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PubMed1991

Transgenic models of tumor development.

Numerous cancer-prone strains of mice have been created by the introduction of candidate tumor-promoting genes into fertilized eggs. Each transgenic strain is predisposed to develop specific types of tumors, but they usually arise stochastically because of the need for spontaneous mutation of genes that collaborate with the introduced oncogene. These mice are providing insights into the effects of individual oncogenes on cellular proliferation, differentiation, and viability, as well as on oncogene cooperativity. Their predisposed state imposes sensitivity to viral and chemical carcinogenesis, and the mice should prove valuable in tests of potential carcinogens, therapies, and preventive measures.

Animals↗
PubMed1994

Phosphorylation of varicella-zoster virus open reading frame (ORF) 62 regulatory product by viral ORF 47-associated protein kinase.

Varicella-zoster virus (VZV) encodes within its unique long region a gene product with protein kinase motifs. In a previous study, we demonstrated that immunoprecipitated VZV open reading frame (ORF) 47 protein was associated with a functional protein kinase activity, on the basis of its ability to both autophosphorylate and phosphorylate artificial substrates. To further define potential substrates of ORF 47-associated protein kinase, we analyzed individual viral phosphoproteins to determine whether any were modified by the viral protein kinase. These candidates included gene products of VZV ORFs 4, 61, 62, and 63, which are homologs of herpes simplex virus type 1 (HSV-1) immediate-early proteins. Each of the above VZV proteins was coimmunoprecipitated with ORF 47 kinase, and the immune complex was incubated in a protein kinase assay. Under these conditions, only the VZV immediate-early ORF 62 protein was phosphorylated by ORF 47-associated protein kinase. The specificity of this phosphorylation event was analyzed by a competition assay in which a recombinant ORF 47 protein lacking enzymatic activity was able to reduce the amount of phosphorylation of ORF 62 protein by VZV ORF 47-associated kinase. To provide an additional evaluation of specificity, the experiment was repeated with [32P]GTP instead of [32P]ATP, because the VZV ORF 47 kinase has the distinctive property of using GTP as a phosphate donor. Again the ORF 62 substrate was phosphorylated. In summary, the VZV ORF 47-associated protein kinase (the HSV-1 UL13 homolog) catalyzed the in vitro phosphorylation of the VZV ORF 62 protein, the homolog of the HSV-1 ICP4 regulatory protein.

Amino Acids↗
PubMed1998

Multigenic control of lupus-associated antiphospholipid syndrome in a model of (NZW x BXSB) F1 mice.

In a subset of systemic lupus erythematosus (SLE) patients, antiphospholipid syndrome, characterized by occurrence of anti-cardiolipin (CL) antibodies, thrombocytopenia, thrombosis and recurrent intrauterine fetal death occurs. Male (NZW x BXSB)F1 mice, carrying the BXSB Yaa gene, serve as a model for SLE-associated antiphospholipid syndrome. Using microsatellite markers in the NZW x (NZW x BXSB)F1 backcross male progeny, we mapped BXSB alleles contributing to the generation of anti-CL antibodies, platelet-binding antibodies, thrombocytopenia and myocardial infarction. Generation of each disease character was controlled by two major independently segregating dominant alleles, i.e. those on chromosomes (Chr.) 4 and 17 for anti-CL antibodies, Chr. 8 and 17 for both anti-platelet antibodies and thrombocytopenia and, to our surprise, Chr. 7 and 14 for myocardial infarction, and that a combination of the two alleles appeared to produce full expression of each character, as a complementary gene action. The alleles on Chr. 17 linked to the above three characters were all mapped in close proximity to the H-2 complex. Therefore, no single factor such as anti-CL antibodies can explain the pathogenesis of SLE-associated antiphospholipid syndrome. Rather, a combination of susceptibility alleles such as described here, along with additional modifying loci, i.e. BXSB Yaa and some from NZW, characterizes unique SLE features in male (NZW x BXSB) F1 mice. There are potentially important candidate genes which may be linked to the syndrome.

Animals↗
PubMed2002

Tumor vaccines: a role in preventing recurrence in melanoma?

Patients presenting with thick primary melanomas or those with regional nodal metastases have a high risk of recurrence after surgery alone. Chemotherapy has limited efficacy in the adjuvant setting, and while the use of high-dose interferon in the adjuvant setting has been reported to improve survival, treatment with interferon is not without significant cost and toxicity. Mounting evidence suggests a prominent role for the immune system in the natural history of melanoma, and the clinical success of interferon highlights the potential for immunotherapy to prevent recurrence. Many researchers hope to use melanoma vaccines to reduce recurrence without significant toxicity, and many different vaccine strategies are under investigation. Peptide vaccines attempt to induce immunity to melanoma MHC-restricted peptide antigens by delivering the peptide to the patient along with an immune adjuvant meant to induce inflammation and stimulate immunity. While peptide vaccines have advantages with regard to cost and feasibility, it is still unclear whether highly purified peptides will stimulate an adequate immune response. An alternative approach is the use of cellular vaccines. Autologous cellular vaccines present all biologically relevant antigens to the immune system, but this is limited to individuals with sufficient tumor to prepare a vaccine. Allogeneic cellular vaccines are based on the fact that melanoma-associated antigens are shared among a large number of patients, so a vaccine prepared from a cultured cell line could stimulate an anti-tumor immune response in many patients. Allogeneic vaccines are available for all patients, and can be standardized, preserved and distributed in a manner akin to any other therapeutic agent. Because of this, they are more readily available for evaluation in large trials, and there are two major allogeneic vaccines presently being evaluated as an adjuvant therapy for melanoma. Several additional approaches to vaccine therapies are being investigated including among others ganglioside vaccines, viral oncolysates, cytokine gene-modified tumor cell vaccines, dendritic cell vaccines, anti-idiotype antibodies and DNA vaccines. While there appears to be tremendous potential for vaccines, it must be remembered that there has been significant interest in immunotherapy for melanoma for over 50 years and, to date, no large prospective, randomized trial has shown a survival benefit.

Antigens, Neoplasm↗
PubMed2001

Health and safety issues pertaining to genetically modified foods.

Genetic modification involves the insertion of genes from other organisms (within or between species) into host cells to select for desirable qualities. Potential benefits of GM foods include increased nutritional value; reduced allergenicity; pest and disease-resistance; and enhanced processing value. Possible detrimental outcomes include producing foods with novel toxins, allergens or reduced nutritional value, and development of antibiotic resistance or herbicide-resistant weeds. Benefits to individuals or populations need to be weighed against adverse health and environmental risks, and may differ between developing and Westernised countries. Whether testing and monitoring should exceed requirements for conventional foods is under debate. While not necessarily scientifically justifiable, consumer concerns have resulted in Australian and New Zealand requirements to label foods containing GM-produced proteins. Dissatisfied consumer advocacy groups are calling for all foods involving GM technology to be labelled, irrelevant of whether the final product contains novel protein. Goals to improve the quantity, quality and safety of foods are laudable; however, the primary aim of the bio-food industry is financial gain. GM foods may be as safe as conventional foods but public distrust runs high. It is important that discussion is informed by science and that claims of both benefits and risks are evidence-based, to ensure that the process is driven neither by the vested interest of the bio-technical multinational companies on the one hand, nor ill-informed public fears on the other.

Attitude to Health↗
PubMed2004

Gene therapy for inherited disorders of haematopoietic cells.

Over the last decade, the majority of inborn errors of haematopoiesis has been elucidated on a molecular level. For some of these diseases, gene transfer into transplantable cells offers new therapeutic perspectives. Improved retroviral or lentiviral techniques allow stable gene transfer in >10% of repopulating cells cultured in vitro. However, severe impediments are still encountered with respect to achieving sufficient and long-lasting transgene expression levels and appropriate numbers of transgenic cells in vivo. Improving the techniques for manipulation of stem cells in vitro, and the development of regimens promoting engraftment and selection of gene-modified cells are important areas of current research. Further activities address the level and persistence of transgene expression within individual cell clones, and the functional characteristics of progeny cells in vivo. Promises with respect to the potential impact of gene therapy for patients suffering from inherited disorders are often triggered by 'proof of concept' in preclinical disease models. However, recent observations of side effects related to random vector insertion or transgene expression indicate that even more careful quantitative and qualitative investigations of efficiency and toxicity may be needed for individual transgenes before approaching clinical trials.

Animals↗
PubMed2002

Exon-specific RNAi: a tool for dissecting the functional relevance of alternative splicing.

The goal of functional genomics is to determine the function of each protein encoded by an organism. Typically, this is done by inactivating individual genes and, subsequently, analyzing the phenotype of the modified organisms. In higher eukaryotes, where a tremendous amount of alternative splicing occurs, such approaches are not feasible because they have the potential to simultaneously affect multiple proteins that could have quite distinct and important functions. Thus, it is necessary to develop techniques that inactivate only a subset of proteins synthesized from genes encoding alternatively spliced mRNAs. Here we demonstrate that RNA interference (RNAi) can be used to selectively degrade specific alternatively spliced mRNA isoforms in cultured Drosophila cells. This is achieved by treating the cells with double-stranded RNA corresponding to an alternatively spliced exon. This technique may prove to be a powerful tool to assess the function of proteins synthesized from alternatively spliced mRNAs. In addition, these results have implications regarding the mechanism of RNAi in Drosophila.

Alternative Splicing↗
PubMed2005

Targeted expression of the anti-apoptotic gene CrmA to NOD pancreatic islets protects from autoimmune diabetes.

The activation of apoptosis is a critical mechanism by which pancreatic beta cells are destroyed in type 1 diabetes (T1DM). Strategies aimed at interfering with the apoptotic pathways could therefore be of potential therapeutic value. To this end, we generated NOD transgenic mice with targeted expression of the anti-apoptotic gene Cytokine response modifier A (CrmA) to pancreatic beta cells using the rat insulin promoter and the reverse tetracycline transactivator to express CrmA in a temporally controlled manner. Two lines of transgenic mice were studied whose expression of CrmA occurred only after feeding doxycycline food. Islet expression of CrmA partially protected pancreatic beta cells from the cytokine-mediated cytotoxicity in vitro and reduced modestly the spontaneous development of diabetes in NOD mice in vivo. In addition, beta cells from NOD CrmA mice were significantly protected from the destruction by diabetogenic T cells after adoptive transfer. More strikingly, NODCrmA mice were significantly resistant to the diabetogenic activity of a potent insulin-specific CD8 T-cell clone. Since these adoptive transfer models mainly represent the effector phase rather than the initiation phase of autoimmune diabetes, our data suggest that the latter is more sensitive to CrmA protection. We conclude that anti-apoptotic genes such as CrmA might be potential candidates to enhance islet graft survival in T1DM.

Adoptive Transfer↗
PubMed1995

Site directed chromosomal marking of a fluorescent pseudomonad isolated from the phytosphere of sugar beet; stability and potential for marker gene transfer.

A plasmid-free, non-pathogenic, ribosomal RNA group 1 fluorescent pseudomonad, Pseudomonas fluorescens SBW25, was selected from the microflora of sugar beet (Beta vulgaris) and modified to contain constitutively expressed marker genes. By site directed homologous recombination a KX cassette [kanamycin resistance (kanr) and catechol 2,3 dioxygenase (xylE)] and a ZY cassette [lactose utilization (lacZY, beta-galactosidase, lactose permease)] were introduced at least 1 Mbp apart on the 6.6 Mbp bacterial chromosome. Separate sites were selected to provide sensitive detection methods and allow assessments of marker gene stability of the genetically modified micro-organism (GMM), SBW25EeZY6KX, when it colonized the leaves and roots of sugar beet plants following seed inoculation.

Base Sequence↗
PubMed2001

Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice.

Inhibition of tumor-induced neovascularization appears to be an effective anticancer approach, although long-term angiogenesis inhibition may be required. An alternative to chronic drug administration is a gene therapy-mediated approach in which long-term in vivo protein expression is established. We have tested this approach by modifying murine bone marrow-derived cells with a gene encoding an angiogenesis inhibitor: a soluble, truncated form of the vascular endothelial growth factor receptor-2, fetal liver kinase-1 (Flk-1). Murine bone marrow cells were transduced with a retroviral vector encoding either truncated, soluble Flk-1 (tsFlk-1) together with green fluorescent protein (GFP) or GFP alone. Tumor growth in mice challenged 3 months after transplantation with tsFlk-1-expressing bone marrow cells was significantly inhibited when compared with tumor growth in control-transplanted mice. Immunohistochemical analysis of tumors in each group demonstrated colocalization of GFP expression in cells staining with endothelial cell markers, suggesting that the endothelial cells of the tumor-induced neovasculature were derived, at least in part, from bone marrow precursors. These results suggest that long-term expression of a functional angiogenesis inhibitor can be generated through gene-modified, bone marrow-derived stem cells, and that this approach can have significant anticancer efficacy. Modifying these cells seems to have the added potential benefit of targeting transgene expression to the tumor neovasculature, because bone marrow-derived endothelial cell precursors seem to be recruited in the process of tumor-induced angiogenesis.

Angiogenesis Inhibitors↗
PubMed2000

Synaptic ultrastructure in nerve terminals of Drosophila larvae overexpressing the learning gene dunce.

We investigated synaptic ultrastructure of individual nerve ending varicosities at the Drosophila larval neuromuscular junction in transgenic larvae overexpressing the learning gene dunce (dnc) in the nervous system. It was previously shown that cAMP is reduced to one-third normal in these larvae and that they have fewer nerve terminal varicosities and smaller junction potentials, although transmitter release from individual nerve ending varicosities is not significantly altered. We tested the hypothesis that synaptic ultrastructure is modified to compensate for possible reduced efficacy of synaptic transmission resulting from lower than normal cAMP. Synaptic size and number of presynaptic dense bodies (active zone structures) per synapse are modestly enhanced in transgenic larvae overexpressing the dnc gene product and in rutabaga (rut(1)) mutant larvae, which have reduced adenylyl cyclase activity and reduced neural cAMP. The incidence of complex synapses (possessing 2 or more presynaptic dense bodies) was not consistently different in experimental larvae compared to controls. The observations suggest that chronic reduction of cAMP levels in the nervous system of Drosophila larvae, although leading to a modest compensatory change in synaptic structure, does not markedly alter several synaptic ultrastructural parameters which are thought to influence the strength of transmitter release; thus, homeostatic mechanisms do not act to maintain normal-sized junction potentials by altering synaptic structure.

Animals↗
PubMed2001

Cytokines of birds: conserved functions--a largely different look.

Targeted disruptions of the mouse genes for cytokines, cytokine receptors, or components of cytokine signaling cascades convincingly revealed the important roles of these molecules in immunologic processes. Cytokines are used at present as drugs to fight chronic microbial infections and cancer in humans, and they are being evaluated as immune response modifiers to improve vaccines. Until recently, only a few avian cytokines have been characterized, and potential applications thus have remained limited to mammals. Classic approaches to identify cytokine genes in birds proved difficult because sequence conservation is generally low. As new technology and high throughput sequencing became available, this situation changed quickly. We review here recent work that led to the identification of genes for the avian homologs of interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma, various interleukins (IL), and several chemokines. From the initial data on the biochemical properties of these molecules, a picture is emerging that shows that avian and mammalian cytokines may perform similar tasks, although their primary structures in most cases are remarkably different.

Adjuvants, Immunologic↗
PubMed1994

Nervous system modification by transplants and gene transfer.

New possibilities to modify function and direct repair in the central nervous system (CNS) have been established by the merger of gene transfer technology with neural transplantation. Rapid advances in viral-mediated DNA-delivery procedures permit the study of novel gene expression in neurons and glial cells. Foreign genes, transferred by a virus vector, can be used to generate new cell lines, identify transplanted cells, and express growth factors or enzymes for neurotransmitter synthesis. In addition to CNS cell types, non-neural cells are also being studied with transgene technology in the nervous system. Functional effects have been obtained with grafts of genetically modified cells in animal models of several nervous system disorders, and the recent results set the stage for potential application of these techniques to human CNS gene therapy.

Adenoviruses, Human↗
PubMed2006

Effects of codon modification on human BMP2 gene expression in tobacco plants.

Bone morphogenetic protein 2 (BMP2) has great potential in therapeutic applications. We are working on generating transgenic plants as a bioreactor to produce BMP2. We have studied the effects of codon optimization on the expression of human BMP2 (hBMP2) in tobacco plants. Three modified hBMP2 genes were transformed into tobacco under the control of either cauliflower mosaic virus 35S (CaMV35S) promoter or double-CaMV35S promoter plus alfalfa mosaic virus (AMV) enhancer. The fused beta-glucuronidase (GUS) reporter gene was used to facilitate the assay of protein expression. The results indicated that codon optimization could increase the protein expression level obviously under CaMV35S promoter. However, under relatively stronger initiation condition (double-CaMV35S promoter plus AMV enhancer), only the gene with the lowest degree of codon optimization could increase the protein expression level. Our findings suggest that the action of codon optimization may be influenced by the factors of promoter strength and A+T content in tobacco plants.

Base Sequence↗
PubMed2001

Epstein-Barr virus complementary strand transcripts (CSTs/BARTs) and cancer.

Epstein-Barr virus (EBV) encodes a family of related transcripts, the complementary strand transcripts (CSTs) or BARTs (Bam A rightward transcripts). These are present in all types of EBV infection but are expressed to particularly high levels in nasopharyngeal carcinomas. Although convincing demonstration of protein expression from these transcripts is still subject to some debate, potential proteins encoded by them have been shown to modify Notch signalling pathways.

Gene Expression Regulation, Viral↗
PubMed2006

Potential role of a CD36-like class B scavenger receptor in the binding of modified low-density lipoprotein (acLDL) to the tegumental surface of Schistosoma mansoni sporocysts.

Previous studies have documented the binding of low density lipoproteins (LDLs) to the tegumental surface of the mammalian stage of the human blood fluke Schistosoma mansoni, and that such binding may be functioning in the acquisition of host lipids for nutritional and/or immune evasion purposes. To determine if the intramolluscan mother sporocyst stage of S. mansoni also possess the ability to acquire exogenous LDL, live sporocysts, derived by in vitro transformation of isolated miracidia, were treated with DiI-labeled LDL (LDL-DiI) or acetylated LDL (acLDL-DiI). Sporocysts markedly differed in their binding, exhibiting strong labeling at the tegumental surface with acLDL-DiI, and only weak binding of LDL-DiI. As scavenger receptors (SRs) are known to selectively bind modified (acetylated or oxidized) LDL and other polyanionic molecules, various potential ligands of known SRs were used in an acLDL-DiI binding inhibition assay. Significant acLDL-DiI binding inhibition was observed for fucoidan, polyinosinic acid and dextran sulfate, but not for polycytidylic acid and dextran, a binding inhibition pattern consistent with SR class A or C activity. From a S. mansoni EST sequence, we cloned a scavenger receptor homologue from sporocyst cDNA that encoded a protein with 31% amino acid sequence identity and 50% similarity to a SR class B (SRB) molecule, belonging to the CD36 superfamily. Using an RNA interference assay, treatment of miracidia with a 517bp double-stranded RNA of the S. mansoni SRB gene resulted in a significant and specific knockdown (60-70%) of SRB transcript levels in sporocysts after 6 days of dsRNA exposure and was associated with a significant reduction in acLDL-DiI binding to sporocysts at 8 and 10 days post-dsRNA incubation. There also was a time-dependent decrease in sporocyst length following dsRNA treatments. The functional linkage of acLDL binding to the cloned SRB-like S. mansoni gene using RNA interference (RNAi) suggests a possible role of the tegumental SRB-like protein as a receptor for modified LDL. Inhibition of sporocyst growth also indicates a potential involvement of this SR homologue in some aspect of larval growth and/or development.

Amino Acid Sequence↗
PubMed1993

Suicidal genetic elements and their use in biological containment of bacteria.

The potential risks of unintentional releases of genetically modified organisms, and the lack of predictable behavior of these in the environment, are the subject of considerable concern. This concern is accentuated in connection with the next phase of gene technology comprising deliberate releases. The possibilities of reducing such potential risks and increasing the predictability of the organisms are discussed for genetically engineered bacteria. Different approaches towards designing disabled strains without seriously reducing their beneficial effects are presented. Principally two types of strain design are discussed: actively contained bacteria based on the introduction of controlled suicide systems, and passively contained strains based on genetic interference with their survival under environmental-stress conditions.

Bacteria↗
PubMed2005

Anchorage of Candida albicans Ssr1 to the cell wall, and transcript profiling of the null mutant.

Incorporation into the wall of Candida albicans Ssr1, a GPI-dependent protein, was investigated by construction of different truncated genes for which the three potential omega sites (S199, S215 and G216) and the corresponding omega+1 and omega+2 were eliminated or modified. Cells of the C. albicans ssr1Delta mutant were transformed with pADH-pl harboring the truncated versions of CaSSR1, pADH-DeltaCaSSR1t(217-234) (lacking a C-terminal hydrophobic stretch of 18 aa including the putative omega+2 and omega+1, omega+2 of S215 and G216) or pADH-DeltaCaSSR1t(199-201) (lacking three serine residues), and their walls were analyzed for the protein. Results suggested that the three serine residues are essential for incorporation of CaSsr1 into the wall beta-glucan. This interpretation was confirmed when the truncated protein CaSsr1pt(199-201) was found in the spent medium. The transcription profile of the 6039 genes in C. albicans ssr1Delta showed that seven genes are upregulated (1.4-fold), including SRP54 (a signal recognition particle subunit), IPF29 (a zinc finger protein) and PTR3 (a transcriptional regulator), whereas 27 genes are downregulated (0.7-fold), including IPF6318 (a beta-glucosidase) and SOU1 (a sorbitol utilization protein). Additional genes showed a reduced increase, or decreased expression, suggesting that some current orphan genes may have unknown cell wall functions. In addition, a compensatory mechanism would appear to occur, as a substantial increase in the amount of beta-1,3-glucan (2.34-fold) was detected in the cell wall of the mutant cells.

Amino Acid Sequence↗