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Results for “Potential modifier genes”

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PubMed1994

Potential applications of apoptosis in modifying the biological behavior of therapeutically refractory cancers.

Recent information about apoptosis or programmed cell death, the anti-apoptotic gene, BCL2, its interaction with reactive oxygen species and the role of these agents in senescence and apoptosis, suggests a discussion of their relationships could be of interest. Such information may eventually provide alternative approaches to modifying the biological behavior of therapeutically resistant cancers. Some of these comments probably are self-evident, others may be less so and provide ideas for further studies.

Apoptosis↗
PubMed2004

Gene therapy approaches to prolonging corneal allograft survival.

Irreversible immunological rejection is the major cause of human corneal allograft failure and occurs despite the use of topical glucocorticoid immunosuppression. Systemic pharmacological interventions have not found widespread favour in corneal transplantation because of associated morbidities and inadequate demonstration of efficacy. Gene therapy offers tantalising prospects for improving corneal allograft survival, especially in those recipients at high risk of graft rejection. Donor corneas can be gene-modified ex vivo, while in storage prior to implantation, and the relative isolation of the transplanted cornea from the circulation decreases the risk of potential systemic complications. A wide variety of vectors have been found suitable for gene transfer to the cornea. The mechanisms involved in corneal graft rejection have been placed on a relatively secure footing over the past decade and in consequence a number of transgenes with promise for modulating rejection have been identified. However, relatively few studies have thus far demonstrated significant prolongation of corneal allograft survival after gene transfer to the donor cornea. In these instances, the therapeutic protein almost certainly acted at a proximal level in the afferent immune response, within the ocular environs.

Animals↗
PubMed2006

Inhibitors of histone deacetylases and DNA methyltransferases alter imprinted gene regulation in embryonic stem cells.

Pluripotent embryonic stem cells are able to differentiate into a variety of cell types, thereby making them a valuable source for transplantation medicine. Recent studies have reported the use of pharmacological agents, namely 5-Aza-Cytidine (5AzaC) and Trichostatin A (TSA), to guide embryonic stem (ES) cells to differentiate into specific cellular lineages. However, those drugs are known to be potent inhibitors of DNA methyltransferases and/or histone deacetylases. Since both epigenetic mechanisms are involved in the expression of imprinted genes in fetal and adult somatic tissues, it is essential to investigate further the role of these agents in regulating imprinted gene expression in embryonic cells. Embryonic stem cells were exposed to 5AzaC and TSA and analyzed for transcript abundance of a number of imprinted and non-imprinted marker genes. Most imprinted gene transcripts increased following exposure to 5AzaC or TSA alone and responded in either an additive or synergistic manner when exposed to both drugs together. Interestingly, transcript levels of several imprinted genes remained high and in some cases, increased further after drug removal or even after passaging the cells, indicating a long lasting and retarded effect on gene expression. Together, our results suggest that DNA methylation and histone acetylation play jointly an important epigenetic role in governing imprinted gene expression in embryonic stem cells. Moreover, these results describe the sensitivity and irreversibility of embryonic stem cells to epigenetic modifiers, highlighting potential risks for their use in therapeutic applications.

Animals↗
PubMed1994

Inheritance of chromatin states.

The packaging of regulatory DNA within the eukaryotic chromosome has considerable potential not only for modulating the transcriptional activity of genes, but also for propagating states that are permissive or restrictive for transcription. Sequence-specific transcription factors, histones and their modifications, chromodomain proteins and enzymes that modify histones, DNA methylation and proteins that recognize methylated DNA could all play independent or interrelated roles in regulating gene activity. They all also have the potential of propagating their interactions with nascent DNA following replication. However, observations on the phenomenon of X chromosome inactivation suggest that the formation and stability of specific histone-DNA interactions through replication may be central to the inheritance of chromatin states, and that other molecular mechanisms have supporting roles. The future offers the exciting prospect of reconstructing the propagation of stable active or repressed chromatin states in vitro, and consequently understanding the events occurring at the replication fork in molecular detail.

Animals↗
PubMed2002

Recent progress in gene therapy for cardiovascular disease.

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases, such as peripheral arterial disease, ischemic heart disease, restenosis after angioplasty, vascular bypass graft occlusion and transplant coronary vasculopathy, for which no known effective therapy exists. The first human trial in cardiovascular disease started in 1994 treating peripheral vascular disease with vascular endothelial growth factor (VEGF) and since then, many different potent angiogenic growth factors have been tested in clinical trials for the treatment of peripheral arterial disease. In addition, therapeutic angiogenesis using the VEGF gene has been used to treat ischemic heart disease since 1997. The results from these clinical trials have exceeded expectations; improvement in the clinical symptoms of peripheral arterial disease and ischemic heart disease has been reported. Another strategy for combating the disease processes, targeting the transcriptional process, has been tested in a human trial. IN particular, transfection of cis-element double-stranded (ds) oligodeoxynucleotides (ODN) (= decoy) is a powerful tool in a new class of anti-gene strategies. Transfection of ds-ODN corresponding to the cis sequence will attenuate the authentic cis-trans interaction, leading to removal of trans-factors from the endogenous cis-elements and subsequent modulation of gene expression. Genetically modified vein grafts transfected with a decoy against E2F, an essential transcription factor in cell cycle progression, appear to have long-term potency in human patients. There is great potential in gene therapy for cardiovascular disease.

Angioplasty, Balloon, Coronary↗
PubMed2002

Role of USF1 phosphorylation on cardiac alpha-myosin heavy chain promoter activity.

Contractile activity of the cardiac myocyte is required for maintaining cell mass and phenotype, including expression of the cardiac-specific alpha-myosin heavy chain (alpha-MHC) gene. An E-box hemodynamic response element (HME) located at position -47 within the alpha-MHC promoter is both necessary and sufficient to confer contractile responsiveness to the gene and has been shown to bind upstream stimulatory factor-1 (USF1). When studied in spontaneously contracting cardiac myocytes, there is enhanced binding of USF1 to the HME compared with quiescent cells, which correlates with a threefold increase in alpha-MHC promoter activity. A molecular mechanism by which contractile function modulates alpha-MHC transcriptional activity may involve signaling via phosphorylation of USF1. The present studies showed that purified rat USF1 was phosphorylated in vitro by protein kinase C (PKC) and cAMP-dependent protein kinase (PKA) but not casein kinase II. Phosphorylated USF1 by either PKC or PKA had increased DNA binding activity to the HME. PKC-mediated phosphorylation also leads to the formation of USF1 multimers as assessed by gel shift assay. Analysis of in vivo phosphorylated nuclear proteins from cultured ventricular myocytes showed that USF1 was phosphorylated, and resolution by two-dimensional gel electrophoresis identified at least two distinct phosphorylated USF1 molecules. These results suggest that endogenous kinases can covalently modify USF1 and provide a potential molecular mechanism by which the contractile stimulus mediates changes in myocyte gene transcription.

Animals↗
PubMed1980

Vitellogenin as a multigene family. Not all Xenopus vitellogenin genes may be in an "expressible" configuration.

DNA-cDNA titrations suggest that the Xenopus genome comprises two albumin genes, whereas there are 12 to 16 vitellogenin-like genes. Both sets of genes are expressed in liver, those coding for albumin constitutively, but vitellogenin only when induced by estrogen in both male and female frogs. Mild micrococcal nuclease digestion of liver nuclei to separate "expressed" from "unexpressed" gene fractions (Tata, J. R., and Baker, B. S. (1978) J. Mol. Biol. 118, 249-272) revealed that the multiple vitellogenin genes are found in two chromosomal states, here termed as "expressible" and "nonexpressible." Both albumin genes were in the chromosomal state associated with expression, but of the 12 to 16 vitellogenin genes, only 4 to 6 are in the potentially expressible state. This distribution pattern is independent of sex and only slightly modified during induction or de-induction of vitellogenesis by estrogenic stimulation or withdrawal.

Animals↗
PubMed1997

Microcapsules as bio-organs for somatic gene therapy.

Current human gene therapy relies on genetic modification of the patient's own cells. An alternate non-autologous approach is to use universal cell lines engineered to secrete therapeutic products. Protection with immuno-isolation devices would allow the same recombinant cell line to be used for different patients, thus potentially lowering the cost of treatment. The feasibility of this idea has now been demonstrated in vitro and in vivo. Recombinant gene products with potential therapeutic applications (human growth hormone, factor IX, lysosomal enzymes, adenosine deaminase) have been expressed from genetically modified cells after encapsulation with alginate-poly-L-lysine-alginate or hydroxyethyl methacrylate-methyl methacrylate. We have also demonstrated the feasibility of this idea in vivo. After intraperitoneal implantation, genetically modified mouse Ltk- fibroblasts or C2C12 myoblasts encapsulated in alginate-poly-L-lysine-alginate could deliver recombinant gene products (human growth hormone, human factor IX) to the systemic circulation of mice. The clinical efficacy of this novel approach to gene therapy has now been shown in murine models of human diseases. In the Snell dwarf mice deficient in growth hormone production, implantation of encapsulated mouse myoblasts engineered to secrete mouse growth hormone resulted in increases in body weight, length and organ sizes, some to > 25% above those of the controls. In the Gus/Gus mice suffering from the lysosomal storage disease mucopolysaccharidosis type VII due to deficient beta-glucuronidase, implantation of encapsulated mouse fibroblasts engineered to secrete mouse beta-glucuronidase resulted in delivery of normal levels of the enzyme in the plasma and significant correction of the organ histopathology. Hence, delivery of recombinant gene products through bioartificial devices appears to be a promising strategy for the treatment of genetic diseases.

Alginates↗
PubMed2004

In vivo activity of nuclease-resistant siRNAs.

Chemical modifications have been incorporated into short interfering RNAs (siRNAs) without reducing their ability to inhibit gene expression in mammalian cells grown in vitro. In this study, we begin to assess the potential utility of 2'-modified siRNAs in mammals. We demonstrate that siRNA modified with 2'-fluoro (2'-F) pyrimidines are functional in cell culture and have a greatly increased stability and a prolonged half-life in human plasma as compared to 2'-OH containing siRNAs. Moreover, we show that the 2'-F containing siRNAs are functional in mice and can inhibit the expression of a target gene in vivo. However, even though the modified siRNAs have greatly increased resistance to nuclease degradation in plasma, this increase in stability did not translate into enhanced or prolonged inhibitory activity of target gene reduction in mice following tail vein injection. Thus, this study shows that 2'-F modified siRNAs are functional in vivo, but that they are not necessarily more potent than unmodified siRNAs in animals.

Animals↗
PubMed1995

APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.

Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.

Adult↗
PubMed1993

Control of gene expression by redox potential and the requirement for chloroplast and mitochondrial genomes.

Recent experiments with bacteria have shown that light and oxygen can control gene expression through effects on oxidation-reduction potential. The term "redox sensor" is proposed as a general term for electron carriers that initiate control of gene expression upon oxidation or reduction. The term "redox response regulator" is proposed for DNA-binding proteins that modify gene expression as a result of the action of redox sensors. Redox sensors and redox response regulators may function together in feedback control of redox potential in photosynthesis and respiration, protecting the cell from damage caused by electrochemistry operating on inappropriate electron donors and acceptors. Chloroplast and mitochondrial redox sensors and redox response regulators, themselves encoded in the nucleus, may place expression of chloroplast and mitochondrial genes under redox regulatory control. This hypothesis offers an explanation for the persistence, in evolution, of chloroplast and mitochondrial genomes, and for the constancy of the subset of chloroplast and mitochondrial proteins encoded and synthesized within the organelle.

Animals↗
PubMed2005

Pharmacogenetic approaches in the treatment of asthma.

A patient's response to asthma therapy is determined by both genetic and environmental factors. In the past 10 years, we have witnessed significant progress in the field of asthma pharmacogenetics--the study of how a patient's genetic background determines the efficacy and potential for adverse effects to current asthma medication. There are now clear examples of gene polymorphisms that can influence responses to beta(2)-agonists, glucocorticosteroids, and leukotriene modifier drugs, the three main classes of medication used clinically to treat asthma. Identification of genetic polymorphism that predicts drug responses has the potential to lead to the development of new therapeutics, improve asthma management, and reduce serious episodes and hospitalizations. In this review, we discuss the current understanding of asthma pharmacogenetics, focusing on the main three classes of drugs currently used clinically.

Adrenergic beta-2 Receptor Agonists↗
PubMed1990

Cooperative stimulation of specific gene transcription by epidermal growth factor and transforming growth factor type beta 1.

Transforming growth factor type beta 1 (TGF-beta 1) is a pleiotropic regulator of cell growth and differentiation which can potentiate or otherwise modify cellular responses to different growth factors such as epidermal growth factor (EGF). Since cellular responses to peptide growth factors are mediated, in part, through the regulation of specific gene expression, we have studied the effect of TGF-beta 1 on the EGF-dependent transcriptional of a diverse panel of genes which included the fibronectin gene, the cytoskeletal beta- and gamma-actin genes, and the c-fos protooncogene. The addition of a combination of TGF-beta 1 (10 ng/ml) and EGF (10 ng/ml) to quiescent AKR-2B cells maintained in serum-free medium resulted in a strong synergistic stimulation of transcription which was not evident using either growth factor individually at concentrations of 20-100 ng/ml. This effect was evident within 10 min and did not require the continual presence of TGF-beta 1 in the culture medium. Increased responsiveness of some gene promoters to EGF stimulation was evident for up to 6 h following a brief 10-min exposure to TGF-beta 1. Similar exposure to either platelet-derived growth factor or fibroblast growth factor had little or no effect on EGF-stimulated transcription. These results indicate that the transcriptional response of specific genes to EGF can be stably altered as a consequence of exposure to TGF-beta 1.

Actins↗
PubMed2005

LINE-1 retrotransposons: modulators of quantity and quality of mammalian gene expression?

LINE-1 (L1) retrotransposons are replicating repetitive elements that, by mass, are the most-abundant sequences in the human genome. Over one-third of mammalian genomes are the result, directly or indirectly, of L1 retrotransposition. L1 encodes two proteins: ORF1, an RNA-binding protein, and ORF2, an endonuclease/reverse transcriptase. Both proteins are required for L1 mobilization. Apart from the obvious function of self-replication, it is not clear what other roles, if any, L1 plays within its host. The sheer magnitude of L1 sequences in our genome has fueled speculation that over evolutionary time L1 insertions may structurally modify endogenous genes and regulate gene expression. Here we provide a review of L1 replication and its potential functional consequences.

Alleles↗
PubMed2005

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive genetic disease caused by the defects in the phenylalanine hydroxylase (PAH) gene. Individuals homozygous for defective PAH alleles show elevated levels of systemic phenylalanine and should be under strict dietary control to reduce the risk of neuronal damage associated with high levels of plasma phenylalanine. Researchers predict that plant phenylalanine ammonia-lyase (PAL), which converts phenylalanine to nontoxic t-cinnamic acid, will be an effective therapeutic enzyme for the treatment of PKU. The problems of this potential enzyme therapy have been the low stability in the circulation and the antigenicity of the plant enzyme. Recombinant PAL originated from parsley (Petroselinum crispum) chemically conjugated with activated PEG2 [2,4-bis(O-methoxypolyethyleneglycol)-6-chloro-s-triazine] showed greatly enhanced stability in the circulation and was effective in reducing the plasma concentration of phenylalanine in the circulation of mice. PEG-PAL conjugate will be an effective therapeutic enzyme for the treatment of PKU.

Animals↗
PubMed1995

The effects of 5-azacytidine and 5-azadeoxycytidine on chromosome structure and function: implications for methylation-associated cellular processes.

5-Azacytidine (5-aza-C) analogs demonstrate a remarkable ability to induce heritable changes in gene and phenotypic expression. These cellular processes are associated with the demethylation of specific DNA sequences. On the other hand, 5-aza-C analogs have dramatic effects on chromosomes, leading to decondensation of chromatin structure, chromosomal instability and an advance in replication timing. Condensation inhibition of genetically inactive chromatin occurs when the DNA is still hemimethylated or fully methylated. In cell cultures prolonged for several replication cycles, chromosomal rearrangements and instability affect the 5-aza-C-sensitive regions. Moreover, the normally late-replicating inactive chromatin undergoes a transient temporal shift to an earlier DNA replication, characteristic of activatable chromatin. zThe induced alterations of chromosome structure and behavior may trigger the 5-aza-C-dependent process of cellular reprogramming. Apart from their differentiating and gene-modifying effects, 5-aza-C analogs can tumorigenically transform cells and modulate their metastatic potential. High doses of 5-aza-C analogs have cytotoxic and antineoplastic activities.

Animals↗
PubMed2001

Anti-JL1 antibody-conjugated poly (L-lysine) for targeted gene delivery to leukemia T cells.

We have designed the gene delivery carrier targeted to Molt 4 cells, human leukemia T cells, using monoclonal antibody against leukemia-specific JL1 antigen, anti-JL1 antibody, as a targeting moiety. Anti-JL1 antibody has been proven to bind to JL1 antigen and subsequently be internalized into Molt 4 cells, demonstrating that anti-JL1 antibody has the potential as a targeting ligand for leukemia-specific gene transfer. Anti-JL1 antibody was modified with the heterobifunctional crosslinker, PDPH, at carbohydrate sites and conjugated to thiolated poly-L-lysine (PLL) via disulfide bridges. The composition and antigen binding affinity of antibody-PLL conjugates were analyzed by the amino acid analysis and the flow cytometry, respectively. Antibody-PLL conjugates neutralized pSV-beta-galactosidase plasmid DNA at 5:1 weight ratio and condensed into about 200--300-nm complexes. DNA/antibody-PLL complexes were effectively internalized into Molt 4 cells after 4 h incubation at 37 degrees C and showed significantly higher in vitro transfection efficiency than DNA/PLL complexes and DNA/Lipofectin formulation due to the targeting effect of receptor-mediated endocytosis induced by anti-JL1 antibody.

Amino Acids↗
PubMed2002

Systemically delivered antisense oligomers upregulate gene expression in mouse tissues.

Systemically injected 2'-O-methoxyethyl (2'-O-MOE)-phosphorothioate and PNA-4K oligomers (peptide nucleic acid with four lysines linked at the C terminus) exhibited sequence-specific antisense activity in a number of mouse organs. Morpholino oligomers were less effective, whereas PNA oligomers with only one lysine (PNA-1K) were completely inactive. The latter result indicates that the four-lysine tail is essential for the antisense activity of PNA oligomers in vivo. These results were obtained in a transgenic mouse model designed as a positive readout test for activity, delivery, and distribution of antisense oligomers. In this model, the expressed gene (EGFP-654) encoding enhanced green fluorescence protein (EGFP) is interrupted by an aberrantly spliced mutated intron of the human beta-globin gene. Aberrant splicing of this intron prevented expression of EGFP-654 in all tissues, whereas in tissues and organs that took up a splice site-targeted antisense oligomer, correct splicing was restored and EGFP-654 expression upregulated. The sequence-specific ability of PNA-4K and the 2'-O-MOE oligomers to upregulate EGFP-654 provides strong evidence that systemically delivered, chemically modified oligonucleotides affect gene expression by sequence-specific true antisense activity, validating their application as potential therapeutics.

Animals↗