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At least 1,657 records · Page 92Linked to original sources
PubMed2006

Zebrafish genomic instability mutants and cancer susceptibility.

Somatic loss of tumor suppressor gene function comprising the second hit of Knudson's two-hit hypothesis is important in human cancer. A genetic screen was performed in zebrafish (Danio rerio) to find mutations that cause genomic instability (gin), as scored by Streisinger's mosaic-eye assay that models this second hit. The assay, based on a visible test for loss of wild-type gene function at a single locus, golden, is representative of genomewide events. Twelve ENU-induced genomic instability (gin) mutations were isolated. Most mutations showed weak dominance in heterozygotes and all showed a stronger phenotype in homozygotes. Trans-heterozygosity for 7 of these mutations showed greatly enhanced instability. A variety of spontaneous tumors were found in heterozygous adults from all gin lines, consistent with the expectation that genomic instability (mutator) mutations can accelerate carcinogenesis. The incidence of spontaneous cancer at 30-34 months was increased 9.6-fold in heterozygotes for the mutant with the strongest phenotype, gin-10. Tumors were seen in skin, colon, kidney, liver, pancreas, ovary, testis, and neuronal tissues, with multiple tumors in some fish. The study of these mutants will add to our understanding of the mechanisms of somatic loss of gene function and how those mechanisms contribute to cancer susceptibility.

Animals↗
PubMed2005

Large-scale identification of expressed sequence tags involved in rice and rice blast fungus interaction.

To better understand the molecular basis of the defense response against the rice blast fungus (Magnaporthe grisea), a large-scale expressed sequence tag (EST) sequencing approach was used to identify genes involved in the early infection stages in rice (Oryza sativa). Six cDNA libraries were constructed using infected leaf tissues harvested from 6 conditions: resistant, partially resistant, and susceptible reactions at both 6 and 24 h after inoculation. Two additional libraries were constructed using uninoculated leaves and leaves from the lesion mimic mutant spl11. A total of 68,920 ESTs were generated from 8 libraries. Clustering and assembly analyses resulted in 13,570 unique sequences from 10,934 contigs and 2,636 singletons. Gene function classification showed that 42% of the ESTs were predicted to have putative gene function. Comparison of the pathogen-challenged libraries with the uninoculated control library revealed an increase in the percentage of genes in the functional categories of defense and signal transduction mechanisms and cell cycle control, cell division, and chromosome partitioning. In addition, hierarchical clustering analysis grouped the eight libraries based on their disease reactions. A total of 7,748 new and unique ESTs were identified from our collection compared with the KOME full-length cDNA collection. Interestingly, we found that rice ESTs are more closely related to sorghum (Sorghum bicolor) ESTs than to barley (Hordeum vulgare), wheat (Triticum aestivum), and maize (Zea mays) ESTs. The large cataloged collection of rice ESTs in this study provides a solid foundation for further characterization of the rice defense response and is a useful public genomic resource for rice functional genomics studies.

Disease Susceptibility↗
PubMed2004

Exploring type I angiotensin (AT1) receptor functions through gene targeting.

The renin-angiotensin system (RAS) modulates a diverse set of physiological processes including development, blood pressure, renal function and inflammation. The principal effector molecule of this system, angiotensin II, mediates most of these actions. The classically recognized functions of the RAS are triggered via the type 1 (AT(1)) class of angiotensin receptors. Pharmacological blockade of the AT(1) receptor lowers blood pressure and slows the progression of cardiovascular and renal diseases. Gene-targeting technology provides an experimental approach for precisely dissecting the physiological functions of the RAS. Here, we review how gene-targeting experiments have elucidated AT(1) receptor functions.

Animals↗
PubMed2002

Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression.

Ikaros and Aiolos are Kruppel zinc finger proteins that play key roles in hemo-lymphoid development and homeostasis. We have previously shown that they can repress transcription through the recruitment of histone deacetylases (HDACs). Here, we provide the first functional evidence that these proteins can also repress gene function in a manner that does not require deacetylase activity. This functionality can be attributed in part to Ikaros interactions with the HDAC-independent corepressor, C-terminal binding protein (CtBP). However, mutations that block Ikaros-CtBP interactions do not abolish Ikaros's repression activity, implicating the involvement of additional corepressors. Consistent with this expectation, we show that Ikaros can interact with a CtBP-interacting protein (CtIP), which has also been linked to a deacetylase-independent strategy of repression. Despite being a CtBP interactor, CtIP's association with Ikaros does not require CtBP but instead relies upon its Rb interaction domain. Significantly, Ikaros can interact with Rb, which itself can repress gene function in a deacetylase-independent manner. A mutation in Ikaros that abrogates CtIP interactions significantly reduces repression, and a double mutation that prevents interaction with both CtIP and CtBP even further alleviates repression. Finally, we show that CtIP and CtBP can interact with the general transcription factors, TATA binding protein and transcription factor IIB, which suggests a possible mechanism for their deacetylase-independent mode of repression.

3T3 Cells↗
PubMed2000

Transcriptional regulation of the transforming growth factor-beta -inducible mouse germ line Ig alpha constant region gene by functional cooperation of Smad, CREB, and AML family members.

Smads regulate transcription of defined genes in response to transforming growth factor-beta (TGF-beta) receptor activation. This process involves functional cross-talk of Smads with transcription factors at responsive DNA elements to achieve maximal transcription activation and specificity. TGF-beta has been shown to induce transcription of the germ line (GL) Ig alpha constant region gene and to direct class switching to IgA antibodies. It has been shown that acute myeloid leukemia (AML) transcription factors cooperate with Smad3 to stimulate transcription from the GL Ig alpha constant region gene promoter. We report here that the TGF-beta-induced transcription from this promoter requires DNA binding of cAMP-response element-binding protein (CREB) to the nearby ATF/cAMP-response element site and of Smads to a nearby Smad binding sequence. At these sites, Smad3/4 cooperates with CREB to activate transcription in response to TGF-beta, and disruption of either binding sequence abolished TGF-beta-induced transcription. In addition, AML1 or AML2 also binds to the promoter and cooperates with Smad3/4, and in this way further enhances the TGF-beta-induced transcriptional activation of the GL Ig alpha promoter. Thus, whereas Smad3/4, CREB, and AML family members bind independently to the respective DNA sequences in the GL Ig alpha promoter, functional synergy of Smads with CREB and AML proteins results in maximal TGF-beta-induced transcription.

Animals↗
PubMed1999

Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart.

In view of the critical role of sarcoplasmic reticular (SR) Ca(2+) release and the Ca(2+) pump in cardiac contraction-relaxation, this study was undertaken to assess the status of SR function, protein content, and gene expression in isolated rat hearts subjected to global ischemia for 30 min followed by 60 min of reperfusion (I/R). Attenuated recovery of contractile function in the I/R hearts was associated with reduced SR Ca(2+) uptake, Ca(2+) release, and ryanodine-binding activities. mRNA levels and protein contents for SR Ca(2+) pump ATPase and Ca(2+) release channels were markedly depressed in the I/R hearts. Perfusion of hearts with superoxide dismutase plus catalase, well-known scavengers of oxyradicals, prevented the I/R-induced alterations in cardiac function and partially prevented SR Ca(2+) transport activities and mRNA abundance. In hearts perfused with xanthine plus xanthine oxidase or H(2)O(2), changes similar to those in the I/R hearts were observed. These results indicate that oxyradicals may participate in depressing the SR Ca(2+) handling and gene expression in the I/R heart. It is suggested that treatment of hearts with antioxidants may improve the recovery of cardiac function by preserving the SR function and partially protecting the SR gene expression.

Animals↗
PubMed2004

OrthoDisease: a database of human disease orthologs.

One of the greatest promises of genome sequencing projects is to further the understanding of human diseases and to develop new therapies. Model organism genomes have been sequenced in parallel to human genomes to provide effective tools for the investigation of human gene function. Many of their genes share a common ancestry and function with human genes, and this is particularly true for orthologous genes. Here we present OrthoDisease, a comprehensive database of model organism genes that are orthologous to human disease genes. OrthoDisease was constructed by applying the Inparanoid ortholog detection algorithm to disease genes derived from the Online Mendelian Inheritance in Man database (OMIM). Pairwise whole genome/proteome comparisons between Homo sapiens and six other organisms were performed to identify ortholog clusters. OMIM numbers were extracted from the OMIM Morbid Map and were converted to gene sequences using the Locuslink mim2loc and loc2acc tables. These were mapped to Inparanoid ortholog clusters using Blast. The number of ortholog clusters in OrthoDisease with each respective species is currently: M. musculus, 1,354; D. melanogaster, 724; C. elegans, 533; A. thaliana, 398; S. cerevisiae, 290; and E. coli, 153. The database is accessible online at http://orthodisease.cgb.ki.se, and can be searched with disease or protein names. The web interface presents all ortholog clusters that include a selected disease gene. A capability to download the entire dataset is also provided.

Animals↗
PubMed2002

Green fluorescent protein as a convenient and versatile marker for studies on functional genomics in Drosophila.

Gene function can be deduced from lack or gain of activity. For the manipulation of gene doses or activity in Drosophila, a set of P-based vectors was constructed containing green fluorescent protein as marker. pBLUEi, pGREENi and pYELLi were designed for large insert transformation. Mosaicism was generated in vivo with pFlipG which is also ideal for targeted gene disruption. Tissue-specific gene silencing in vivo was performed with the vector set pHIBS and pUdsGFP. pHIBS allows easy cloning and shuttling of double-headed constructs. With pUdsGFP, double stranded RNA can be produced in defined patterns and the area of interference simultaneously visualized by green fluorescence. We demonstrate nearly complete silencing of a ubiquitously expressed gene in a tissue-specific manner.

Animals↗
PubMed1986

Inhibitory effects of flavourings on mutagenesis induced by chemicals in bacteria.

The antimutagenic potential of twenty-five flavourings was tested against the activity of several kinds of chemical mutagens in Escherichia coli and Salmonella typhimurium. Anisaldehyde, ethylvanillin and vanillin showed marked antimutagenic effects on mutagenesis induced by 4-nitroquinoline 1-oxide, furylfuramide (AF-2), captan or methylglyoxal in E. coli WP2s. However, they were not effective against mutations provoked by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in S. typhimurium TA98. Despite the decrease in the number of mutants, a remarkable increase was observed in the survival of mutagen-treated WP2s cells after exposure to these flavourings. We assume that these compounds may act as bio-antimutagens by enhancing an error-free recombinational repair system, because this reactivation of survival was strictly dependent on the recA gene function but not on the lexA and uvrA gene functions.

Benzaldehydes↗
PubMed1996

Function of ets genes is conserved between vertebrates and Drosophila.

The Drosophila pointed gene encodes two ETS transcriptional activators, pointedP1 and pointedP2, sharing a common C-terminal ETS domain. In the embryonic central nervous system pointedP2 is required for midline glial cell differentiation, whereas, in the eye, pointedP2 is essential for photoreceptor cell differentiation. Both vertebrate c-ets-1 and c-ets-2 gene ETS domains are highly homologous to the one of pointed. In addition, the N-terminal region of pointedP2 and vertebrate ets products share another homologous domain, the so-called RII/pointed box which appears to mediate the ras-dependent phosphorylation/stimulation. Here, we show that the vertebrate ets genes are functionally homologous to the Drosophila pointed gene. pointedP2 efficiently binds to an optimized c-Ets-1/c-Ets-2 probe in vitro, and stimulates two distinct c-Ets-1/c-Ets-2-responsive sequences when transiently expressed in vertebrate cells. Conversely, when vertebrate ets transgenes are expressed during fly development, they are capable of rescuing the pointed mutant phenotype in both midline glia and photoreceptor development. As ectopically expressed pointedP1 can also rescue pointedP2 deficiency in photoreceptor development, it appears that the ability of ets products to phenocopy each other in vivo does not require the conserved RII/pointed box, but rather, primarily relies on the presence of the highly conserved ETS domain.

Animals↗
PubMed2002

Lipoxygenase genes and their targeted disruption.

Analysis of the human and mouse genome sequences has enabled a detailed analysis of the structure and organization of the lipoxygenase genes in the respective species. Humans appear to possess six functional genes and at least three pseudogenes while mice have seven functional genes. The arrangement of the genes is quite similar between the species with most of the human lipoxygenase genes appearing on the short arm of chromosome 17 and in mice on the syntenic portion of chromosome 11. The 5-lipoxygenase gene is unique in several respects including its distinct separate chromosomal localization and its size (4-7 x larger than other lipoxygenase genes). Three of the seven murine lipoxygenase genes have been disrupted by gene targeting. While the knockout mice appear outwardly normal, a number of important findings have been discovered using these mice and these will be covered in this review.

Animals↗
PubMed2002

Fragile X and other trinucleotide repeat diseases.

Hereditary unstable DNA is composed of strings of trinucleotide repeats, in which three nucleotides are repeated over and over (ie CAGCAGCAGCAG). These repeats are found in several sites within genes; depending on their location, the number of triplet repeats in a string can change as it is passed on to offspring. When the number of repeats increases to a critical size, it can have a variety of affects on gene function. The repeats may cause a loss in gene function (as in Fragile X) or may result in the gain of a new, abnormal protein and thus a new function (as in myotonic dystrophy and Huntington disease). Although a variety of trinucleotide repeat diseases have been reported and merit consideration, this discussion will focus primarily on Fragile X syndrome, myotonic dystrophy, and Huntington disease.

Female↗
PubMed1991

A chimeric nucleotide-binding protein, encoded by a hisP-malK hybrid gene, is functional in maltose transport in Salmonella typhimurium.

We have isolated a hybrid gene, composed of the first 455 nucleotides of hisP and nucleotides 275-1107 of malK, the genes coding for the nucleotide-binding components of the high-affinity transport systems for histidine and maltose in Salmonella typhimurium, respectively. The fusion had occurred by recombination within 11 homologous base pairs located between the two DNA fragments. In the chimeric protein peptidic motifs A and B, proposed to be part of the nucleotide-binding fold, originate from HisP and MalK, respectively. Plasmid pES42-39, harbouring the hybrid gene, was shown to complement only a malK mutation but failed to complement a hisP deletion mutation. The chimeric protein was identified by immunoblotting as a protein with an apparent molecular mass of 49kDa. Removal of the C-terminal 77 amino acid residues from the chimeric protein resulted in the loss of function in transport. In contrast, 51 amino acid residues could be removed from the C-terminus of wild-type MalK without any effect. Upon overproduction the chimeric protein, as wild-type MalK, inhibited expression of the malB regulon. However, both truncated proteins, when overproduced, did not exhibit this activity. Based on these results, a tentative model of the functional domains of MalK is presented.

ATP-Binding Cassette Transporters↗
PubMed1997

Identification and characterization of a human Vlambda5 (T1) germline gene that encodes structurally unique lambda light chains.

The human germline Vlambda repertoire consists of about 30 functional genes that have been classified into 10 families on the basis of homologies in nucleotide sequences that encode approximately the first 96 to 104 residues of lambda light chains. One family, termed Vlambda5, is of special interest because the lambda light chain products of these genes have unique structural features. We have now isolated from genomic DNA one member of this family, designated IGLV5-1, using as a molecular probe a partial Vlambda5-germline-gene fragment generated by polymerase chain reaction. IGLV5-1 contains all the requisite elements of a potentially functional gene, including a Vlambda exon with an open reading frame specifying 104 residues. A Vlambda5-related cDNA (ZW) was also cloned from a bone marrow-derived plasma-cell population obtained from a patient with light-chain-associated (AL) amyloidosis. Comparison of the predicted protein sequences encoded by the IGLV5-1-germline gene, cDNA ZW, and three other reported Vlambda5-related cDNAs with those of the deduced or expressed products of the other nine known human Vlambda-gene families revealed that Vlambda5 proteins contain distinctive primary structural features. These include the presence within the second complementarity determining region (CDR2) and the third framework region (FR3) of 11 and 34 amino acids, respectively, rather than the 7 and 32 that occur in the most commonly expressed Vlambda1-, Vlambda2- and Vlambda3-type light chains. Although certain of the Vlambda-gene families encode either an elongated CDR2 or FR3, Vlambda5 proteins are remarkable in that they have additional residues in both regions of the molecule. In this respect, these polypeptides are most similar to surrogate light-chain-associated human and mouse VpreB components that also have these unusual primary structural features. Further, the four additional CDR2 residues and the two-residue FR3 insertion have been found among lambda-type light chains of certain non-mammalian species. The evolutionarily conserved nature of human Vlambda5-related genes and, in particular, the presumably novel tertiary structural effects induced by the unique features of the lambda light chains encoded by these elements suggest that the Vlambda5-gene family has biological and functional importance.

Amino Acid Sequence↗
PubMed2006

Cloning of the black seabream (Acanthopagrus schlegeli) antiquitin gene and functional characterization of its promoter region.

Antiquitin (ALDH7) is a member of the aldehyde dehydrogenase superfamily. In plants, ALDH7 is inducible upon dehydration and is thus believed to possess an osmoregulatory role. On the other hand, however, its exact physiological function in animals remains elusive. We herein report the isolation of the black seabream (Acanthopagrus schlegeli) antiquitin gene (sbALDH7) and the functional characterization of its promoter region. The 1.6 kb 5'-flanking region of sbALDH7 exhibits an intense promoter activity (30-170 fold of the basal) in five mammalian and fish cell lines of different origins. Progressive 5'-deletion analysis suggests that the core promoter is located within the region -297/+41 whereas a cis-acting repressor of basal transcription is present in the region -878/-297. In silico analysis of this sbALDH7 promoter region does not reveal any osmotic response element. Instead, it contains potential binding sites for cell cycle related cis-elements such as CCAAT displacement protein and cell cycle-dependent element/cell cycle genes homology region.

5' Flanking Region↗
PubMed2005

Prediction of siRNA knockdown efficiency using artificial neural network models.

Selective knockdown of gene expression by short interference RNAs (siRNAs) has allowed rapid validation of gene functions and made possible a high throughput, genome scale approach to interrogate gene function. However, randomly designed siRNAs display different knockdown efficiencies of target genes. Hence, various prediction algorithms based on siRNA functionality have recently been constructed to increase the likelihood of selecting effective siRNAs, thereby reducing the experimental cost. Toward this end, we have trained three Back-propagation and Bayesian neural network models, previously not used in this context, to predict the knockdown efficiencies of 180 experimentally verified siRNAs on their corresponding target genes. Using our input coding based primarily on RNA structure thermodynamic parameters and cross-validation method, we showed that our neural network models outperformed most other methods and are comparable to the best predicting algorithm thus far published. Furthermore, our neural network models correctly classified 74% of all siRNAs into different efficiency categories; with a correlation coefficient of 0.43 and receiver operating characteristic curve score of 0.78, thus highlighting the potential utility of this method to complement other existing siRNA classification and prediction schemes.

Algorithms↗
PubMed2003

Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

Animals↗
PubMed2005

Evaluation of steroid receptor function by gene targeting in mice.

Corticosteroid hormones regulate a variety of developmental, physiological and pathological processes via their cognate receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Using modern genetic technologies, including bacterial artificial chromosome-based transgenesis and conditional gene targeting, we have generated a panel of tissue-specific and function-selective mutations of the two corticosteroid hormone receptors in the mouse. These mouse models have allowed us to gain new insights into corticosteroid hormone signaling in vivo. By investigating a hepatocyte-specific GR mutation, it has been possible to define a novel biological action of GR, namely to function as a coactivator for Stat5-mediated gene transcription in the control of body growth. The investigation of brain-specific mutations have not only allowed us to better understand hypothalamo-pituitary-adrenal (HPA) axis regulation by glucocorticoids, but also to analyse corticosteroid action in various aspects of brain function like anxiety-related or addiction-related behaviour, and learning and memory. A function-selective mutation in the GR has allowed us to dissect different pathways in the gene expression regulation by this receptor, namely to separate DNA response element-binding dependent gene activation from response element-independent gene regulation via interference with other transcription factors. These different transcriptional activities of GR play an important role in glucocorticoid-mediated immunosuppression.

Alleles↗