-2 and mat A-3 is able to mate, but forms few ascospores. In this study, we describe the isolation and characterization of a mutant deleted for mat (deltamatA), as well as mutants in either mat A-2 or mat A-3. The deltamatA strain is morphologically wild type during vegetative growth, but it is sterile and heterokaryon compatible with both mat A and mat a strains. The mat A-2 and mat A-3 mutants are also normal during vegetative growth, mate as a mat A strain, and produce abundant biparental asci in crosses with mat a, and are thus indistinguishable from a wild-type mat A strain. These data and the fact that the mat A-2 mat A-3 double mutant makes few asci with ascospores indicate that MAT A-2 and MAT A-3 are redundant and may function in the same pathway. Analysis of the expression of two genes (sdv-1 and sdv-4) in the various mat mutants suggests that the mat A polypeptides function in concert to regulate the expression of some sexual development genes.

Base Sequence↗

PubMed2002

Genetic architecture of plastic methyl jasmonate responses in Arabidopsis thaliana.

The ability of a single genotype to generate different phenotypes in disparate environments is termed phenotypic plasticity, which reflects the interaction of genotype and environment on developmental processes. However, there is controversy over the definition of plasticity genes. The gene regulation model states that plasticity loci influence trait changes between environments without altering the means within a given environment. Alternatively, the allelic sensitivity model argues that plasticity evolves due to selection of phenotypic values expressed within particular environments; hence plasticity must be controlled by loci expressed within these environments. To identify genetic loci controlling phenotypic plasticity and address this controversy, we analyzed the plasticity of glucosinolate accumulation under methyl jasmonate (MeJa) treatment in Arabidopsis thaliana. We found genetic variation influencing multiple MeJa signal transduction pathways. Analysis of MeJa responses in the Landsberg erecta x Columbia recombinant inbred lines identified a number of quantitative trait loci (QTL) that regulate plastic MeJa responses. All significant plasticity QTL also impacted the mean trait value in at least one of the two "control" or "MeJa" environments, supporting the allelic sensitivity model. Additionally, we present an analysis of MeJa and salicylic acid cross-talk in glucosinolate regulation and describe the implications for glucosinolate physiology and functional understanding of Arabidopsis MeJa signal transduction.

Acetates↗

PubMed2006

Pathguide: a pathway resource list.

Pathguide: the Pathway Resource List (http://pathguide.org) is a meta-database that provides an overview of more than 190 web-accessible biological pathway and network databases. These include databases on metabolic pathways, signaling pathways, transcription factor targets, gene regulatory networks, genetic interactions, protein-compound interactions, and protein-protein interactions. The listed databases are maintained by diverse groups in different locations and the information in them is derived either from the scientific literature or from systematic experiments. Pathguide is useful as a starting point for biological pathway analysis and for content aggregation in integrated biological information systems.

Databases, Genetic↗

PubMed2006

Novel retinoid targets in the mouse limb during organogenesis.

Bioactive retinoids are potent limb teratogens, upregulating apoptosis, decreasing chondrogenesis, and producing limb-reduction defects. To target the origins of these effects, we examined gene expression changes in the developing murine limb after 3 h of culture with teratogenic concentrations of vitamin A. Embryonic day 12 CD-1 limbs were cultured in the absence or presence of vitamin A (retinol acetate) at 1.25 and 62.5muM (n = 5). Total RNA was used to probe Atlas 1.2 cDNA arrays. Eighty-one genes were significantly upregulated by retinol exposure; among these were key limb development signaling molecules, extracellular matrix and adhesion proteins, oncogenes, and a large number of transcriptional regulators, including Eya2, Id3, Snail, and Hes1. To relate these expression changes to teratogenic outcome, the response of these four genes was assessed after culture with vitamin A and retinoid receptor antagonists that are able to rescue retinoid-induced malformations; expression levels were correlated with limb malformations. Lastly, pathways analysis revealed that a large number of the genes significantly affected by retinoid treatment are functionally linked through direct interactions. Several regulatory gene cascades emerged relevant to morphogenesis, cell-fate, and chondrogenesis; moreover, members of these cascades crosstalk with one other. These results indicate that retinoids act in a coordinated fashion to disrupt development at multiple levels. In sum, this work proposes several unifying mechanisms for retinoid-induced limb malformations, identifies novel retinoid targets, and highlights Eya2, Id3, Snail, and Hes1 as potential key teratogenic effectors.

Animals↗

PubMed1996

Present concept on current water protection and remediation activities for the areas contaminated by the 1986 Chernobyl accident.

The results of radiation monitoring data and migration pathway analysis of water bodies within areas affected by the 1986 Chernobyl accident provide a unique opportunity for decision-makers working in other extensively contaminated regions to optimize their approaches to surface and groundwater protection. Most engineering measures within the Chernobyl 30-km exclusion zone were focused on preventing secondary contamination of surface and groundwater from entering the Pripyat River and the Kiev Reservoir. However, implementation of these measures required huge financial and human resources. Therefore, lessons about post-accidental water protection activities can be learned from the Chernobyl example.

Humans↗

PubMed2006

Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein.

PURPOSE OF REVIEW: Evidence indicates that high density lipoprotein (HDL) is cardioprotective and that several mechanisms are involved. One important pathway is a membrane-associated ATP-binding cassette transporter, ABCA1, that clears cholesterol from macrophage foam cells. Anti-inflammatory and antioxidant properties also might contribute to HDL's ability to inhibit atherosclerosis. RECENT FINDINGS: Myeloperoxidase targets HDL for oxidation, raising the possibility that the enzyme provides a specific mechanism for generating dysfunctional HDL in humans. Myeloperoxidase-dependent oxidation of apolipoprotein A-I, the major protein in HDL, blocks HDL's ability to remove excess cholesterol from cells by the ABCA1 pathway. Analysis of mutated forms of apoA-I and oxidized apoA-I treated with methionine sulfoxide reductase implicate oxidation of specific tyrosine and methionine residues in impairing the ABCA1 transport activity of apoA-I. The crystal structure of lipid-free apoA-I suggests that such oxidative damage might disrupt negatively charged regions on the protein's surface or alter its remodeling, resulting in conformations that fail to interact with ABCA1. SUMMARY: Oxidation of HDL by myeloperoxidase may represent a specific molecular mechanism for converting the cardioprotective lipoprotein into a dysfunctional form, raising the possibility that the enzyme represents a potential therapeutic target for preventing vascular disease in humans. Moreover, oxidized HDL might prove useful as a blood marker for clinically significant cardiovascular disease in humans.

ATP Binding Cassette Transporter 1↗

PubMed2004

Resrad-recycle: a computer model for analyzing radiation exposures resulting from recycling radioactively contaminated scrap metals or reusing radioactively surface-contaminated materials and equipment.

RESRAD-RECYCLE is a computer code designed by Argonne National Laboratory (ANL) to be used in making decisions about the disposition of radioactively contaminated materials and scrap metals. It implements a pathway analysis methodology to evaluate potential radiation exposures resulting from the recycling of contaminated scrap metals and the reuse of surface-contaminated materials and equipment. For modeling purposes, it divides the entire metal recycling process into six steps: (1) scrap delivery, (2) scrap melting, (3) ingot delivery, (4) product fabrication, (5) product distribution, and (6) use of finished product. RESRAD-RECYCLE considers the reuse of surface-contaminated materials in their original forms. It contains representative exposure scenarios for each recycling step and the reuse process; users can also specify scenarios if desired. The model calculates individual and collective population doses for workers involved in the recycling process and for the public using the finished products. The results are then used to derive clearance levels for the contaminated materials on the basis of input dose restrictions. The model accounts for radiological decay and ingrowth, dilution and partitioning during melting, and distribution of refined metal in the various finished products, as well as the varying densities and geometries of the radiation sources during the recycling process. A complete material balance in terms of mass and radioactivity during the recycling process can also be implemented. In an international validation study, the radiation doses calculated by RESRAD-RECYCLE were shown to agree fairly well with actual measurement data.

Body Burden↗

PubMed1999

The Arabidopsis dwarf1 mutant is defective in the conversion of 24-methylenecholesterol to campesterol in brassinosteroid biosynthesis.

Since the isolation and characterization of dwarf1-1 (dwf1-1) from a T-DNA insertion mutant population, phenotypically similar mutants, including deetiolated2 (det2), constitutive photomorphogenesis and dwarfism (cpd), brassinosteroid insensitive1 (bri1), and dwf4, have been reported to be defective in either the biosynthesis or the perception of brassinosteroids. We present further characterization of dwf1-1 and additional dwf1 alleles. Feeding tests with brassinosteroid-biosynthetic intermediates revealed that dwf1 can be rescued by 22alpha-hydroxycampesterol and downstream intermediates in the brassinosteroid pathway. Analysis of the endogenous levels of brassinosteroid intermediates showed that 24-methylenecholesterol in dwf1 accumulates to 12 times the level of the wild type, whereas the level of campesterol is greatly diminished, indicating that the defective step is in C-24 reduction. Furthermore, the deduced amino acid sequence of DWF1 shows significant similarity to a flavin adenine dinucleotide-binding domain conserved in various oxidoreductases, suggesting an enzymatic role for DWF1. In support of this, 7 of 10 dwf1 mutations directly affected the flavin adenine dinucleotide-binding domain. Our molecular characterization of dwf1 alleles, together with our biochemical data, suggest that the biosynthetic defect in dwf1 results in reduced synthesis of bioactive brassinosteroids, causing dwarfism.

Alleles↗

PubMed2001

Efficient screening of Arabidopsis T-DNA insertion lines using degenerate primers.

The sequencing of the Arabidopsis plant genome is providing a fuller understanding of the number and types of plant genes. However, in most cases we do not know which genes are responsible for specific metabolic and signal transduction pathways. Analysis of gene function is also often confounded by the presence of multiple isoforms of the gene of interest. Recent advances in PCR-based reverse genetic techniques have allowed the search for plants carrying T-DNA insertions in any gene of interest. Here we report preliminary screening results from an ordered population of nearly 60,470 independently derived T-DNA lines. Degenerate PCR primers were used on large DNA pools (n = 2,025 T-DNA lines) to screen for more than one gene family member at a time. Methods are presented that facilitated the identification and isolation of isoform-specific mutants in almost all members of the Arabidopsis H(+)-proton ATPase gene family. Multiple mutant alleles were found for several isoforms.

Arabidopsis↗

PubMed2026

Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear. AIMS: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. MATERIALS AND METHODS: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping. RESULTS: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. DISCUSSION: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways. CONCLUSION: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

TWAS↗

PubMed1993

Using tracers to link health services to training through evaluation.

The tracer concept was applied to evaluate the delivery of family health care and the training of family health workers. A retrospective evaluation permitted linking the products of care to process, input and context, by isolating and analysing potential factors contributing to a limited number of representative concerns. Contributory learning deficiencies identified in health workers, one input to health care as well as a product of training, enabled the evaluation of training programmes to be focused on related segments of the courses. The latter were evaluated through a pathway analysis which followed the same deficiency model as the evaluation of health care. Links were thus established between the traditionally compartmentalized training and service sectors in health.

Australia↗

PubMed2006

Transcriptional regulators of stamen development in Arabidopsis identified by transcriptional profiling.

In Arabidopsis, jasmonate is required for stamen and pollen maturation. Mutants deficient in jasmonate synthesis, such as opr3, are male-sterile but become fertile when jasmonate is applied to developing flower buds. We have used ATH1 oligonucleotide arrays to follow gene expression in opr3 stamens for 22 h following jasmonate treatment. In these experiments, a total of 821 genes were specifically induced by jasmonate and 480 genes were repressed. Comparisons with data from previous studies indicate that these genes constitute a stamen-specific jasmonate transcriptome, with a large proportion (70%) of the genes expressed in the sporophytic tissue but not in the pollen. Bioinformatics tools allowed us to associate many of the induced genes with metabolic pathways that are probably upregulated during jasmonate-induced maturation. Our pathway analysis led to the identification of specific genes within larger families of homologues that apparently encode stamen-specific isozymes. Extensive additional analysis of our dataset identified 13 transcription factors that may be key regulators of the stamen maturation processes triggered by jasmonate. Two of these transcription factors, MYB21 and MYB24, are the only members of subgroup 19 of the R2R3 family of MYB proteins. A myb21 mutant obtained by reverse genetics exhibited shorter anther filaments, delayed anther dehiscence and greatly reduced male fertility. A myb24 mutant was phenotypically wild-type, but production of a myb21myb24 double mutant indicated that introduction of the myb24 mutation exacerbated all three aspects of the myb21 phenotype. Exogenous jasmonate could not restore fertility to myb21 or myb21myb24 mutant plants. Together with the data from transcriptional profiling, these results indicate that MYB21 and MYB24 are induced by jasmonate and mediate important aspects of the jasmonate response during stamen development.

Arabidopsis↗