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Results for “Potential modifier genes”

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PubMed1998

GSTM1 and GSTT1 genes are potential risk modifiers for bladder cancer.

The role of the polymorphic glutathione S-transferase genes GSTM1 and GSTT1 in the development and in the clinicopathological outcome of bladder cancer was investigated in 37 Egyptian bladder cancer patients and 34 matched controls. Of the 37 patients studied, 26 had transitional cell carcinoma (TCC) and 11 had squamous cell carcinoma (SCC). Fourteen out of twenty-six TCC and four out of eleven SCC patients were infected with schistosoma. We observed an increased relative risk for bladder cancer associated with the GSTM1 null genotype (OR = 2.99; 95% CL = 1.01-9.00; p = 0.02). The relative risk was more pronounced in squamous cell carcinoma (SCC) (OR = 5.70; 95% CL = 0.91-36.70; p = 0.03) than in transitional cell carcinoma (TCC) (OR = 2.39; 95% CL = 0.73-7.90; p = 0.08). Our results also indicate that the GSTT1 polymorphism is individually associated with increased risk for bladder cancer (OR = 4.93; 95% CL = 1.39-18.42; p = 0.004) with no preferential increase in risk with respect to the type of the carcinoma. Individuals with the null genotype for both GSTM1 and GSTT1 were at a significantly higher risk for developing bladder cancer than individuals with both genes present (OR = 9.92; 95% CL = 1.84-46.90; p = 0.001). These individuals were more susceptible to developing SCC than TCC (OR = 14.16; 95% CL = 1.35-131.35; p = 0.01; and OR = 8.5; 95% CL = 1.38-60.10; p = 0.007, respectively). In conclusion, our results indicate that the null genotypes for GSTM1 and GSTT1, either individually or in combination, are important host risk factors for bladder cancer. In addition, the null GSTM1 genotype may also affect the clinicopathological tumor outcome. Since the deleted genotypes for GSTM1 and GSTT1 are prevalent in the general population, the identification of these individuals may provide a useful public health approach for early detection and prevention of environmental cancers.

Adult↗

PubMed2001

Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.

Abnormalities, Multiple↗

PubMed2006

ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression.

BACKGROUND: TGF-beta1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-beta signalling is mediated by the TbetaRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-beta utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TbetaRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT). METHODS: The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis. RESULTS: After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPeta and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-beta1 induced gene expression in HMEC-1 cells and primary HUVECs was observed. CONCLUSION: Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-beta signalling.

Activin Receptors, Type II↗

PubMed2005

Poly-L-lysine-modified silica nanoparticles: a potential oral gene delivery system.

Poly-L-lysine-modified silica nanoparticles (PMS-NP) is a novel nonviral vector for gene delivery, which can efficiently deliver plasmid DNA and antisense oligonucleotides into cultured cells in vitro in the presence of serum-free medium. However, little is known about whether PMS-NP is a suitable carrier for gene delivery by oral administration. To this end, oral gene delivery assays were performed, and glucose transporting tests showed that PMS-NP had no obvious toxicity to intestine of BALB/C mice. Efficient reporter gene expression was detected in stomach and intestine where expression was mainly observed in mucous membrane cells. These results indicated that PMS-NP was a low-toxicity carrier, hence demonstrating its potential for fundamental research and gene therapy, especially for oral gene therapy.

Administration, Oral↗

PubMed2001

UCP2 muscle gene transfer modifies mitochondrial membrane potential.

OBJECTIVE: The aim of this work was to evaluate the effect of uncoupling protein 2 (UCP2) muscle gene transfer on mitochondrial activity. DESIGN: Five week-old male Wistar rats received an intramuscular injection of plasmid pXU1 containing UCP2 cDNA in the right tibialis anterior muscles. Left tibialis anterior muscles were injected with vehicle as control. Ten days after DNA injection, tibialis anterior muscles were dissected and muscle mitochondria isolated and analyzed. RESULTS: There were two mitochondrial populations in the muscle after UCP2 gene transfer, one of low fluorescence and complexity and the other, showing high fluorescence and complexity. UCP2 gene transfer resulted in a 3.6 fold increase in muscle UCP2 protein levels compared to control muscles assessed by Western blotting. Furthermore, a significant reduction in mitochondria membrane potential assessed by spectrofluorometry and flow cytometry was observed. The mitochondria membrane potential reduction might account for a decrease in fluorescence of the low fluorescence mitochondrial subpopulation. CONCLUSION: It has been demonstrated that UCP2 muscle gene transfer in vivo is associated with a lower mitochondria membrane potential. Our results suggest the potential involvement of UCP2 in uncoupling respiration. International Journal of Obesity (2001) 25, 68-74

Animals↗

PubMed2006

Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?

Cystic fibrosis (CF) is the most common genetic disease among Caucasians and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organs but lung disease is the major determinant for morbidity and mortality. Many studies have focussed on the correlation between CFTR genotype and severity of disease. Since patients with identical CFTR mutations often show considerable variability in disease progression, genes other than CFTR are thought to have the potential to modify the course of lung disease in CF patients. Therefore, identification of CF-modifying genes has become the goal of several studies over the last 15 years. Pharmaceutical approaches for CF lung disease have been developed regardless of the underlying genetic defect and in general target symptoms such as airway obstruction and treatment of bacterial infection. Analysing the pathophysiological processes of modifiers may lead to the discovery of pathways involved in CF pathophysiology and possibly to the design of new therapeutics. The purpose of this review is not only to list potential CFTR modifier genes, but also to discuss new therapeutic strategies that could be derived from knowledge of these CF modifiers.

Cystic Fibrosis↗

PubMed2003

Chromium(VI) down-regulates heavy metal-induced metallothionein gene transcription by modifying transactivation potential of the key transcription factor, metal-responsive transcription factor 1.

The robust induction of metallothionein-I and II (MT-I and MT-II) genes by several heavy metals such as zinc and cadmium requires the specific transcription factor metal-responsive transcription factor 1 (MTF1). Chromium (VI), a major environmental carcinogen, not only failed to activate these genes but also inhibited their induction by Zn2+ or Cd2+. The heavy metal-induced expression of another MTF1 target gene, zinc transporter 1 (ZnT-1), was also down-regulated by Cr6+. By contrast, the expression of two MTF1-independent Cd2+-inducible genes, heme oxygenase 1 (HO-1) and HSP-70, was not sensitive to Cr6+. Cr6+ did not also affect the expression of housekeeping genes such as GAPDH or beta-actin. Stable cell lines overexpressing variable levels of MTF1, the key transactivator of the MT genes, demonstrated differential resistance toward the inhibitory effect of Cr6+, indicating MTF1 as a target of chromium toxicity. The basal and inducible binding of MTF1 to metal response elements was not affected by treatment of cells with Cr6+. Transient transfection studies showed that the ability of MTF1 to transactivate the MT-I promoter was significantly compromised by Cr6+. The fusion protein consisting of a Gal-4 DNA binding domain and one or more of the three transactivation domains of MTF1, namely the acidic domain, proline-rich domain, and serine-threonine rich domain, activated the GAL-4-driven luciferase gene to different degrees, but all were sensitive to Cr6+. MTF1 null cells were prone to apoptosis after exposure to Zn2+ or Cd2+ that was augmented in presence Cr6+, whereas the onset of apoptosis was significantly delayed in cells overexpressing MTF1.

Annexin A5↗

PubMed1997

Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription.

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.

Alzheimer Disease↗

PubMed2000

Unambiguous demonstration of triple-helix-directed gene modification.

Triple-helix-forming oligonucleotides (TFOs), which can potentially modify target genes irreversibly, represent promising tools for antiviral therapies. However, their effectiveness on endogenous genes has yet to be unambiguously demonstrated. To monitor endogenous gene modification by TFOs in a yeast model, we inactivated an auxotrophic marker gene by inserting target sequences of interest into its coding region. The genetically engineered yeast cells then were treated with psoralen-linked TFOs followed by UV irradiation, thus generating highly mutagenic covalent crosslinks at the target site whose repair could restore gene function; the number of revertants and spectrum of mutations generated were quantified. Results showed that a phosphoramidate TFO indeed reaches its target sequence, forms crosslinks, and generates mutations at the expected site via a triplex-mediated mechanism: (i) under identical conditions, no mutations were generated by the same TFO at two other loci in the target strain, nor in an isogenic control strain carrying a modified target sequence incapable of supporting triple-helix formation; (ii) for a given target sequence, whether the triplex was formed in vivo on an endogenous gene or in vitro on an exogenous plasmid, the nature of the mutations generated was identical, and consistent with the repair of a psoralen crosslink at the target site. Although the mutation efficiency was probably too low for therapeutic applications, our results confirm the validity of the triple-helix approach and provide a means of evaluating the effectiveness of new chemically modified TFOs and analogs.

Base Sequence↗

PubMed2000

DNA stability in plant tissues: implications for the possible transfer of genes from genetically modified food.

The potential for transfer of antibiotic resistance genes from genetically modified (GM) plant material to microbes through genetic recombination in the human or animal gut is a consideration that has engendered caution in the use of GM foods. This study was aimed at defining the optimal physical and chemical conditions necessary to ensure sufficient fragmentation of DNA in plant tissues to a size where it would be unlikely to be stably transferred to bacterial gut microflora. The ribulose 1,5-bisphosphate carboxylase/oxygenase small subunit (Rubisco SS) genes are of similar size (approximately 1.4 kb) to transgenes present in GM plants. DNA analysis and PCR amplification of Rubisco SS genes showed that fresh maize and maize silage contained high molecular weight DNA and intact Rubisco SS genes. Relatively high temperatures and pressurised steam were necessary to degrade fully genomic DNA and Rubisco SS genes in maize and wheat grains, the source of most animal feedstuffs. Furthermore, chemical expulsion and extrusion of oilseeds resulted in residues with completely degraded genomic DNA. These results imply that stringent conditions are needed in the processing of GM plant tissues for feedstuffs to eliminate the possibility of transmission of transgenes.

DNA Fragmentation↗

PubMed1995

Adenovirus-mediated expression of a voltage-gated potassium channel in vitro (rat cardiac myocytes) and in vivo (rat liver). A novel strategy for modifying excitability.

Excitability is governed primarily by the complement of ion channels in the cell membrane that shape the contour of the action potential. To modify excitability by gene transfer, we created a recombinant adenovirus designed to overexpress a Drosophila Shaker potassium channel (AdShK). In vitro, a variety of mammalian cell types infected with AdShK demonstrated robust expression of the exogenous channel. Spontaneous action potentials recorded from cardiac myocytes in primary culture were abbreviated compared with noninfected myocytes. Intravascular infusion of AdShK in neonatal rats induced Shaker potassium channel mRNA expression in the liver, and large potassium currents could be recorded from explanted hepatocytes. Thus, recombinant adenovirus technology has been used for in vitro and in vivo gene transfer of ion channel genes designed to modify cellular action potentials. With appropriate targeting, such a strategy may be useful in gene therapy of arrhythmias, seizure disorders, and myotonic muscle diseases.

3T3 Cells↗

PubMed1999

Xyloglucan endotransglycosylases: diversity of genes, enzymes and potential wall-modifying functions.

Plant cells are enclosed by walls that define the shapes and sizes of cells and mediate cell-to-cell contact. The dynamics of plant growth, morphogenesis and differentiation require concomitant modifications of the walls. A class of enzymes known as xyloglucan endotransglycosylases have the potential to enzymatically modify wall components, but although their biochemical activity has been defined, the physiological roles of xyloglucan endotransglycosylases remain undefined. Xyloglucan endotransglycosylases are encoded by large gene families, and in an attempt to clarify their physiological role, the diverse regulation of the genes and properties of the proteins are being determined.

Amino Acid Sequence↗

PubMed2006

Identification of atherosclerosis-modifying genes: pathogenic insights and therapeutic potential.

Atherosclerosis is a common, complex trait, with genetic variation in many genes and the environment contributing to risk for this condition, which has multiple and highly variable phenotypic manifestations. Progress has been made in the identification of atherosclerosis-modifying genes in both human studies and through the use of animal models. In the future, it may be possible to administer a genetic test for variation in a handful of the most common atherosclerosis-modifier genes, and thus predict if a patient is likely to develop atherosclerosis and ischemic heart disease. These patients could then be treated aggressively to lower their low-density lipoprotein cholesterol levels and other risk factors, including counseling to make adjustments in their lifestyle. This review will summarize the methods and results thus far in the identification of atherosclerosis-modifier genes.

Animals↗

PubMed2003

A major locus on mouse chromosome 18 controls XX sex reversal in Odd Sex (Ods) mice.

We have previously reported a dominant mouse mutant, Odd sex (Ods), in which XX Ods/+ mice on the FVB/N background show complete sex reversal, associated with expression of Sox9 in the fetal gonads. Remarkably, when crossed to the A/J strain approximately 95% of the (AXFVB) F(1) XX Ods/+ mice developed as fully fertile, phenotypic females, the remainder developing as males or hermaphrodites. Using a (AXFVB) F(2) population, we conducted a genome-wide linkage scan to identify the number and chromosomal location of potential Ods modifier genes. A single major locus termed Odsm1 was mapped to chromosome 18, tightly linked to D18Mit189 and D18Mit210. Segregation at this locus could account for the presence of sex reversal in 100% of XX Ods/+ mice which develop as males, for the absence of sex reversal in approximately 92% of XX Ods/+ mice which develop as females, and for the mixed sexual phenotype in approximately 72% of XX Ods/+ mice that develop with ambiguous genitalia. We propose that homozygosity for the FVB-derived allele strongly favors Ods sex reversal, whereas homozygosity for the A/J-derived allele inhibits it. In mice heterozygous at Odsm1, the phenotypic outcome, male, female or hermaphrodite, is determined by a complex interaction of several minor modifying loci. The close proximity of Smad2, Smad7 and Smad4 to D18Mit189/210 provides a potential mechanism through which Odsm1 might act.

Animals↗

PubMed1998

Gene-modified tumor vaccine with therapeutic potential shifts tumor-specific T cell response from a type 2 to a type 1 cytokine profile.

Vaccination with a poorly immunogenic/nonimmunogenic tumor fails to protect the host from a subsequent challenge with the same tumor. The mechanisms underlying the failure of these tumors to sensitize therapeutic T cells are not clearly understood, but the inability of host T cells to recognize tumor has been implicated. In this study, vaccination with the poorly immunogenic B16BL6-D5 (D5 H-2b) tumor fails to generate therapeutic T cells from the tumor vaccine-draining lymph nodes (TVDLN) in our adoptive immunotherapy model. However, if vaccination is performed with an allogeneic MHC class I gene (H-2 Kd)-modified tumor, the T cells obtained from the TVDLN are therapeutic after activation with anti-CD3 and IL-2. Lymph nodes (LN) draining both D5 and D5-Kd tumor vaccines contained increased numbers of cells with reduced expression of L-selectin (L-selectin(low/-)) compared with naive LN. This implies that vaccination led to sensitization of T cells even in LN draining the unmodified D5 tumor. L-selectin(low/-) cells from D5-Kd, but not D5, TVDLN were therapeutic in our animal model. No antitumor activity was seen in the high level L-selectin T cells. L-selectin(low/-) T cells exhibited tumor-specific cytokine release that was type 2 (IL-4, IL-10) following vaccination with native D5 and type 1 (IFN-gamma) following vaccination with gene-modified D5-Kd. Our data suggest that the failure of unmodified D5 to generate therapeutic T cells is not due to an inability to recognize tumor Ags, but, rather, to the induction of an immune response that is ineffective in mediating tumor regression, i.e., immune deviation.

Animals↗

PubMed1997

Discovering antisense reagents by hybridization of RNA to oligonucleotide arrays.

Antisense reagents have the potential to modify gene expression by interacting with DNA or mRNA to down-regulate transcription or translation. There have been a number of successful demonstrations of antisense activity in vivo. However, a number of problems must be solved before the method's full potential can be realized. One problem is the need for the antisense agent to form a duplex with the target molecule. We have found that most regions of mRNAs are not open to duplex formation with oligonucleotides because the bases needed for Watson-Crick base pairing are involved in intramolecular pairing. Using arrays of oligonucleotides that are complementary to extensive regions of the mRNA target, we are able to find those antisense oligonucleotides which bind optimally. There is good correspondence between the ability of an oligonucleotide to bind to its target and its activity as an antisense agent in in vivo and in vitro tests. To understand more fully the rules governing the process of duplex formation between a native RNA and complementary oligonucleotides, we have studied the interactions between tRNAphe and a complete set of complementary dodecanucleotides. Only four of the set of 65 oligonucleotides interact strongly. The four corresponding regions in the tRNA share structural features. However, other regions with similar features do not form a duplex. It is clear that ab initio prediction of patterns of interaction require much greater knowledge of the process of duplex formation than is presently available.

Animals↗

PubMed2003

Huntington's disease.

Huntington's disease (HD) research is aimed at understanding the root cause of the disorder, for the thrill of uncovering new biology, and for the serious purpose of finding effective therapeutic agents. Molecular genetics has revealed the disease trigger, an inherited unstable CAG expansion in a novel 4p16.3 gene (HD), that lengthens a polyglutamine segment in huntingtin. Now studies with HD patients and model systems that are genetic HD replicas are homing in on the trigger mechanism and the first formative steps that cast HD as a distinct clinical entity. At the same time, assays at the biochemical, cellular, and whole organism levels are starting to yield potential disease modifying genes and candidate drugs. These can be prioritized by testing in a panel of genetic and phenotypic HD mouse models to yield analytical tools for dissecting the early and late stages of the disease process and to maximize the chance of success in trials with HD patients.

Animals↗

PubMed2006

Ischemic epigenetics and the transplanted kidney.

The primary purpose of this investigation was to study oxidative demethylation of DNA following ischemia/reperfusion injury (I/RI) that putatively influences posttransplant gene expression in transplanted kidneys. Our hypothesis was that as a result of I/RI, oxidative damage, which is inherent in solid organ transplantation, may lead to aberrant demethylation of cytosine-guanine (CpG) sites within gene promoter regions of DNA. The methylated CpG sites normally contribute to the binding of proteins that render DNA inaccessible to transcription factors. Therefore, conversion of methylated cytosines to nonmethylated cytosines by oxidative damage in postischemic organs might facilitate enhanced gene expression in donor organs by exposing the demethylated CpG site in a gene promoter to DNA-binding proteins that enhance gene transcription. In this study, we investigated the demethylation of a specific CpG within the IFNgamma response element resident in the promoter region of the C3 gene in the rat kidney. In response to 24 hours of cold ischemia and a subsequent 2 hours of reperfusion in an isolated ex-vivo circuit, we observed a significant change in the ratio of methylated to unmethylated cytosines at this site. Epigenetic modifications to donor DNA have not been previously investigated, but our own data suggests that they have the potential to modify gene expression posttransplantation. Since epigenetic modification may become stable and heritable upon mitosis, such changes to the donor organ DNA may persist with enormous implications for transplant outcomes.

Animals↗