Cellular and genetic control of antibody responses. VI. Expression of Ir gene function by H-2a accessory cells, but not H-2a T or B cells in responses to TNP-(T,G)-A--L.
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Animals↗
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Technology advancement for studying gene expression and gene function: a workshop report. Sponsored by National Institute of Child Health and Human Development, National Institute of General Medical Sciences, National Center for Human Genome Research, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Animals↗
Loss of adenomatous polyposis coli gene function disrupts thymic development.
Loss of the adenomatous polyposis coli (APC) protein is a common initiating event in colon cancer. Here we show that thymocyte-specific loss of APC deregulated beta-catenin signaling and suppressed Notch-dependent transcription. These events promoted the proliferation of cells of the double-negative 3 and 4 stages and reduced rearrangements between the variable, diversity and joining regions of the gene encoding T cell receptor (TCR) beta, encouraging developmental progression of aberrant thymocytes lacking pre-TCR and alphabeta TCR. Simultaneously, the loss of APC prolonged the mitotic metaphase-to-anaphase checkpoint and impaired chromosome segregation, blocking development beyond the double-negative 4 stage. The result was extensive thymic atrophy and increased frequencies of thymocytes with chromosomal abnormalities. Thus, loss of APC in immature thymocytes has consequences distinct from those of deregulation of beta-catenin signaling and is essential for T cell differentiation.
Adenomatous Polyposis Coli Protein↗
Evidence that intergenic spacer repeats of Drosophila melanogaster rRNA genes function as X-Y pairing sites in male meiosis, and a general model for achiasmatic pairing.
In Drosophila melanogaster males, X-Y meiotic chromosome pairing is mediated by the nucleolus organizers (NOs) which are located in the X heterochromatin (Xh) and near the Y centromere. Deficiencies for Xh disrupt X-Y meiotic pairing and cause high frequencies of X-Y nondisjunction. Insertion of cloned rRNA genes on an Xh- chromosome partially restores normal X-Y pairing and disjunction. To map the sequences within an inserted, X-linked rRNA gene responsible for stimulating X-Y pairing, partial deletions were generated by P element-mediated destabilization of the insert. Complete deletions of the rRNA transcription unit did not interfere with the ability to stimulate X-Y pairing as long as most of the intergenic spacer (IGS) remained. Within groups of deletions that lacked the entire transcription unit and differed only in length of residual IGS material, pairing ability was proportional to the dose of 240-bp intergenic spacer repeats. Deletions of the complete rRNA transcription unit or the 28S sequences alone blocked nucleolus formation, as determined by binding of an antinucleolar antibody, yet did not interfere with pairing ability, suggesting that X-Y pairing may not be mechanistically related to nucleolus formation. A model for achiasmatic pairing in Drosophila males based upon the combined action of topoisomerase I and a strand transferase is proposed.
Animals↗
RNA editing in hornwort chloroplasts makes more than half the genes functional.
RNA editing in chloroplasts alters the RNA sequence by converting C-to-U or U-to-C at a specific site. During the study of the complete nucleotide sequence of the chloroplast genome from the hornwort Anthoceros formosae, RNA editing events have been systematically investigated. A total of 509 C-to-U and 433 U-to-C conversions are identified in the transcripts of 68 genes and eight ORFs. No RNA editing is seen in any of the rRNA but one tRNA suffered a C-to-U conversion at an anticodon. All nonsense codons in 52 protein-coding genes and seven ORFs are removed in the transcripts by U-to-C conversions, and five initiation and three termination codons are created by C-to-U conversions. RNA editing in intron sequence suggests that editing can precede intercistronic processing. The sequence complementary to the edited site is proposed as a distant cis-recognition element.
Amino Acid Substitution↗
Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis.
UNLABELLED: Recurrent aphthous stomatitis (RAS) is characterized by recurrent episodes of oral ulceration in an otherwise healthy individual. Some reports in the literature indicate that RAS may have immunological, psychological, genetic and microbiological bases. OBJECTIVE: The purpose of the present study was to investigate, using binary logistic regression analyses, a possible association between the functional IL-1beta +3954 (C/T), IL-6 -174 (G/C), IL-10 -1082 (G/A) and TNF-alpha -308 (G/A) genetic polymorphism and RAS in a sample of Brazilian patients, using a multivariate statistical analysis. DESIGN: Sixty-four consecutive subjects affected by minor and major forms of RAS and 64 healthy volunteers were genotyped. To investigate the association between the single nucleotide polymorphisms and risk of RAS, binary logistic regression models were fitted. The associations were expressed by odd ratios (ORs) and adjusted for age and gender, with the corresponding 95% CIs. P-values less than 0.05 were considered significant. RESULTS: A significant increase in the IL-1beta and TNF-alpha heterozygous genotypes were associated with an increased risk of RAS development (OR 2.40 and 3.07, respectively), in the multivariate model. CONCLUSION: Our findings demonstrate that polymorphisms of high IL-1beta and TNF-alpha production were associated with an increased risk of RAS development. Our findings also give additional support to a genetic basis for RAS pathogenesis.
Adolescent↗
Two polyoma virus gene functions involved in the expression of the transformed phenotype in FR 3T3 rat cells. I. Localization of a transformation maintenance function in the proximal half of the large T coding region.
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Animals↗
Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system.
The establishment of topographic projections in the developing visual system depends on the spatially and temporally controlled expression of axon guidance molecules. In the developing chick tectum, the graded expression of the repulsive guidance molecule (RGM) has been proposed to be involved in controlling the topography of the retinal ganglion cell (RGC) axon termination zones along the anteroposterior axis of the tectum. We now show that there are three mouse proteins homologous to chick RGM displaying similar proteolytic processing but exhibiting differential cell-surface targeting by glycosyl phosphatidylinositol anchor addition. Two members of this gene family (mRGMa and mRGMb) are expressed in complementary patterns in the nervous system, and mRGMa is expressed prominently in the superior colliculus at the time of anteroposterior targeting of RGC axons. The third member of the family (mRGMc) is expressed almost exclusively in skeletal muscles. Functional studies in the mouse reveal a role for mRGMa in controlling cephalic neural tube closure, thus defining an unexpected role for mRGMa in early embryonic development. In contrast, mRGMa mutant mice did not exhibit defects in anteroposterior targeting of RGC axons to their stereotypic termination zones in the superior colliculus.
Amino Acid Sequence↗
Function, gene organization and protein structures of 11beta-hydroxysteroid dehydrogenase isoforms.
Enzymatic interconversion of active and inactive glucocorticoid hormone is important, and is carried out physiologically by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isoforms, explaining their role in cellular and toxicological processes. Two forms of the enzyme, 11beta-HSD-1 and 11beta-HSD-2, belonging to the protein superfamily of short-chain dehydrogenases/reductases, have been structurally and functionally characterised. Although displaying dehydrogenase and reductase activities in vitro, the dominant in vivo function of the type-1 enzyme might be to work as a reductase, thus generating active cortisol from inactive cortisone precursors. On the other hand, for adrenal glucocorticoids the type-2 enzyme seems to be exclusively a dehydrogenase and, by inactivating glucocorticoids, confers specificity to peripheral mineralocorticoid receptors.
11-beta-Hydroxysteroid Dehydrogenases↗
The peroxisome proliferator response element (PPRE) present at positions -681/-669 in the rat liver 3-ketoacyl-CoA thiolase B gene functionally interacts differently with PPARalpha and HNF-4.
Although previous data showed that the putative thiolase B PPRE located at -681/-669 bind the PPARalpha-RXRalpha heterodimer in vitro (Kliewer et al. (1992) Nature 358, 771-774), there is no evidence about the functional role of this element. By gel mobility-shift assay, we found an interaction of this PPRE with not only PPARalpha but also with HNF-4. By transfection of cells with the putative PPRE-driven luciferase reporter vector and PPARalpha, we found no significant activation of the luciferase gene expression, in contrast to the case with reporter expression driven by the PPRE of the peroxisomal bifunctional enzyme. On the other hand, HNF-4 activated the luciferase gene expression driven by the putative thiolase PPRE. We suggest that the thiolase B gene induction by peroxisome proliferators employs either another PPRE or this one in combination with other gene regulatory element(s) to lead to the strong gene expression observed in the presence of peroxisome proliferators.
Acetyl-CoA C-Acyltransferase↗
The human multidrug resistance protein 2 gene: functional characterization of the 5'-flanking region and expression in hepatic cells.
The human multidrug resistance protein 2 (MRP2), also termed as the canalicular multispecific organic anion transporter (cMOAT), is a member of the adenosine triphosphate-binding cassette transporter superfamily. In the liver, MRP2 mediates the multispecific efflux of various types of organic anions, including glucuronate, sulfate, and glutathione conjugates, across the canalicular hepatocyte membrane to the bile. To investigate how the MRP2 gene is expressed in liver cells, the 5'-flanking region of the human MRP2 gene was isolated from a human placental genomic library. Sequence analysis of the MRP2 promoter showed a number of consensus binding sites for both ubiquitous and liver-enriched transcription factors. Transfection of human hepatic HepG2 cells with a series of 5'-deleted promoter luciferase constructs identified a putative silencer element localized in the -1,659/-491 region and a liver-specific positive regulatory element localized in the -491/-258 region. This latter region contained the liver-abundant transcription factor CCAAT-enhancer binding protein beta (C/EBPbeta). The transcriptional activity of the promoter construct containing a mutation in the C/EBPbeta binding site was significantly decreased in HepG2 cells. This study suggests that C/EBPbeta (-356 to -343) may regulate the liver expression of the MRP2 gene.
ATP Binding Cassette Transporter, Subfamily B↗
A dependent pathway of gene functions leading to chromosome segregation in Saccharomyces cerevisiae.
Methyl-benzimidazole-2-ylcarbamate (MBC) inhibits the mitotic cell cycle of Saccharomyces cerevisiae at a stage subsequent to DNA synthesis and before the completion of nuclear division (Quinlan, R. A., C. I. Pogson, and K, Gull, 1980, J Cell Sci., 46: 341-352). The step in the cell cycle that is sensitive to MBC inhibition was ordered to reciprocal shift experiments with respect to the step catalyzed by cdc gene products. Execution of the CDC7 step is required for the initiation of DNA synthesis and for completion of the MBC-sensitive step. Results obtained with mutants (cdc2, 6, 8, 9, and 21) defective in DNA replication and with an inhibitor of DNA replication (hydroxyurea) suggest that some DNA replication required for execution of the MBC-sensitive step but that the completion of replication is not. Of particular interest were mutants (cdc5, 13, 14, 15, 16, 17, and 23) that arrest cell division after DNA replication but before nuclear division since previous experiments had not been able to resolve the pathway of events in this part of the cell cycle. Execution of the CDC17 step was found to be a prerequisite for execution of the MBC-sensitive step; the CDC13, 16 and 23 steps are executed independently of the MBC-sensitive step; execution of the MBC-sensitive step is prerequisite for execution of the MBC-sensitive step; execution of the MBC-sensitive step is prerequisite for execution of the CDC14 and 23 steps. These results considerably extend the dependent pathway of events that constitute the cell cycle of S. cerevisiae.
Benzimidazoles↗
Use of transgenic mice to study myc family gene function in normal mammalian development and in cancer.
The myc family of cellular oncogenes (c-, N- and L-myc) encode for nuclear phosphoproteins that appear to regulate cellular proliferation and differentiation during normal vertebrate development. In addition, their overexpression has been correlated with malignant transformation and apoptotic cell death. The transgenic mouse technology has been utilized to study the unique and overlapping functions of the myc family in these cellular processes in the context of the developing animal. These studies suggest that Myc oncoproteins serve important roles during normal development and that their deregulated expression is causal in the development of many malignancies. Furthermore, these experiments have provided insight into the cell type specific activities of each gene and into the unique and overlapping roles of the genes during normal development.
Animals↗
[Isolation and study of bacteriophage T4B mutants according to genes functioning at an early stage of the infectious process].
In previous study irreversible inactivation of rII(ts)-infected lambda-lysogenic bacteria at 42 degrees C was revealed. The inactivationprocess depended on active protein synthesis...
Coliphages↗
Treatments for choroidal and retinal neovascularization: a focus on oligonucleotide therapy and delivery for the regulation of gene function.
Blinding eye diseases caused by neovascularization of the retinal tissue are the leading cause of blindness in Western societies. Current treatments, such as laser photocoagulation, are limited in their effectiveness at halting the progression of angiogenesis and are unable to reduce the number of vessels once they have developed. In addition, although complete blindness is often avoided, vision is often permanently impaired by the treatment itself. Several less invasive treatments are being developed and one of these is oligonucleotide gene therapy in which short stretches of nucleotides are being used as inhibitors of key, metabolic processes involved in angiogenesis. Combined with this is the development of new and improved nucleotide chemistries aimed at overcoming many of the problems associated with oligonucleotide gene therapy, such as poor longevity because of endonuclease activity. In addition, advancements in delivery systems have further enhanced the efficacy of oligonucleotide gene therapy by increasing cellular penetration and localizing delivery to specific cell types and organs.
Choroidal Neovascularization↗
Origin of eukaryotic cell nuclei by symbiosis of Archaea in Bacteria supported by the newly clarified origin of functional genes.
In the previous report, we demonstrated the origin of eukaryotic cell nuclei as the symbiosis of Archaea in Bacteria by the newly developed "Homology-Hit Analysis". In that case, we counted yeast Open Reading Frames (ORFs) showing the highest similarity to a bacterial ORF as orthologous ORFs (Orthologous ORFs were produced by speciation from a common ancestor, and have the highest similarity to each other.) by comparing whole ORFs of yeast with those of individual bacteria. However, we could not count all yeast ORFs showing the highest similarity to a bacterial ORF in functional categories of yeast. Therefore, the origin of ORFs in the functional categories of yeast could not be inferred strictly. Here, we have improved the method for detecting orthologous ORFs. In this method, we count the numbers of ORF with the highest similarity between individual yeast functional categories and individual bacteria as orthologous ORFs. By this method, it was possible to detect the correct orthologous ORFs and to infer the origins of the functional categories in eukaryotic cells. As a result, two categories, assembly of protein complexes and DNA repair were newly judged to be of Archaeal origin, while five categories, lipid (fatty-acid and isoprenoid) metabolism, protein folding and stabilization, signal transduction, organization of the plasma membrane and organization of the cytoplasm, were newly judged to be of Bacterial origin. On the other hand, the origins of two categories (meiosis and cellular import, which were determined in the previous analysis) could not be judged. It is considered that functional categories related to the nucleus have origins common to Archaea, while those related to the cytoplasm have origins common to Bacteria. From these data including the origin of plasma membrane, it was further clarified that cell nucleus originated by the symbiosis of Archaea in Bacteria.
Archaea↗
22q11 DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome.
22q11 deletion syndrome (22qDS), also known as DiGeorge or velocardiofacial syndrome (DGS/VCFS), is a relatively common genetic anomaly that results in malformations of the heart, face and limbs. In addition, patients with 22qDS are at significant risk for psychiatric disorders as well, with one in four developing schizophrenia, and one in six developing major depressive disorders. Like several other deletion syndromes associated with psychiatric or cognitive problems, it has been difficult to determine which of the specific genes in this genomic region may mediate the syndrome. For example, patients with different genomic deletions within the 22q11 region have been found that have similar phenotypes, even though their deletions do not compromise the same set of genes. In this review, we discuss the individual genes found in the region of 22q11 that is commonly deleted in 22qDS patients, and the potential roles each of these genes may play in the syndrome. Although many of these genes are interesting candidates by themselves, we hypothesize that the full spectrum of anomalies associated with 22qDS may result from the combined result of disruptions to numerous genes within the region that are involved in similar developmental or cellular processes.
Animals↗
Viruses as gene delivery vectors: application to gene function, target validation, and assay development.
A Biochemical Pharmacology Discussion Group Conference, was held at the headquarters of the New York Academy of Sciences on December 4, 2001 as part of an ongoing series designed to highlight and review areas important to modern drug development (Figure 1). Briefly introduced by Tom Kost (GlaxoSmithKline) and Michael Lotze (University of Pittsburgh), the focus was on the intersection of genomics, proteomics, and now "viromics." The latter term refers to the use of viruses and viral gene transfer to explore the complexity arising from the vast array of new targets available from the human and murine genomes. Indeed, access to large numbers of genes using viral vectors is a key tool for drug discovery and drug delivery. With 38,000 genes identified within the human genome, only 5000 are considered readily druggable. Generating tools such as these to validate targets represents a major part of the armamentarium of the postgenomic scientist. During the last 12 years alone, there have been over 26,000 publications on virus vectors. Many of them have been found useful in target validation, assay development, and evaluation in in vivo models and gene therapy. Thus, there is now an extensive knowledge base for several viral vectors, with unique attributes within each of them providing versatility, efficiency, and ease of use. The individual scientists presenting at the meeting illustrated many of the unique and useful characteristics of such vector systems including retrovirus, adenovirus, herpes virus, simbis virus, and baculovirus.
Animals↗