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At least 1,693 records · Page 94Linked to original sources
PubMed2000

Structure of the murine Pit1 phosphate transporter/retrovirus receptor gene and functional characterization of its promoter region.

The Pit1 phosphate transporter (formerly also called Glvr-1) probably plays an important role in regulated phosphate handling in bone-forming cells. In this study, we describe the structure of the mouse Pit1 gene, as well as some functional characteristics of its promoter region in murine bone cells. Screening of a genomic library led to the isolation of two overlapping lambda clones containing 7kb of 5' flanking region, as well as the 10 exons of the mouse Pit1 gene corresponding to the published cDNA. The translation start site is located within exon I and the stop codon within exon X. The overall structure of the mouse gene is very similar to that of its human homolog, except for the presence of an additional 5' untranslated exon in human. The structure of the 5' untranslated region of the mouse gene was thus further investigated using rapid amplification of cDNA ends in murine ATDC5, MC3T3-E1 and Swiss 3T3 cells. The results indicate that, compared to the published cDNA, the mouse Pit1 gene contains in fact one additional 5' exon, which we named exon IA. Reporter gene assays demonstrate the presence of a functional TATA box containing promoter upstream of exon IA. This description of the murine Pit1 gene and of its promoter region paves the way to more detailed analyses concerning the regulation of Pit1 transcription in mouse cells. Furthermore, a comparison of mouse and human promoters will hopefully allow a better understanding of general mechanisms regulating Pit1 expression in different species.

3T3 Cells↗
PubMed1998

Abnormal cortical development; towards elucidation of the LIS1 gene product function (review).

Lissencephaly is a relatively common brain malformation. Lissencephaly type 1 is characterized by the smooth appearance of the cortex and the presence of four abnormally positioned layers instead of the normal six. Lissencephaly is considered to be an abnormality in neuronal migration. The gene mutated in type 1 lissencephaly was cloned by us and designated LIS1. Recently, several genes involved in cortical development have been cloned in the mouse. In human an additional X-linked lissencephaly gene has been identified. We summarize here our current knowledge on the LIS1 gene and its function. It has been identified as a non-catalytic subunit of PAF-acetylhydrolase, a heterotrimeric enzyme which inactivates the platelet-activating factor (PAF). In addition, we have demonstrated that LIS1 interacts with tubulin, and affects the dynamics properties of microtubles. LIS1 contains seven WD repeats and may structurally resemble the beta-subunit of heterotrimeric G proteins. Interestingly, the catalytic subunit of PAF-acetylhydrolase was found to resemble the alpha subunit of heterotrimeric G proteins. We raise the possibility that LIS1 is part of an intracellular signaling pathway involved in neuronal migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Understanding gene and allele function with two-hybrid methods.

Two-hybrid schemes for detecting protein-protein interactions have deepened our understanding of biology by allowing scientists to identify individual important proteins. Recent developments will allow biologists to chart regulatory networks and to rapidly generate hypotheses for the function of genes, allelic variants, and the connections between proteins that make up these networks. Future developments will allow biologists to test inferences about the function of network elements, and allow global approaches to questions of biological function.

Alleles↗
PubMed2002

Novel genes and functional relationships in the adult mouse gastrointestinal tract identified by microarray analysis.

BACKGROUND & AIMS: A genome-level understanding of the molecular basis of segmental gene expression along the anterior-posterior (A-P) axis of the mammalian gastrointestinal (GI) tract is lacking. We hypothesized that functional patterning along the A-P axis of the GI tract could be defined at the molecular level by analyzing expression profiles of large numbers of genes. METHODS: Incyte GEM1 microarrays containing 8638 complementary DNAs (cDNAs) were used to define expression profiles in adult mouse stomach, duodenum, jejunum, ileum, cecum, proximal colon, and distal colon. Highly expressed cDNAs were classified based on segmental expression patterns and protein function. RESULTS: 571 cDNAs were expressed 2-fold higher than reference in at least 1 GI tissue. Most of these genes displayed sharp segmental expression boundaries, the majority of which were at anatomically defined locations. Boundaries were particularly striking for genes encoding proteins that function in intermediary metabolism, transport, and cell-cell communication. Genes with distinctive expression profiles were compared with mouse and human genomic sequence for promoter analysis and gene discovery. CONCLUSIONS: The anatomically defined organs of the GI tract (stomach, small intestine, colon) can be distinguished based on a genome-level analysis of gene expression profiles. However, distinctions between various regions of the small intestine and colon are much less striking. We have identified novel genes not previously known to be expressed in the adult GI tract. Identification of genes coordinately regulated along the A-P axis provides a basis for new insights and gene discovery relevant to GI development, differentiation, function, and disease.

Animals↗
PubMed1987

Escherichia coli dnaA initiation function is required for replication of plasmids derived from coliphage lambda.

The dnaA gene function, indispensable for the initiation of Escherichia coli replication from oriC is not essential for the growth of phage lambda. The in-vitro replication of plasmids derived from phage lambda does not seem to require DnaA protein either. However, we present evidence that in vivo the normal replication of lambda plasmids is dnaA-dependent. After inactivating the dnaA gene function, half of the plasmid molecules may enter a single round of replication. Rifampicin sensitivity of this abortive, as well as normal, replication indicates involvement of RNA polymerase. The rifampicin resistance of the normal replication of lambda plasmids in E. coli carrying the dnaAts46 or dnaAts5, but not the dnaAts204 allele at 30 degrees C implies the interaction of DnaA protein and RNA polymerase in this process. We propose that DnaA protein co-operates with RNA polymerase in the initiation of replication at ori lambda. The dispensability of DnaA in the growth of phage lambda and in lambda plasmid replication in vitro is discussed.

Bacterial Proteins↗
PubMed2006

Expression of a novel gene, MafB, in Dupuytren's disease.

PURPOSE: Dupuytren's disease (DD) is characterized by fibroblastic proliferation of the palmar fascia, often leading to flexion contracture in the hand. Although there is a strong genetic component the genome-wide expression of novel genes is not known. The purpose of this study was to use DNA microarray technology to identify upregulated genes in DD. METHODS: Human tissue samples were harvested from 3 patient sources: DD cord tissue (n = 20), normal-appearing adjacent control fascia (n = 15), and palmar fascia from patients having carpal tunnel release (n = 15). DNA microarray analysis was performed on amplified sample RNA. Novel genes were compared with known gene functions. A candidate gene of interest was studied further by using immunohistochemistry on DD tissue samples and controls. RESULTS: Several novel genes not described previously in the study of DD were upregulated significantly, including MafB, collagen type V, alpha-2 (COL5A2), collagen type VIII, alpha-1 (COL8A1), contactin I (CNTN1), and leucine-rich repeat containing 17 (LRRC17). These upregulated genes were compared with their known gene-expression profiles in other tissues and their purported functions. MafB was found to be of particular interest because of its prominent role in tissue development and cellular differentiation. MafB immunohistochemistry showed positive staining in 50% of the DD specimens but complete absence of MafB in all control tissues (adjacent control fascia, carpal tunnel fascia). Co-localization experiments with MafB and alpha-smooth muscle actin showed staining properties in similar regions but these 2 proteins were not confined solely to the same cells. CONCLUSIONS: Microarray analysis of DD tissue has identified significant upregulated gene expression of MafB. MafB protein also is found in Dupuytren's cords but not in control fascia. Co-localization data suggest that the association of MafB with DD is not related exclusively to myofibroblast proliferation. Because of its role in fibroblastic transformation in other models MafB and its relationship to the pathogenesis of DD deserves further study.

Actins↗
PubMed2002

[The cloning and sequencing of H-2Kk gene cDNA of 615 mice].

OBJECTIVE: The purposes of this study were to clone and sequence the major histocompatibility complex type I (MHC I) molecular antigen recognizing gene (H-2Kk) of 615 mice, and to provide the functional gene for transgenic therapy. METHODS: The 1.4 kb full-length fragment of H-2Kk gene complementary DNA (cDNA) was amplified from the total RNA of 615 mouse liver by using reverse transcription polymerase chain reaction (RT-PCR). The cDNA was inserted into PGEM3Zf(+) vector directionally, and the competent E. coli JM109 was transformed with the ligated product. The recombinant PGEM3Zf(+)-H-2Kk cDNA plasmid was obtained using restricted enzyme analysis of the transfectants. The complete sequence of 615 mouse H-2Kk cDNA was determined by using Sanger's method. RESULTS: The sequences of 615 mouse H-2Kk cDNA were 99% similar with those of H-2Kk cDNA which were reported by other researchers, and the sequences encoding antigen recognizing regions (ARS) were identical with each other. CONCLUSION: The authors cloned the MHC I molecular antigen recognizing gene (H-2Kk) of 615 mice successfully and got the functional gene of MHC I.

Animals↗
PubMed2003

Small RNA: can RNA interference be exploited for therapy?

CONTEXT: RNA interference (RNAi) is the sequence-specific gene-silencing induced by double-stranded RNA (dsRNA), and gives information about gene function quickly, easily, and inexpensively. The use of RNAi for genetic-based therapies is widely studied, especially in viral infections, cancers, and inherited genetic disorders. RNAi has been used to make tissue-specific knockdown mice for studying gene function in a whole animal. Combined with genomics data, RNAi-directed gene-silencing could allow functional determination of any gene expressed in a cell or pathway. The term RNAi came from the discovery that the injection of dsRNAs into Caenorhabditis elegans interferes with the expression of specific genes containing a complementary region to the delivered dsRNA. Although stalled for a time by the non-gene-specific interferon response elicited by dsRNA molecules longer than about 30 nucleotides in mammalian cells, Tom Tuschl's group found that transfection of synthetic 21-nucleotide small-interfering RNA (siRNA) duplexes were highly selective and sequence-specific inhibitors of endogenous genes. STARTING POINT: siRNA expression has been studied with siRNA from plasmid and viral vectors that efficiently deliver siRNAs into both dividing and non-dividing cells, stem cells, zygotes, and their differentiated progeny. A collection of RNA interference vectors that suppress 50 human de-ubiquitinating enzymes allowed Thijn Brummelkamp and colleagues to study this gene family and to identify de-ubiquitinating enzymes in cancer-relevant pathways (Nature 2003; 424: 797-801). These researchers found that the familial cylindromatosis tumour suppressor gene (CYLD), previously of unknown function, could enhance the activation of the transcription factor NF-kappaB, leading to increased resistance to apoptosis. They have now started to investigate the use of CYLD inhibitors in clinical trials. WHERE NEXT: The ability to efficiently and stably produce and deliver sufficient amounts of siRNA to the proper target tissues require refinement before this new technology can be tried clinically. Initial in-vivo studies reported effective transgene suppression in adult mice by chemically synthesised siRNAs. More recently many researchers have used plasmid and viral vectors for transcription of short-hairpin RNAs, both in vitro and in vivo. With these expression systems, gene expression was more stably inhibited than with the transient knockdown recorded with chemically synthesised siRNA. Human trials exploiting these latest findings are likely to soon follow.

Animals↗
PubMed1998

Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells.

The dramatic increase in sequence information in the form of expressed sequence tags (ESTs) and genomic sequence has created a 'gene function gap' with the identification of new genes far outpacing the rate at which their function can be identified. The ability to create mutations in embryonic stem (ES) cells on a large scale by tagged random mutagenesis provides a powerful approach for determining gene function in a mammalian system; this approach is well established in lower organisms. Here we describe a high-throughput mutagenesis method based on gene trapping that allows the automated identification of sequence tags from the mutated genes. This method traps and mutates genes regardless of their expression status in ES cells. To facilitate the study of gene function on a large scale, we are using these techniques to create a library of ES cells called Omnibank, from which sequence-tagged mutations in 2,000 genes are described.

Animals↗
PubMed1999

Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioural disorders.

Preliminary observations concerning increased chromosomal fragility in association with certain behavioural disorders in humans allow an opportunity to suggest a cohesive theory regarding the possible importance of higher-order DNA modification in the coordination of gene function in brain evolution and during development. Visible or submicroscopic acentric chromosomal fragments are formed as an accompaniment to chromosomal breakage and are associated with sequence amplification. During genomic reintegration of such extra chromosomally amplified repeat sequence elements, functional consequences could include unequal crossing over with gain-of-function, and/or deletion with loss-of-function. This process could result in regulatory changes in gene function in association with normal coding regions, since fragile sites appear to be located at or near upstream DNase-I hypersensitive areas. Earlier research on chromosomal breakage in relation to transposon behaviour in maize has set a precedent by which many elements in a network could be coordinately controlled, a principle which may allow transcriptional control over multiple areas in the genome simultaneously. The hypothesis proposed in this paper implies that a small number of fundamental higher order changes may be responsible for influencing a wide range of genetic alterations leading to complex phenotypes, sometimes segregating as distinct entities within pedigrees, or alternatively, and perhaps more commonly, presenting with several overlapping phenotypes in some other families. Current emphasis on the investigation of only pure multiplex families in psychiatric genetics may assist with identification of a number of discrete behaviour-modifying genes, but may not be sufficient for an understanding of the broad underlying genetic diathesis in these, and perhaps other 'multifactorial type' disorders. Validation of a role for altered fragile site expression and the molecular consequences thereof as proposed in this paper may offer additional avenues for gene therapy based either on preferential integration of exogenous DNA at fragile sites, or utilizing the acentric fragments formed during chromosome breakage to modify sequence amplification extrachromosomally.

Animals↗
PubMed1998

Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioral disorders.

Preliminary observations concerning increased chromosomal fragility in association with behavioural disorders in humans allow an opportunity to suggest a cohesive theory regarding the possible importance of higher-order DNA modifications in the coordination of gene function in brain evolution and during development. Visible or submicroscopic acentric chromosomal fragments are formed as an accompaniment to chromosomal breakage and are associated with sequence amplification. During genomic reintegration of extrachromosomally amplified repeat sequence elements, functional consequences could include unequal crossing over with gain-of-function, and/or deletion with loss-of-function. This process could result in regulatory changes in gene function in association with normal coding regions, since fragile sites appear to be located at or near upstream DNaseI-hypersensitive areas. Earlier research on chromosomal breakage in relation to transposon behaviour in maize has set a precedent by which many elements in a network could be coordinately controlled, a principle which may allow transcriptional control over multiple areas in the genome simultaneously. The hypothesis proposed in this paper implies that a small number of fundamental higher-order changes may be responsible for influencing a wide range of genetic alterations leading to complex phenotypes, sometimes segregating as distinct entities within pedigrees, or alternatively, and perhaps more commonly, presenting with several overlapping phenotypes in some other families. Studying only pure multiplex families in psychiatric genetics may not be sufficient for an understanding of the underlying genetic diathesis in this group of disorders. Validation of the fragile site hypothesis for complex neurobehavioural disorders may offer additional avenues for gene therapy based either on preferential integration of exogenous DNA at fragile sites, or utilizing the acentric fragments to modify sequence amplification extrachromosomally.

Chromosome Breakage↗
PubMed2000

The chicken genome contains no HMG1 retropseudogenes but a functional HMG1 gene with long introns.

We have cloned the genomic sequence coding for the high mobility group 1 (HMG1) protein in chickens. Multiple sequence alignment shows that the chicken HMG1 gene is highly homologous to the human and the mouse HMG1 genes. The gene structure of chicken HMG1 is similar to that of the mouse and the human HMG1 genes, with the same exon-intron boundaries. However, in contrast to other avian genes that have shorter introns, the chicken HMG1 gene has introns that are twice as long as their mammalian homologues. In addition to the functional, intron-containing HMG1 gene, all mammalian genomes contain more than 50 copies of HMG1 retropseudogenes each, while in the chicken genome there are no HMG1 retropseudogenes. This finding suggests that the HMG1 retropseudogenes arose in mammals after their divergence away from the birds.

Amino Acid Sequence↗
PubMed1990

Rescue of the albino phenotype by introduction of a functional tyrosinase gene into mice.

The c-locus of the mouse is thought to encode tyrosinase, the key enzyme for melanin synthesis in melanocytes of the skin and the eye. Recently, a mouse cDNA was isolated and shown to confer tyrosine activity on a cell line which expressed no specialized functions for melanin synthesis. To verify that the isolated tyrosinase gene is encoded at the genetically well characterized c-locus, a minigene was assembled from tyrosinase cDNA and tyrosinase genomic DNA and used for generation of transgenic mice. Following microinjection of this construct into fertilized eggs of an albino mouse strain, transgenic mice were obtained which showed pigmentation in skin and eyes. By in situ hybridization, we show expression of the transgene in melanocytes of the hairbulb and in the pigmented cell layers of the eye. We conclude that we have rescued the albino mutation (c/c) by introduction and expression of a functional tyrosinase gene.

Albinism↗
PubMed2002

Malignant worms: what cancer research can learn from C. elegans.

Developmental processes in the nematode C. elegans are controlled by pathways of gene functions that are analogous to those used in mammals. Hence, genetic studies in C. elegans have helped build the frameworks for these regulatory pathways. Many homologs of human genes that are targets for mutation in cancer have been found to function at distinct steps within such genetic pathways. This way, studies in C. elegans have provided important clues about the functions of human oncogenes and tumor suppressors. Understanding how human cancer genes function and act in signaling cascades is of great importance. This information reveals what kind of molecular changes contribute to the process of cell transformation. Moreover, additional candidate oncogenes and tumor suppressors may be revealed by identifying the functional partners of genes with an established role in cancer. Furthermore, identifying a cascade of gene functions increases the number of potential targets for therapeutic intervention, as blocking either one of multiple genes may interfere with signal transduction through the pathway. Simultaneous approaches in a number of different model systems act synergistically in solving pathways of gene functions. By using multiple models, the field takes advantage of the strengths of each system and circumvents its limitations. As one of the most powerful genetic animal systems, C. elegans will continue to reveal new mammalian signaling components. In addition, now that the C. elegans genome sequence has been completed, an increasing number of researchers are likely to discover homologs of human disease genes in the nematode and to analyze gene function in the worm model. Combined with the great potential of this animal in drug screens, it is simple to predict that C. elegans will worm its way deeper and deeper into cancer research.

Animals↗
PubMed1991

Cloning and functional characterization of the rat glutamine synthetase gene.

Glutamine synthetase catalyzes the formation of glutamine from glutamate and ammonia. It plays a central role in both amino acid neurotransmitter metabolism and ammonia detoxification in the central nervous system. Glutamine synthetase expression is regulated in developmental, hormonal, and in tissue- and cell-specific manners. We have cloned a full-length cDNA coding for rat glutamine synthetase, and have found an AT-rich area of conservation in the 3' untranslated regions between rat, mouse, and chicken, which may play a part in the regulation of the stability of the glutamine synthetase message. We have also cloned and mapped the gene coding for rat glutamine synthetase, and identified, by sequence analysis, areas potentially important for the regulation of glutamine synthetase transcription. Transient transfection of a variety of cell lines with deletion constructs of the glutamine synthetase promoter driving a chloramphenicol acetyltransferase reporter gene functionally demonstrates regions of the promoter containing elements important for transcriptional regulation.

Amino Acid Sequence↗
PubMed1991

An essential gene of Escherichia coli that has sequence similarity to a chloroplast gene of unknown function.

The dedB gene of Escherichia coli has sequence similarity to the zfpA gene of the chloroplast chromosome. The functions of dedB and zfpA are unknown. We constructed derivatives of temperature-sensitive polA strains into whose chromosomes a plasmid containing the disrupted dedB gene was integrated by homologous recombination. These strains contained normal and disrupted dedB genes in their chromosomes. We then selected plasmid-segregated strains and found no cells containing the disrupted dedB gene, indicating that disruption of the dedB gene was lethal in polA strains of E. coli.

Blotting, Southern↗
PubMed2001

Double-stranded RNA injection produces nonspecific defects in zebrafish.

We have investigated the ability of dsRNA to inhibit gene functions in zebrafish using sequences targeted to the maternal gene pouII-1, the transgene GFP, and an intron of the zebrafish gene terra. We found that embryos injected with all of these dsRNAs at approximately 7.5 pg/embryo or higher had general growth arrest during gastrulation and displayed various nonspecific defects at 24 h postfertilization, although embryonic development was unaffected before the midblastula stage. Reducing dsRNA concentration could alleviate the global defects. Injection of GFP dsRNA (7.5-30 pg/embryo) did not inhibit GFP expression in transgenic fish, although abnormal embryos were induced. Co-injection of GFP mRNA with either GFP or non-GFP dsRNA caused reduction of GFP expression. Whole-mount in situ hybridization clearly showed that embryos injected with dsRNA degraded co-injected and endogenous mRNA without sequence specificity, indicating that dsRNA has a nonspecific effect at the posttranscriptional level. It appears that RNAi is not a viable technique for studying gene function in zebrafish embryos.

Abnormalities, Multiple↗
PubMed2005

Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis.

BACKGROUND: A common functional polymorphism (Val/Met) in the catechol-O-methyltransferase gene (COMT) that markedly affects enzyme activity has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans. It is hypothesized that the high activity Val allele slightly increases risk for schizophrenia through its effect on dopamine-mediated prefrontal information processing. METHODS: We compared the allele/genotype frequencies of the Val/Met polymorphism in a large independent patient-control sample (862 patient and 928 healthy control subjects) from Han Chinese population, and an update meta-analysis was performed to assess the collective evidence across individual studies. RESULTS: No statistically significant differences were found in allele or genotype frequencies between patient and normal control subjects, although a nonsignificant overrepresentation of the Val allele in schizophrenia patients (odds ratio [OR] = 1.09, 95% confidence interval [CI] = .94-1.26) was suggested. Comparatively, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among the group of studies. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the Val allele in Asian population (OR = .96, 95% CI = .85-1.09), nor in European population (OR = 1.06, 95% CI = .95-1.19). CONCLUSIONS: Our data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations.

Amino Acid Substitution↗