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PubMed2000

MHC class I-subversive gene functions of cytomegalovirus and their regulation by interferons-an intricate balance.

Multiple glycoproteins of human cytomegalovirus (HCMV) encoded by the genes US2, US3, US6 and US11 interrupt the MHC class I pathway of antigen presentation at distinct checkpoints to avoid recognition of infected cells by cytotoxic CD8+ T lymphocytes. The action of cytokines like interferon (IFN)-gamma, IFN-alpha/beta and tumour necrosis factor alpha (TNF-alpha) compensate for the viral inhibition and restore antigen presentation in HCMV-infected cells. This finding was explained by their effects on cellular rather than viral genes and reflected by an increase in the production, assembly and maturation of MHC class I molecules resulting in an escape of MHC I from viral control. Here we reproduce the IFN-gamma-mediated effect when MHC I-subversive gene functions of HCMV are tested in isolation, but the efficacy of IFN-gamma to restore MHC I surface expression in US2-, US6- and US11-transfectants differs significantly. In addition, in HCMV-infected cells IFN-gamma strongly affects the synthesis of the US6-encoded glycoprotein. Despite the capability of HCMV to block the interferon signaling pathway the IFN-gamma driven enhancement of MHC class I and class II expression remains effective provided that cells are exposed to IFN-gamma before infection. Our findings illustrate a complex interplay between host immune factors and viral immune evasion functions.

Amino Acid Sequence↗

PubMedDate not supplied

[Target delivery of functional genes in gene therapy using carbohydrate containing vectors].

Various aspects of use of specific interactions with a participation of carbohydrate and oligosaccharide ligands to increase an efficiency of gene transfer into eukaryotic cells (including in vivo experiments) are considered in details. Data on addressed gene delivery with applying carbohydrate-containing ligands (such as asialoglycoproteins and galactosides) are discussed in the paper. Results on the usage of glycoside ligands, containing lactose, mannose, glucose residues, for receptor-mediated gene transfer, are analysed. Special attention is paid to application of chitosans for functional gene transfer into eukaryotic cells, which is considered by authors as a case of receptor-mediated gene transfer. It is notice that neo-oligosaccharide vectors, recognizing surface lectins, represent very perspective type of gene delivery systems.

Animals↗

PubMed1990

Escherichia coli 4.5S RNA gene function can be complemented by heterologous bacterial RNA genes.

The essential 4.5S RNA gene of Escherichia coli can be complemented by 4.5S RNA-like genes from three other eubacteria, including both gram-positive and gram-negative organisms. Two of the genes encode RNAs similar in size to the E. coli species; the third, from Bacillus subtilis, specifies an RNA more than twice as large. The heterologous genes are expressed efficiently in E. coli, and the product RNAs resemble those produced by cognate cells. We conclude that the heterologous RNAs can replace E. coli 4.5S RNA and that the essential function of 4.5S RNA is evolutionarily conserved. A consensus structure is presented for the functionally related 4.5S RNA homologs.

Base Sequence↗

PubMed2003

Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population.

We investigated the association of beta2 adrenoceptor functional gene variants (Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms), obesity phenotypes, and blood pressure levels in a large, ethnically mixed urban population. The individuals (n=1576) were randomly selected for a cross-sectional study of cardiovascular risk factors in Vitória, Brazil. Statistically significant associations among systolic blood pressure and the Arg16Gly and Thr164Ile variants were identified in univariate analysis. The Gly16/Gly16 genotype was still associated with systolic blood pressure (SBP) in multivariate analysis adjusting for age, gender, ethnicity, total cholesterol, diabetes, and body mass index (BMI) (P=0.01). The Arg16 allele was the only genotypic variable associated with BMI, and, in a dominant model, it remained associated with an increased BMI even after adjustment for age, gender, ethnicity, triglycerides, HDL cholesterol, LDL cholesterol, diabetes, and hypertension status (P=0.02). Although the different polymorphisms did not interact in the determination of SBP, a significant interaction with BMI (P=0.02), not through linkage disequilibrium, was identified between the Gln27Glu and the Thr164Ile variants. Furthermore, a significant interaction among the Arg16Gly polymorphism and BMI (P=0.036) and waist-hip ratio (P=0.003) in determining SBP was disclosed by ANOVA factorial modeling, with SBP used as the dependent variable. An interaction between the Thr164Ile polymorphism and waist-hip ratio was also identified (P=0.018). Finally, multiple logistic regression models showed a 1.48-fold increase in the risk of hypertension in individuals harboring the Gly16/Gly16 genotype and a 1.31-fold (P=0.01) and a 1.49-fold (P=0.003) increased risk of obesity in individuals harboring the Gln27/Gln27 genotype or the presence of the Arg16 allele, respectively. Taken together, these data provide evidence for a strong but complex relation between beta-adrenoceptor gene variants, hypertension, and obesity.

Adult↗

PubMed1994

Effect of restoration of retinoblastoma gene function on the radiosensitivity of cells of human tumor cell lines.

To assess the role of expression of the retinoblastoma (RB) gene on the sensitivity of cells to the cytotoxic effects of ionizing radiation, we transfected a normal RB gene into cells of RB+ and RB- osteosarcoma cell lines and an RB- prostate carcinoma line and studied the radiosensitivity of the cells before and after transfection. Four transfected clones were isolated from the two RB- tumor cell lines that expressed the product of the transfected normal RB gene and contained no mutations in the pocket and C-terminal regions by sequencing. A small increase in radiosensitivity was observed in cell lines transfected with the pDOL plasmid vector alone, containing the neo gene and a long terminal repeat (LTR) promoter. However, no significant change in radiosensitivity occurred in transfected cells expressing the normal RB gene compared to controls transfected with an RB- plasmid. Based on this and other information, we conclude that RB gene function is not involved in the response of these human tumor cells to the cytotoxic effects of radiation.

Base Sequence↗

PubMed1973

Regulation of gene function: a comparison of X-linked enzyme activity levels in normal and intersexual triploids of Drosophila melanogaster.

We have measured gene function in normal and male-like intersexual triploids of Drosophila melanogaster by assaying crude extracts of whole flies or thoraces for levels of an X-linked (6-phosphogluconate dehydrogenase) and an autosomal (NADP-dependent isocitrate dehydrogenase) enzyme activity. Our observations lead us to conclude that each dose of the X-linked gene is more active in the cells of these intersexes than it is in normal triploid or diploid female cells. These results indicate that a level of activity intermediate between the normal male and female levels is possible for X-linked genes.

Animals↗

PubMed2003

Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation.

OBJECTIVES: Description of two unrelated Italian kindreds with familial hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease mostly caused by heterozygous inactivating mutations of the Ca2+ sensing receptor (CaR). PATIENTS AND DESIGN: We studied 11 members of the two families. Genomic DNA was isolated from peripheral blood leucocytes in all family members and in 50 unrelated Italian controls. Total serum and ionized calcium, PTH, creatinine, phosphate, magnesium, and urinary calcium clearance to creatinine clearance ratio were measured. Direct sequencing of the entire coding region of the CaR was performed in the probands. Functional studies were performed in COS-7 cells transiently expressing the mutated CaR. RESULTS: In the proband of family A direct sequencing revealed a novel heterozygous Y218C missense mutation in exon 4. The same mutation was identified in the affected but not in the unaffected family members or in any of the 50 unrelated Italian controls. Transient expression of the Y218C CaR in COS-7 cells revealed a blunted Ca2+-evoked accumulation of inositol trisphosphates, indicating that the Y218C is a loss-of-function mutation. Cotransfection experiments showed that the mutant receptor had no impact on the function of the wild-type receptor, suggesting that a reduced expression of the normal CaR, rather than a dominant-negative effect, accounted for the functional impairment. In the proband of family B an already described heterozygous P55L missense mutation in exon 2 of the CaR gene was found. The same mutation was identified in the affected family members. CONCLUSIONS: We described two familial hypocalciuric hypercalcaemia kindreds with loss-of-function mutations of the Ca2+ receptor gene and identified a novel heterozygous mutation (Y218C) characterized by a blunted response to Ca2+ stimulation compared to the wild-type receptor and no interference with the function of the wild-type Ca2+ receptor.

Adult↗

PubMed1996

p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin's lymphomas: a potential marker of p53 tumor-suppressor gene function.

p21WAF1 (wild-type p53-activated fragment 1) is involved in the control of mammalian cell cycle through the binding and inhibition of cyclin-dependent kinases (Cdk). Because the product of WAF1 gene is a potent downstream effector of the p53 tumor-suppressor gene function, its pattern of cellular expression might correlate with nuclear accumulation of p53-encoded protein and/or p53 gene mutations occurring in malignant lymphomas. To investigate this issue, we analyzed immunohistochemically the expression of p53 and p21WAF1 proteins in tissue involved by non-Hodgkin's lymphomas (NHLs;253 cases) of various histologic types. In a proportion of them (80 cases), we also investigated the possible presence of p53 gene mutations using single-strand conformation polymorphism analysis and direct DNA sequencing. The absence of both p21WAF1 and p53 proteins was observed in 147 of 217 cases (67.7%) among CD30-NHL and in only 8 of 36 (22.2%) CD30+cases, which were mostly anaplastic large-cell lymphomas. A consistent number (> 10%) of p21WAF1-expressing cells was shown in 48 of 253 (18.9%) NHL cases, with a higher incidence in CD30+cases (25/36 [69.4%]), which mostly (21/36) coexpressed p53. These latter cases were characterized by a germline configuration of the p53 gene. In 50 of 253 NHL samples (19.7%), 47 of which (21.6%) belong to the CD30-group, neoplastic cells were p53+/p21-. In all of these cases, the p53+cells accounted for more than 50% of neoplastic cells, up to 100%. Point mutations of p53 gene were solely observed in all investigated cases with this latter phenotype. Our findings strongly suggest that the combined immunohistochemical evaluation of p53 and p21WAF1 is a valuable means of assessing the functional status of the p53 tumor-suppressor gene product in NHL with potential application in the monitorage and prognostication of individual cases.

Biomarkers↗

PubMed1993

Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila.

The origin of new genes includes both the initial molecular events and subsequent population dynamics. A processed Drosophila alcohol dehydrogenase (Adh) gene, previously thought to be a pseudogene, provided an opportunity to examine the two phases of the origin of a new gene. The sequence of the processed Adh messenger RNA became part of a new functional gene by capturing several upstream exons and introns of an unrelated gene. This novel chimeric gene, jingwei, differs from its parent Adh gene in both its pattern of expression and rate of molecular evolution. Natural selection participated in the origin and subsequent evolution of this gene.

Alcohol Dehydrogenase↗

PubMed1997

Muscles in the Drosophila second thoracic segment are patterned independently of autonomous homeotic gene function.

BACKGROUND: In Drosophila, segment-specific muscle pattern is thought to be determined by the autonomous function of homeotic selector genes in the mesoderm in combination with inductive cues from the developing epidermis and nervous system. Here, we have examined the roles of homeotic genes in the patterning of the somatic muscles of the thoracic segments of Drosophila. RESULTS: We determined the expression patterns of homeoproteins in the mesoderm of the thoracic segments during embryonic and adult development. We found that, unlike the mesoderm of the first and third thoracic segments which express Sex combs reduced and Antennapedia (Antp), respectively, the mesoderm of the second thoracic segment does not express any known homeotic selector gene of the Antp or bithorax complex. In animals homozygous for Antp null mutations, the muscles of the second thoracic segment were affected in the embryo, probably as an indirect consequence of its requirement in the ectoderm. Animals that specifically lacked Antp function in the mesoderm, but expressed the gene in the epidermis, developed with a normal muscle pattern in the second thoracic segment. Furthermore, specific ectopic expression of Antp and other homeotic selector genes in the mesoderm of the second thoracic segment respecified its muscle pattern, indicating that these genes are not required autonomously during muscle development in this segment. Finally, we showed that Antp continues to be expressed in the mesoderm of the homeotically transformed third thoracic segment in the 'four-winged fly', and suggest that this is a likely reason for the failure of flight muscle development in the transformed segment. CONCLUSIONS: We present a model for muscle development in the second thoracic segment whereby mesodermal properties are specified entirely by induction, in contrast to muscle development in other segments, where autonomous function for homeotic selector genes is also required.

Animals↗

PubMed1998

Molecular evolution of the Cecropin multigene family in Drosophila. functional genes vs. pseudogenes.

Approximately 4 kb of the Cecropin cluster region have been sequenced in nine lines of Drosophila melanogaster and one line of the sibling species D. simulans, D. mauritiana, and D. sechellia. This region includes three functional genes (CecA1, CecA2, and CecB), which are involved in the insect immune response, and two pseudogenes (CecPsi1 and CecPsi2). The level of silent polymorphism in the three Cec genes is rather high (0.028), and there is no excess of nonsynonymous polymorphism. There is no evidence of gene conversion in the history of these genes. The interspecific comparison has revealed that in the three species of the simulans cluster the CecA2 gene is partially deleted and has therefore lost its function and become a pseudogene; in each of the species, subsequent deletions have accumulated. Divergence estimates indicate that the CecPsi1 and CecPsi2 pseudogenes are highly diverged, both between themselves and relative to the other three Cec genes. However, both CecPsi1 and CecPsi2 have conserved transcriptional signals and splice sites, and they present an open reading frame; also, correctly spliced transcripts have been detected for both CecPsi1 and CecPsi2. The data support that these genes are either active genes with some null alleles or young pseudogenes.

Amino Acid Sequence↗

PubMed1981

Cloning of a functional gene responsible for the expression of a cell surface antigen correlated with human chronic lymphocytic leukemia.

A cell--cell hybrid of a Chinese hamster ovary (CHO) cell line and human peripheral blood lymphoblasts from a patient with B-cell chronic lymphocytic leukemia produces a surface antigen detectable by a monoclonal antibody. This surface antigen can be detected at significant levels on a fraction of chronic lymphocytic leukemia cells, but not on normal human lymphocytes from peripheral blood or bone marrow. Two different clones capable of transforming mouse cells to produce the surface antigen were isolated from a gene library of the hybrid cell by identification of small portions of the library containing functional genes, followed by detection of clones with human-specific reiterated sequences. Both clones also contain CHO-specific reiterated sequences and are therefore human--CHO recombinants. From the frequency of antigen-producing clones in the library, we estimate that they were present in the hybrid cell genome at a copy number of 100 to 1000.

Animals↗

PubMed1990

[Methods of studying genes and gene function].

In several fields, such as immunology, biochemistry, and structural biology, but particularly in molecular genetics, modern methods enable genes and their protein products to be analysed and described. The tools are now available to study any physiological process or disease at the molecular level. As a result, genetic diseases and viral infections can be better identified and understood. Basic cellular and physiological mechanisms are beginning to be elucidated, the disturbance of which is a factor involved in cancerogenesis, for instance, or the development of hypercholesterolaemia. The article is intended as a brief review of current methods of studying genes and their function. The isolation and characterisation of genes by means of recombinant DNA technology, the identification of defective genes, and the analysis of gene function, both in vitro and in vivo are presented.

Chromosome Mapping↗

PubMed1997

The evolution of Msx gene function: expression and regulation of a sea urchin Msx class homeobox gene.

Msx- class homeobox genes, characterized by a distinct and highly conserved homeodomain, have been identified in a wide variety of metazoans from vertebrates to coelenterates. Although there is evidence that they participate in inductive tissue interactions that underlie vertebrate organogenesis, including those that pattern the neural crest, there is little information about their function in simple deuterostomes. Both to learn more about the ancient function of Msx genes, and to shed light on the evolution of developmental mechanisms within the lineage that gave rise to vertebrates, we have isolated and characterized Msx genes from ascidians and echinoderms. Here we describe the sequence and expression of a sea urchin (Strongylocentrotus purpouratus) Msx gene whose homeodomain is very similar to that of vertebrate Msx2. This gene, designated SpMsx, is first expressed in blastula stage embryos, apparently in a non-localized manner. Subsequently, during the early phases of gastrulation, SpMsx transcripts are expressed intensely in the invaginating archenteron and secondary mesenchyme, and at reduced levels in the ectoderm. In the latter part of gastrulation, SpMsx transcripts are concentrated in the oral ectoderm and gut, and continue to be expressed at those sites through the remainder of embryonic development. That vertebrate Msx genes are regulated by inductive tissue interactions and growth factors suggested to us that the restriction of SpMsx gene expression to the oral ectoderm and derivatives of the vegetal plate might similarly be regulated by the series of signaling events that pattern these embryonic territories. As a first test of this hypothesis, we examined the influence of exogastrulation and cell-dissociation on SpMsx gene expression. In experimentally-induced exogastrulae, SpMsx transcripts were distributed normally in the oral ectoderm, evaginated gut, and secondary mesenchyme. However, when embryos were dissociated into their component cells, SpMsx transcripts failed to accumulate. These data show that the localization of SpMsx transcripts in gastrulae does not depend on interactions between germ layers, yet the activation and maintenance of SpMsx expression does require cell-cell or cell-matrix interactions.

Animals↗

PubMed1980

DNA methylation and gene function.

In most higher organisms, DNA is modified after synthesis by the enzymatic conversion of many cytosine residues to 5-methylcytosine. For several years, control of gene activity by DNA methylation has been recognized as a logically attractive possibility, but experimental support has proved elusive. However, there is now reason to believe, from recent studies, that DNA methylation is a key element in the hierarchy of control mechanisms that govern vertebrate gene function and differentiation.

Animals↗

PubMed2003

Use of RNA interference to investigate gene function in the human filarial nematode parasite Brugia malayi.

We describe the successful use of the reverse genetic technique RNA interference (RNAi) to investigate gene function in the human filarial nematode parasite Brugia malayi. We used fluorescently labelled double stranded RNA (dsRNA) to demonstrate that 300 bp molecules are able to enter adult females in culture while they remain excluded from microfilariae (mf). We have developed an optimised microvolume culture system to allow the exposure of parasites to high concentrations of dsRNA for extended periods. Culturing of adult female parasites in this system for 24h does not significantly reduce parasite lifespan or mf release in culture. Three B. malayi genes, beta-tubulin (Bm-tub-1), RNA polymerase II large subunit (Bm-ama-1) and B. malayi mf sheath protein 1/mf22 (Bm-shp-1) were targeted by soaking adult female B. malayi in dsRNA complementary to these transcripts in the optimised culture system. Targeting of the two housekeeping genes Bm-tub-1 and Bm-ama-1 led to a reduction in the levels of their transcripts, as assessed by reverse transcriptase coupled PCR (RT-PCR), and resulted in parasite death in culture. In contrast, targeting of the Bm-shp-1 gene was not lethal to adult females in culture. A marked reduction in mf release was observed for shp-1 RNAi parasites compared to controls and in addition 50% of mf released did not have fully elongated sheaths. This "short" phenotype correlated with the loss of the stockpiled shp-1 transcript from developing mf in treated adult female gonads. From these data we conclude that RNAi may be a useful method for assessment of drug target potential of genes identified in filarial gene discovery projects.

Alternative Splicing↗

PubMed1999

Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.

We describe a genetic mosaic system in Drosophila, in which a dominant repressor of a cell marker is placed in trans to a mutant gene of interest. Mitotic recombination events between homologous chromosomes generate homozygous mutant cells, which are exclusively labeled due to loss of the repressor. Using this system, we are able to visualize axonal projections and dendritic elaboration in large neuroblast clones and single neuron clones with a membrane-targeted GFP marker. This new method allows for the study of gene functions in neuroblast proliferation, axon guidance, and dendritic elaboration in the complex central nervous system. As an example, we show that the short stop gene is required in mushroom body neurons for the extension and guidance of their axons.

Animals↗

PubMed1986

An estrogen-responsive element derived from the 5' flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells.

In the human breast cancer cell line MCF-7, we observe estrogen induction of the stable transfected Xenopus vitellogenin A2 gene. An estrogen-responsive element (ERE) could be defined by using a vitellogenin-chloramphenicol acetyltransferase hybrid gene in transient transfection experiments. The ERE is located in the 5' flanking region and is able to confer estrogen inducibility to the thymidine kinase gene promoter. By 5' and 3' deletions we have determined a 35 bp sequence sufficient for high stimulation by estradiol. Even 18 bp give a small estrogen response. The 35 bp ERE contains the palindromic sequence 5'GGTCACAGTGACC-3' as an essential element. The fact that the ERE of a frog gene functions in human cells demonstrates that signals and factors involved in the control have been conserved during evolution.

Acetyltransferases↗