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Results for “Potential modifier genes”

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At least 415 records · Page 23Linked to original sources
PubMed2006

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan.

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.

Adult↗
PubMed2006

Influence of interleukin-1alpha on androgen receptor expression and cytokine secretion by cultured human dermal papilla cells.

Dermal papilla cells (DPC) control the growth character of the hair follicle through their elaboration of mitogenic factors and extracellular matrix components. Further, the dermal papilla is a primary site of androgen action in the hair follicle. Interleukin-1alpha (IL-1alpha) is prominent in skin wounding and inflammatory responses although regarded as a negative hair growth regulator. We studied the effect of IL-1alpha and the potent androgen 5alpha-dihydrotestosterone (DHT) on the expression of the androgen receptor (AR) and various factors secreted by cultured human temporal scalp DPC. IL-1alpha triggered cellular changes consistent with nuclear factor-kappaB pathway activation as well as reduced AR mRNA and protein expression levels for DHT-stimulated DPC. This cytokine also increased DPC supernatant keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. IL-1alpha did not influence DPC supernatant levels of transforming growth factor-beta1, a negative hair growth regulator. The stimulatory effect of IL-1alpha on DPC VEGF, GM-CSF, KGF, and IL-8 expression was also evident at the mRNA level for these cytokines. IL-1alpha also increased mRNA transcript levels of protease-nexin-1, a secreted serine protease inhibitor expressed in the dermal papilla of anagen-stage hair follicles. Although DHT did not affect supernatant cytokine concentrations, the androgen altered mRNA transcript levels of several factors for DPC co-stimulated with IL-1alpha. In consideration of its in vitro activity profile, IL-1alpha may be an important modifier of dermal papilla activity as well as potentially influence androgen-regulated gene expression in DPC.

Amyloid beta-Protein Precursor↗
PubMed1998

Muscle regeneration by bone marrow-derived myogenic progenitors.

Growth and repair of skeletal muscle are normally mediated by the satellite cells that surround muscle fibers. In regenerating muscle, however, the number of myogenic precursors exceeds that of resident satellite cells, implying migration or recruitment of undifferentiated progenitors from other sources. Transplantation of genetically marked bone marrow into immunodeficient mice revealed that marrow-derived cells migrate into areas of induced muscle degeneration, undergo myogenic differentiation, and participate in the regeneration of the damaged fibers. Genetically modified, marrow-derived myogenic progenitors could potentially be used to target therapeutic genes to muscle tissue, providing an alternative strategy for treatment of muscular dystrophies.

Animals↗
PubMed2001

Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice.

BACKGROUND: Transforming growth factor-beta(2) (TGF-beta(2)) is a member of a family of growth factors with the potential to modify multiple processes. Mice deficient in the TGF-beta(2) gene die around birth and show a variety of defects of different organs, including the heart. METHODS AND RESULTS: We studied the hearts of TGF-beta(2)-null mouse embryos from 11.5 to 18.5 days of gestation to analyze the types of defects and determine which processes of cardiac morphogenesis are affected by the absence of TGF-beta(2). Analysis of serial sections revealed malformations of the outflow tract (typically a double-outlet right ventricle) in 87.5%. There was 1 case of common arterial trunk. Abnormal thickening of the semilunar valves was seen in 4.2%. Associated malformations of the atrioventricular (AV) canal were found in 62.5% and were composed of perimembranous inlet ventricular septal defects (37.5%), AV valve thickening (33.3%), overriding tricuspid valve (25.0%), and complete AV septal defects (4.2%). Anomalies of the aorta and its branches were seen in 33.3%. Immunohistochemical staining showed failure of myocardialization of the mesenchyme of the atrial septum and the ventricular outflow tract as well as deficient valve differentiation. Morphometry documented this to be associated with absence of the normal decrease of total endocardial cushion volume in the older stages. Apoptosis in TGF-beta(2)-knockout mice was increased, although regional distribution was normal. CONCLUSIONS: TGF-beta(2)-knockout mice exhibited characteristic cardiovascular anomalies comparable to malformations seen in the human population.

Animals↗
PubMed1998

HVJ (Sendai virus) liposome-mediated gene transfer: current status and future perspectives (review).

Haemagglutinating virus of Japan (HVJ; Sendai virus), a member of the mouse paramyxovirus family, has been combined with liposomes to produce a novel gene transfer system, namely HVJ liposomes. This vector system is defined as a , constructed with inactivated viral particles and non-viral (artificial) multi- or unilamellar liposomes containing gene expression cassettes and has several advantages in comparison with other viral or non-viral systems. Many studies have shown that this vector system can, not only produce efficient gene transfer using reporter genes, but also with resulting in vivo functional changes in several animal models of diseases. Despite these results, it is likely that the construct will need to be modified to improve gene transfer and expression efficiency and also to extend the potential disease targets. We review the present status of this hybrid vector system and also discuss possible modifications for future application to either in vivo analysis of specific gene expression or human gene therapy strategies for congenital or acquired diseases.

Forecasting↗
PubMed2005

Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.

OBJECTIVE: To determine whether frequencies of the mutations in the 21-hydroxylase (CYP21) gene and the G972R variant of the insulin receptor substrate-1 (IRS1) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95). INTERVENTION(S): Blood and DNA sampling before hormonal therapy. MAIN OUTCOME MEASURE(S): Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants. RESULT(S): Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3). CONCLUSION(S): The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

Adrenal Glands↗
PubMed2005

A role for stem cell biology in the physiological and pathological aspects of aging.

The stem cell is an essential component of a developmental phenomenon-one of the key components of a program fundamental to organogenesis and the maintenance of homeostasis throughout life. The stem cell confers plasticity to the process. Because aging is part of the developmental arc, an understanding of the stem cell is essential to understanding aging and some of the degenerative conditions that accompany it. Because stem cells may be isolated and manipulated ex vivo and then reimplanted into organs, they may serve a variety of functions. They have the capability of migrating long distances and targeting pathological conditions, of expressing therapeutic genes and responding to cues that shift their differentiation toward deficient lineages. Therefore, stem cells may be used for cell replacement, for therapeutic interventions, and potentially to modify aging.

Aging↗
PubMed2004

MSP domain proteins show enhanced expression in male germ line cells.

Nematode sperm utilize a crawling motility based on polymerization--depolymerization of a nematode-specific cytoskeletal molecule-major sperm protein (MSP). While several proteins that interact with and regulate MSP filament formation have been identified using in vitro approaches, it is likely that additional molecules participate in vivo in the regulation of MSP cytoskeletal dynamics. By comparing EST data generated from an Ascaris suum testis germinal zone cDNA library with EST data from other tissue- and stage-specific A. suum cDNA libraries and with expression profile data from Caenorhabditis elegans, 42 genes were selected with exclusive or enhanced expression in male germ line cells. In addition to 11 protein kinases and seven protein phosphatases, 10 genes encoding proteins with protein-protein interaction domains were identified. These potential cytoskeletal modifiers included five novel MSP-domain proteins (As-MDPs). All five As-mdps were highly expressed in male germ line cells, but only As-mdp-2, 3 and 5 were transcribed exclusively in the testis. The prediction that As-MDP-1, 2 and 3 were cytosolic components and that As-MDP-4 and 5 were associated with the sperm cell membrane proteins was supported by the results of immunoblotting experiments. The 23 members of the MDP family of proteins from C. elegans were predicted to be transcribed in the testis. The findings provide additional candidates to the growing list of molecules that regulate MSP cytoskeletal dynamics.

Amino Acid Sequence↗
PubMedDate not supplied

[Redox-dependent regulation of gene expression induced by nitric oxide].

Nitric oxide (NO) is a mobile, highly reactive signal molecule, and changes the expression of specific genes in effector cells. Under physiological conditions, NO reacts with molecular oxygen and with reactive oxygen species (ROS) to produce intermediates known as reactive nitrogen species (RNS). The production of NO and RNS in the cell is controlled by hormones, neurotransmitters, cytokines, and growth factors. Hence NO and its derivatives act as secondary paracrinous factors and transmit the signal from NO-producing to neighboring cells. Intracellular reception of NO and RNS is due to Src-related tyrosine protein kinases, G-protein Ras, cytochrome oxidase, and guanylate cyclase. Receptor proteins mostly contain heme, active thiol, or iron-sulfur groups, and are both on the plasma membrane and in internal cell compartments. Many of the NO receptors are the key components of cell regulatory systems controlling the transcription factors AP-1, HIF-1, NF-kappa B, and p53 and the expression of their target genes. A distinguishing feature of NO signaling is that changes in redox potential of the cell switch the NO receptor and, consequently, modify the NO effect. Depending on the ROS level, NO activates different signal transduction pathways to induce (or suppress) different gene sets. The data considered indicate that antioxidants may be used to directionally change the transcriptional response of the cell to NO.

Enzyme Activation↗
PubMed1996

In vitro inhibition of hepatitis C virus gene expression by chemically modified antisense oligodeoxynucleotides.

We have explored different domains within the hepatitis C virus (HCV) 5' noncoding region as potential targets for inhibition of HCV translation by antisense oligodeoxynucleotides (ODNs). Inhibition assays were performed with two different cell-free systems, rabbit reticulocyte lysate and wheat germ extract, and three types of chemical structures for the ODNs were evaluated: natural phosphodiesters (beta-PO), alpha-anomer phosphodiesters (alpha-PO), and phosphorothioates (PS). A total of six original ODNs, displaying sequence-specific inhibition ranging from 62 to 96%, that mapped in the pyrimidine-rich tract (nucleotides [nt] 104 to 127) and in the initiator AUG codon (nt 338 to 357) were identified. Two ODNs, which were targeted at the initiatory AUG (nt 341 to 367 and 351 to 377) and which had been previously described as active against genotype 1b and 2a sequences, were shown to exhibit inhibition of expression (> 95%) of a type 1a sequence. Control experiments with the irrelevant chloramphenicol acetyltransferase sequence as a marker and randomized ODNs demonstrated that levels of inhibition associated with the use of PS compounds (of as much as 94%) were mainly due to nonspecific effects. Both alpha- and beta-PO ODNs were found equally active, and no difference could be seen in the activity of beta-PO when it was tested in either rabbit reticulocyte lysate or wheat germ extract, suggesting that RNase H-independent mechanisms may be involved in the inhibitions observed. However, specific RNA cleavage products generated from beta-PO inhibition experiments could be identified, indicating that, with these compounds, control of translation also involves RNase H-dependent mechanisms. This study further delimits the existence of favorable target sequences for the action of ODNs within the HCV 5' noncoding region and indicates the possibility of using nuclease-resistant alpha-PO compounds in cellular studies.

Animals↗
PubMed1996

Polygenic determinants of Alzheimer's disease: modulation of the risk by alpha-1-antichymotrypsin.

The identification of apolipoprotein E (APOE) as a genetic risk factor modifying the chances of developing Alzheimer's disease (AD) has opened the possibility that other susceptibility genes exist that either independently modify the risk of developing AD or alter the risk imparted by APOE. We have identified alpha-1-antichymotrypsin (ACT) as a potential risk gene, by virtue of the interactive effect of either of its two alleles (A and T) on the risk of AD associated with the APOE epsilon 4 allele. In a large population of AD (n = 308) and control (n = 579) cohorts, we found the expected elevation in the APOE epsilon 4 allele frequency in the AD cases compared to controls, with threefold and sevenfold increases in the risk of AD for APOE epsilon 4/X and APOE epsilon 4/epsilon 4, respectively. Of the three ACT genotypes, the ACT A/T genotype did not affect the risk of AD beyond that which is conferred by the APOE epsilon 4 allele. However, the ACT A/A genotype greatly increased the risk associated with APOE epsilon 4 homozygosity. On the other hand, the ACT T/T genotype suppressed the gene dosage effect of the APOE epsilon 4 allele; the risk of AD in APOE epsilon 4/epsilon 4, ACT T/T cases was the same as that of APOE epsilon 4/X. A variety of potential mechanisms for interactions of ACT and APOE are discussed.

Adult↗
PubMed1989

Codon usage determines translation rate in Escherichia coli.

We wish to determine whether differences in translation rate are correlated with differences in codon usage or with differences in mRNA secondary structure. We therefore inserted a small DNA fragment in the lacZ gene either directly or flanked by a few frame-shifting bases, leaving the reading frame of the lacZ gene unchanged. The fragment was chosen to have "infrequent" codons in one reading frame and "common" codons in the other. The insert in these constructs does not seem to give mRNAs that are able to form extensive secondary structures. The translation time for these modified lacZ mRNAs was measured with a reproducibility better than plus or minus one second. We found that the mRNA with infrequent codons inserted has an approximately three-seconds longer translation time than the one with common codons. In another set of experiments we constructed two almost identical lacZ genes in which the lacZ mRNAs have the potential to generate stem structures with stabilities of about -75 kcal/mol. In this way we could investigate the influence of mRNA structure on translation rate. This type of modified gene was generated in two reading frames with either common or infrequent codons similar to our first experiments. We find that the yield of protein from these mRNAs is reduced, probably due to the action in vivo of an RNase. Nevertheless, the data do not indicate that there is any effect of mRNA secondary structure on translation rate. In contrast, our data persuade us that there is a difference in translation rate between infrequent codons and common codons that is of the order of sixfold.

Bacterial Proteins↗
PubMed2002

Peritoneal dialysis in the 21st century: the potential of gene therapy.

One of the greatest biotechnologic advances of the last 25 yr is genetic engineering--the ability to identify and isolate individual genes and transfer genetic elements between cells. Genetic engineering forms the basis of a unique biotechnology platform called gene therapy: an approach to treating disease through genetic manipulation. It is becoming clear that during peritoneal dialysis, the peritoneal membrane undergoes various structural and functional changes that compromise the dialyzing efficiency of the membrane and eventually lead to membrane failure. A gene therapy strategy based on genetic modification of the peritoneal membrane could improve the practice of peritoneal dialysis through the production of proteins that would be of therapeutic value in preventing membrane damage and preserving its dialyzing capacity. The peritoneal membrane can be genetically modified by either ex vivo or in vivo gene transfer strategies with a variety of potentially therapeutic genes, including those for anti-inflammatory cytokines, fibrinolytic factors, and antifibrotic molecules. These genes could be administered either on an acute basis, such as in response to peritonitis, or on an intermittent basis to maintain physiologic homeostasis and perhaps to prevent the adverse changes in the membrane that occur over time. The anticipated effect of a gene therapy strategy could be measured in maintenance of desired transport characteristics and in patients being able to remain on the therapy for longer periods of time without the negative outcomes. In summary, the use of a gene therapy strategy to enhance peritoneal dialysis is an innovative and exciting concept with the potential to provide new treatment platforms for patients with end-stage renal disease.

Fibrosis↗
PubMed1997

[Transduction of the IL-2 gene into human gastric cancer cell: an experimental study].

We evaluated the possibility of inducing a productive transfer of the IL-2 gene into human gastic cancer cells (GCC) and assessed the phenotypic and proliferative changes generated in the nude mice. The plasmid vector (BMGNeo-IL-2) carrying the human IL-2 gene was used to transduce the SGC-7901 GCC line by the lipofectin reagent. The IL-2 gene was analyzed by Southern blot and productive IL-2 release using IL-2-dependent CTLL. Cytotoxicity of LAK cells was tested by MTT colorimetry. The kinetics of in vitro growth and proliferation of parental and engineered cells were also measured. Parental and IL-2 gene transduced GCC were injected into nude mice. The tumorigenic potential of IL-2 gene-transfected GCC was evaluated by examining their in vivo growth in nude mice. The productive insertion of the IL-2 gene was achieved in SGC-7901. The amounts of IL-2 constitutively released by the engineered neoplastic cells ranged from 20 to 131 U/ml of IL-2 produced from 10(6) cells in 24 hours. Transduction of GCC with IL-2 gene did not modify the morphology and growth rate. IL-2 gene transfected cells demonstrated increased susceptibility to cell killing by LAK cells. IL-2 producing cells lost their tumorigenicity as evidenced by failure to grow in nude mice. The results demonstrate that IL-2 gene can be productively transduced into human gastric cancer cells without modifying their morphology and growth rate and this transduction leads to reduced or abrogated in vivo tumorigenic potential.

Animals↗
PubMed2001

Inhibitory effect of modified 5'-capped short RNA fragments on influenza virus RNA polymerase gene expression.

We have shown previously that the 5'-capped short phosphodiester RNA fragments, Cap decoy, (Gm 12 nt) are potent inhibitors of influenza virus RNA polymerase gene expression. Here we investigate the modified capped RNA derivative containing phosphorothioate oligonucleotides (Cap decoy) as a potential influenza virus RNA polymerase inhibitor. The modified 5'-capped short phosphorothioate RNA fragments (Gms 12-15 nt) with the 5'-capped structure (m7GpppGm) were synthesized by T7 RNA polymerase. The 5'-capped short RNA fragments (Gms 12-15 nt) were encapsulated in liposome particulates and tested for their inhibitory effects on influenza virus RNA polymerase gene expression in the clone 76 cells. The 12-15 nt long Gms RNA fragments showed highly inhibitory effects. By contrast, the inhibitory effects of the 13 nt long short RNA fragments (Gm 13 nt) were considerably less in comparison with the 5'-capped short phosphorothioate RNA fragments (Gms 12-15 nt). In particular, the various Gms RNA chain lengths showed no significant differences in the inhibition of influenza virus RNA polymerase gene expression. Furthermore, the capped RNA with a phosphorothioate backbone was resistant to nuclease activity. These phosphorothioate RNA fragments exhibited higher inhibitory activity than the 5'-capped short RNA fragments (Gm 12 nt). These decoys may prove to be useful in anti-influenza virus therapeutics.

Animals↗
PubMed2003

A plant-based allergy vaccine suppresses experimental asthma via an IFN-gamma and CD4+CD45RBlow T cell-dependent mechanism.

Allergic asthma is currently considered a chronic airway inflammatory disorder associated with the presence of activated CD4(+) Th2-type lymphocytes, eosinophils, and mast cells. Interestingly, therapeutic strategies based on immune deviation and suppression have been shown to successfully attenuate the development of the asthma phenotype. In this investigation, we have for the first time used a genetically modified (GM) plant, narrow leaf lupin (Lupinus angustifolius L.), expressing a gene for a potential allergen (sunflower seed albumin) (SSA-lupin) to examine whether a GM plant/food-based vaccine strategy can be used to suppress the development of experimental asthma. We show that oral consumption of SSA-lupin promoted the induction of an Ag-specific IgG2a Ab response. Furthermore, we demonstrate that the plant-based vaccine attenuated the induction of delayed-type hypersensitivity responses and pathological features of experimental asthma (mucus hypersecretion, eosinophilic inflammation, and enhanced bronchial reactivity (airways hyperreactivity). The suppression of experimental asthma by SSA-lupin was associated with the production of CD4(+) T cell-derived IFN-gamma and IL-10. Furthermore, we show that the specific inhibition of experimental asthma was mediated via CD4(+)CD45RB(low) regulatory T cells and IFN-gamma. Thus, our data demonstrate that a GM plant-based vaccine can promote a protective immune response and attenuate experimental asthma, suggesting that plant-based vaccines may be potentially therapeutic for the protection against allergic diseases.

2S Albumins, Plant↗
PubMed1999

Gene therapy clinical trials for HIV.

Despite advances in drug treatment for human immunodeficiency virus (HIV), new therapeutics are needed for sustained treatment of this infection. Gene therapy has great potential for HIV due to its specificity for viral targets and prolonged expression of therapeutics. In this review, the various approaches that current gene therapy clinical trials are using to treat HIV disease are described. Results reported from these trials indicate that the approaches tested appear to be safe and confer some benefit to the genetically-modified cell. However, technical improvements must be made in order for gene therapy to realize its true potential.

Adoptive Transfer↗
PubMed2003

CD200 is a novel p53-target gene involved in apoptosis-associated immune tolerance.

During apoptotic cell death, biochemical processes modify self-proteins and create potential autoantigens. To maintain self-tolerance in the face of natural cell turnover, the immune system must prevent or control responses to apoptosis-associated autoantigens or risk autoimmunity. The molecular mechanisms governing this process remain largely unknown. Here, we show that expression of the immunoregulatory protein CD200 increases as murine dendritic cells (DCs) undergo apoptosis. We define CD200 as a p53-target gene and identify both p53- and caspase-dependent pathways that control CD200 expression during apoptosis. CD200 expression on apoptotic DCs diminishes proinflammatory cytokine production in response to self-antigens in vitro and is required for UVB-mediated tolerance to haptenated self-proteins in vivo. Up-regulation of CD200 may represent a novel mechanism, whereby immune reactivity to apoptosis-associated self-antigens is suppressed under steady state conditions.

Animals↗