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At least 1,225 records · Page 68Linked to original sources
PubMed1993

Lactogenic hormones and extracellular matrix regulate expression of IGF-1 linked to MMTV-LTR in mammary epithelial cells.

The cell line MD-IGF-1, containing an ovine IGF-1 cDNA driven by the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter, was used to study expression of IGF-1 linked to the MMTV-LTR in bovine mammary epithelial cells in response to various hormonal and substratum stimuli. Acute sensitivity of the MMTV-LTR promoter to glucocorticoids and sex steroids was ascertained by transient transfection of parental MAC-T cells with an MMTV-CAT construct. Specifically, CAT activity was induced by glucocorticoids, but not by 17 beta-estradiol or progesterone. Induction of MD-IGF-1 cells with dexamethasone (DEX) alone triggered a 29.5-fold increase in secretion of recombinant IGF-1 (348.9 vs 11.8 pg/micrograms DNA), and stimulated a 1.7-fold increase in total DNA within 72 h. Growth of MD-IGF-1 cells was enhanced by exogenous IGF-1, insulin, and TGF-alpha. In contrast, TGF-beta inhibited cell proliferation, while epidermal growth factor, estrogen, progesterone, and testosterone had no effect. Extracellular matrix from the Engelbreth-Holm-Swarm (EHS) tumor, in the presence of DEX, prolactin (PRL), and insulin stimulated a 29.4-fold increase in secretion of IGF-1 (591.9 pg/microgram DNA), compared with cells in absence of hormones (20.1 pg/micrograms DNA). EHS and DEX plus PRL triggered a 63.2-fold increase in IGF-1 secretion (689.1 pg/micrograms DNA), compared with MD-IGF-1 cells cultured on plastic (10.9 pg/micrograms DNA), in the absence of hormones. These data indicate that the MMTV-LTR is regulated by both lactogenic hormones and extracellular matrix in MD-IGF-1 cells and that the MMTV-LTR may be a useful regulatory element for targeting expression of foreign proteins in bovine mammary epithelial cells.

Animals↗
PubMed2002

Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene.

Mice devoid of all TRs are viable, whereas Pax8(-/-) mice, which lack the follicular cells producing T4 and T3 in the thyroid gland, die during the first weeks of postnatal life. A precise comparison between the two types of mutants reveals that their phenotypes are similar, but the defects in spleen, bone, and small intestine are more pronounced in Pax8(-/-) mice. This is interpreted as the result of a negative effect of the unliganded TR on thyroid hormone target genes expression in the Pax8(-/-) mutants. Pax8/TRalpha compound mutants can survive to adulthood, and the expression of target genes is partially restored. This demonstrates the importance of TRalpha aporeceptor activity in several aspects of postnatal development.

Animals↗
PubMed2003

[Construction and verification of the effectiveness of pMBL: a cloning vector of exported proteins encoding genes].

The beta-lactamase was used as the reporter of expression and transmembrane secretion in this paper. A fragment of Amp resistance gene encoding the mature part of beta-lactamase (delta P delta SP Amp, i.e. without promoter and signal peptide coding sequences) was amplified from pUC18 vector. The upstream primer has BglII, BclI, BamHI in three reading frame respectively, in order to in frame fuse and express target genes together with the downstream reporter in finally constructed vector. Meanwhile, pET-28 was digested with the restriction enzymes BglII and Bst1107 I. The 2.8 kb fragment with replication origin, Kan resistance gene and MCS was recovered, filled, self-ligated and resulted in a plasmid pKan-B. The Bgl II site on pKan-B was then filled and the plasmid pKan was obtained. The delta P delta SP Amp gene, which was first cloned into pGEM-T-EASY vector, was inserted into pKan between EcoR I and XbaI sites. A plasmid pMBL-E was selected, with which the bacteria host could grew on Kan plate but not on plate with both Amp and Kan. An EcoRI site beside HindIII on the plasmid pMBL-E was then filled, and the plasmid pMBL, a cloning vector of the exported proteins encoding genes was finally obtained. Both results of the restriction enzyme digestion and sequencing demonstrated the correctness of the construction. The Tet resistance gene, a transmemebrane protein encoding gene, was applied to verify the effectiveness of the reporter in the vector. Cut with EcoRI and BamHI, a 375 bp fragment including promoter and 96 animo acids coding sequence (including signal peptide) of Tet was obtained from pBR322 vector. The fragment was then ligated to the vector pMBL which had been cut with both enzymes of EcoRI and BglI, or EcoRI and BclI, or EcoRI and BamHI (as 0, +1, +2 respectively of the beta-lactamase gene reading frame). Kan and Amp double resistant colonies only grew with the EcoRI and BglII combination (0 position). Restriction enzyme digestion and sequencing results of the recombinant plasmid showed that Tet resistance gene, which promoted the expression and transmembrane secretion of downstream beta-lactamase, was inserted in a correct reading frame into the vector. Thus, the results verified the effectiveness of the constructed vector pMBL, which may be used effectively to clone genes encoding exported proteins with promoters and signal peptide sequences.

Bacterial Proteins↗
PubMed2007

Directed evolution and structural analysis of N-carbamoyl-D-amino acid amidohydrolase provide insights into recombinant protein solubility in Escherichia coli.

One of the greatest bottlenecks in producing recombinant proteins in Escherichia coli is that over-expressed target proteins are mostly present in an insoluble form without any biological activity. DCase (N-carbamoyl-D-amino acid amidohydrolase) is an important enzyme involved in semi-synthesis of beta-lactam antibiotics in industry. In the present study, in order to determine the amino acid sites responsible for solubility of DCase, error-prone PCR and DNA shuffling techniques were applied to randomly mutate its coding sequence, followed by an efficient screening based on structural complementation. Several mutants of DCase with reduced aggregation were isolated. Solubility tests of these and several other mutants generated by site-directed mutagenesis indicated that three amino acid residues of DCase (Ala18, Tyr30 and Lys34) are involved in its protein solubility. In silico structural modelling analyses suggest further that hydrophilicity and/or negative charge at these three residues may be responsible for the increased solubility of DCase proteins in E. coli. Based on this information, multiple engineering designated mutants were constructed by site-directed mutagenesis, among them a triple mutant A18T/Y30N/K34E (named DCase-M3) could be overexpressed in E. coli and up to 80% of it was soluble. DCase-M3 was purified to homogeneity and a comparative analysis with wild-type DCase demonstrated that DCase-M3 enzyme was similar to the native DCase in terms of its kinetic and thermodynamic properties. The present study provides new insights into recombinant protein solubility in E. coli.

Amidohydrolases↗
PubMed1991

Targeting of transgene expression to monocyte/macrophages by the gp91-phox promoter and consequent histiocytic malignancies.

A component of a heterodimeric cytochrome b, designated gp91-phox, is required for the microbicidal activity of phagocytic cells and is expressed exclusively in differentiated myelomonocytic cells (granulocytes; monocyte/macrophages). In an attempt to identify cis-elements responsible for this restricted pattern of expression, we produced transgenic mice carrying reporter genes linked to the human gp91-phox promoter. Immunohistochemical and RNA analyses indicate that 450 base pairs of the proximal gp91-phox promoter is sufficient to target reporter expression to a subset of monocyte/macrophages. Mice expressing simian virus 40 large tumor antigen under control of the gp91-phox promoter develop monocyte/macrophage-derived malignancies with complete penetrance at 6-12 mo of age and provide an animal model of true histiocytic lymphoma. As these transgenes are inactive in most phagocytic cells that express the endogenous gp91-phox-encoding gene, we infer that additional genomic regulatory elements are necessary for appropriate targeting to the full complement of phagocytes in vivo.

Animals↗
PubMed2005

Selection of control genes for quantitative RT-PCR based on microarray data.

Use of internal reference gene(s) is necessary for adequate quantification of target gene expression by RT-PCR. Herein, we elaborated a strategy of control gene selection based on microarray data and illustrated it by analyzing endomyocardial biopsies with acute cardiac rejection and infection. Using order statistics and binomial distribution we evaluated the probability of finding low-varying genes by chance. For analysis, the microarray data were divided into two sample subsets. Among the first 10% of genes with the lowest standard deviations, we found 14 genes common to both subsets. After normalization using two selected genes, high correlation was observed between expression of target genes evaluated by microarray and RT-PCR, and in independent dataset by RT-PCR (r = 0.9, p < 0.001). In conclusion, we showed a simple and reliable strategy of selection and validation of control genes for RT-PCR from microarray data that can be easily applied for different experimental designs and tissues.

Algorithms↗
PubMed2000

[Mode of action of glucocorticoids].

RECEPTORS: The effect of glucocorticoids is mediated by a receptor mainly found in the cytoplasm. The glucocorticoid receptor is a member of the nuclear receptor superfamily. RECEPTOR ACTIVATION: When unstimulated, the glucocorticoid receptor is inactivated by its integration within a multiple-protein complex associating heat shock proteins, immunophilins and cyclophilins. When the hormone binds to its receptor, the complex dissociates and the receptor migrates to the nucleus. In the nucleus, the activated receptor provokes an upregulation or downregulation of target gene expression. GENE REGULATION: Gene expression may be regulated via an interaction between specific nucleic acid sequences of the glucocorticoid receptor and nuclear DNA (direct mechanism) or by protein-protein interactions (indirect mechanism). The expression of target genes is either inhibited or stimulated. PHARMACOLOGICAL CONSEQUENCES: The main pharmacological applications of glucocorticoids can be explained by these different mechanisms. The antiinflammatory action of glucocorticoids results from an inhibition of the transcription of the collagenase gene via an interaction with the AP-1 transcription factor. The anticancer action of glucocorticoids results from the induction of apoptotic cell death via a mechanism which would require the transcriptional activity of the glucocorticoid receptor.

Anti-Inflammatory Agents↗
PubMed2006

Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.

Wnt signaling pathways are important for multiple biological processes during development and disease. Wnt proteins are secreted factors that activate target-gene expression in both a short- and long-range manner. Currently, little is known about how Wnts are released from cells and which factors facilitate their secretion. Here, we identify a conserved multipass transmembrane protein, Evenness interrupted (Evi/Wls), through an RNAi survey for transmembrane proteins involved in Drosophila Wingless (Wg) signaling. During development, evi mutants have patterning defects that phenocopy wg loss-of-function alleles and fail to express Wg target genes. evi's function is evolutionarily conserved as depletion of its human homolog disrupts Wnt signaling in human cells. Epistasis experiments and clonal analysis place evi in the Wg-producing cell. Our results show that Wg is retained by evi mutant cells and suggest that evi is the founding member of a gene family specifically required for Wg/Wnt secretion.

Animals↗
PubMed2006

Hypoxia-inducible factors, hypoxia, and tumor angiogenesis.

PURPOSE OF REVIEW: The transcription factor hypoxia-inducible factor is activated by low oxygen to promote the expression of target genes that allow cellular, tissue, and organismal adaptation to low oxygen. Hypoxia-inducible factor is activated not only by hypoxia but also as a consequence of genetic mutations in a variety of tumors. This review summarizes recent studies on hypoxia-inducible factor-alpha functions in development and tumorigenesis. RECENT FINDINGS: Deficiency of the tumor suppressor von Hippel-Lindau leads to constitutively active hypoxia-inducible factor and hypoxia-inducible factor target gene expression. Other genetic lesions, however, e.g. in JunD, can also result in elevated hypoxia-inducible factor levels. The specific functions of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during development and tumor growth remain incompletely understood. Whereas hypoxia-inducible factor-2alpha seems to be the critical hypoxia factor in renal cell carcinoma, hypoxia-inducible factor-1alpha plays a significant role in the growth of tumors in other tissues. Loss of von Hippel-Lindau is not sufficient for neoplastic transformation, suggesting that hypoxia-inducible factor does not act alone to cause tumors. SUMMARY: It will be important to further characterize the specific roles of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during tumorigenesis to design therapies targeting the relevant isoform for specific diseases. It is also necessary to investigate the effect of reducing hypoxia-inducible factor levels on other angiogenic factors.

Animals↗
PubMed1998

Tissue-specific, cell cycle-regulated chimeric transcription factors for the targeting of gene expression to tumor cells.

A major challenge in the gene therapy of proliferative diseases is the specific targeting of gene expression. Here we describe a new approach based on the development of dual-specificity promoters that are both cell type specific and cell cycle regulated. The gene of interest is driven by an artificial heterodimeric transcription factor, whose DNA-binding subunit is expressed from a tissue-specific promoter, whereas the trans-activating subunit is transcribed from a cell cycle-regulated promoter. As a result gene expression occurs preferentially in the proliferating cells of a specific type of tissue. The selectivity of this strategy is demonstrated for the expression of a transgene in proliferating melanoma cells, using a combination of cyclin A and tyrosinase promoter elements. We also show that the level of expression that can be achieved by this system is sufficient to induce a clear biological effect in a TNF-alpha cytotoxicity assay.

Animals↗
PubMed1992

Effects of beta-2 microglobulin anti-sense oligonucleotides on sensitivity of HER2/neu oncogene-expressing and nonexpressing target cells to lymphocyte-mediated lysis.

The mechanism by which HER2/neu overexpressing tumor cells resist NK, LAK, and LDCC cytotoxic lymphocytes was investigated. Resistance was not explained by a delay in kinetics of lysis, concurrent resistance to TNF, or a diminished expression of the transferrin receptor. HLA-class I expression, however, was markedly elevated compared to HER2 nonexpressing targets suggesting a reason for resistance. To test the role of class I, we selectively decreased expression by incubation of targets with beta-2 microglobulin anti-sense oligonucleotides. Anti-sense-treated HER2+ targets, displaying levels of class I comparable to HER2- targets, were still markedly resistant to cytotoxic effectors. Down-regulation of class I expression in HER2- carcinoma cells also had no effect on sensitivity to cytotoxicity by anti-sense treatment of Raji and U937 targets resulted in enhanced sensitivity to NK and LAK effectors but not to T cells mediating LDCC. These data indicate resistance to cytotoxicity in HER2-expressing targets cannot be solely explained by heightened expression of class I. The data also support the concept that class I expression regulates sensitivity to NK and LAK cells (but not LDCC effectors) in selected targets.

Animals↗
PubMed1999

Induction of carcinoembryonic antigen (CEA)-specific cytotoxic T-lymphocyte responses in vitro using autologous dendritic cells loaded with CEA peptide or CEA RNA in patients with metastatic malignancies expressing CEA.

The application of dendritic cells (DC) to the active immunotherapy of cancer currently relies on the generation of potent DC capable of presenting tumor antigens such as carcinoembryonic antigen (CEA). It is unknown whether the T cells of patients with advanced malignancies can be reliably stimulated against tumor antigens by their autologous DC. In this study, starting with the peripheral blood mononuclear cells (PBMC) of patients with metastatic malignancies expressing CEA, autologous DCs were generated in vitro in serum-free media supplemented with GM-CSF and IL-4. The DCs from HLA A2 positive patients were loaded with the CEA peptide CAP-1 and the DCs from HLA A2 negative patients were depleted of bystander lymphocytes and loaded with mRNA encoding CEA. The DC preparations were tested to determine their phenotype and were used to stimulate autologous PBMC twice, separated by 10-14 days. The stimulated cells were then tested for their ability to lyse CEA-expressing target cells. We successfully generated an adequate number of DC for a clinical trial from all patients. The harvested DC preparations contained 49% DC and 87% DC if depleted of bystander lymphocytes. Phenotypic analysis showed the typical pattern of CD11c+ CD40+ CD86+ HLA-DR+ CD80(low) CD83(low) CD14(low). All preparations but one were able to stimulate CEA-specific cytotoxic T-lymphocyte (CTL) activity, suggesting that the majority of patients are not anergic to CEA and possess functional DC. The CTL activity was similar for the CEA peptide and CEA RNA-loaded DC.

Carcinoembryonic Antigen↗
PubMed2001

The generation of LMP2a-specific cytotoxic T lymphocytes for the treatment of patients with Epstein-Barr virus-positive Hodgkin disease.

Based upon the success of using polyclonal, Epstein-Barr virus (EBV)-specific CTL lines for the prophylaxis and treatment of patients with post-transplant lymphoproliferative disease (PTLPD), there is now considerable incentive to develop CTL directed against the sub-dominant EBV antigens EBNA1, LMP1 and LMP2, which are expressed by the tumor cells of Hodgkin disease and nasopharyngeal carcinoma. To develop a system for generating LMP2a-specific CTL in vitro, we transfected autologous immature dendritic cells (DC), which had been grown in the absence of serum, with LMP2a RNA in the presence of the cationic lipid DOTAP. This transfection method did not adversely affect the DC in terms of immunophenotyping and they expressed high levels of HLA class I and II and critical costimulatory molecules. These LMP2a(+) DC, as compared to DC which had been transfected with irrelevant RNA, were shown to be highly immunostimulatory in autologous mixed lymphocyte reactions and, importantly, could stimulate the generation of CD8(+) and CD4(+) CTL which exclusively recognized LMP2a-expressing targets. This specific cytotoxicity was confirmed using antibody blocking experiments and cytotoxicity assays of the separated T cell subsets. Using this DC-based system we could also reactivate LMP2a-specific memory in EBV-seropositive donors whose polyclonal CTL response to LCL stimulation did not contain a LMP2a-specific component.

Antigens, Viral↗
PubMed1992

HTLV-I-specific cytotoxic T lymphocytes in the cerebrospinal fluid of patients with HTLV-I-associated neurological disease.

Recently, it has been shown that in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated neurological disease, high levels of HTLV-I-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood. These CTLs predominantly recognized products of the pX region of HTLV-I, had a CD8+ phenotype, and were human leukocyte class I restricted. Moreover, these responses were not detected in asymptomatic, HTLV-I-seropositive individuals. This implied a role for these CTLs in the pathogenesis of the neurological disorder associated with HTLV-I. We have extended these observations by demonstrating HTLV-I-specific CTLs directly from lymphocytes obtained from the cerebrospinal fluid of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Uncultured cerebrospinal fluid lymphocytes were used directly as effectors on a variety of targets expressing HTLV-I. These cells were lysed in a virus-specific and HLA class I-restricted manner. Moreover, the cerebrospinal fluid lymphocytes were sorted into purified CD8+ populations, cloned by limiting dilution, and assayed for CTL activity. An exceedingly high proportion of these resultant lines were shown to be cytolytic and precursor frequency analysis indicated that as many as 1 in 500 cells were HTLV-I-specific CTLs. The majority of these CTL lines recognized HTLV-I gene products encoded within the pX region of HTLV-I. The significance of these HTLV-I-specific CTLs in the central nervous system of patients with HTLV-I-associated neurological disease is discussed with regard to the potential role of CTLs in the pathogenesis of this disease.

Adult↗
PubMed2004

The calpain-system of Drosophila melanogaster: coming of age.

Drosophila melanogaster is one of the most popular and powerful model organisms that help our understanding of mammalian (human) life processes at the molecular level. Calpains are Ca(2+)-activated cytoplasmic proteases thought to play multiple roles in intracellular signal processing by limited proteolysis of target substrate proteins, thereby changing their function. The calpain superfamily consists of 14 genes in mammals, but only 4 genes in Drosophila. One may assume that the calpain system, i.e. recognizing calpain-dependent life processes and identifying the substrates cleaved while exerting their functions, would prove easier to solve in Drosophila than in mammals. Recently, major progress has been made in characterizing Drosophila Calpain A, Calpain B and Calpain C. The fourth member, Calpain D (or SOL), was analyzed earlier. At this juncture, it seems justifiable to summarize our knowledge about the Drosophila enzymes, in comparison to the ubiquitous mammalian ones, as regards structure-function relations, mode of activation by Ca(2+) and other factors, inhibition, potential targeting, expression pattern in vivo, etc. Equipped with all this information, we may now embark on the genetic modification of family members, interpreting mutant phenotypes in terms of the cell biology of calpains.

Amino Acid Sequence↗
PubMed2005

Amnioserosa is required for dorsal closure in Drosophila.

Dorsal closure in the fruit fly Drosophila melanogaster is a complex morphogenetic process, driven by sequential signaling cascades and involving multiple forces, which contribute to cell movements and rearrangements as well as to changes in cell shape. During closure, lateral epidermal cells elongate along the dorsoventral axis and subsequently spread dorsally to cover the embryonic dorsal surface. Amnioserosal cells, which are the original occupants of the most dorsal position in the developing embryo, constrict during closure; thus, the increase in epidermal surface area is accommodated by a reduction in the amnioserosal surface area. Several of the epidermal requirements for closure have been established in functional assays. In contrast, amnioserosal requirements for closure have remained elusive, in part because laser ablation and clonal approaches are limited to only subsets of amnioserosal cells. Here, we report our use of the UAS-GAL4 system to target expression of the cell autonomous toxin Ricin-A to all cells of the amnioserosa. We show that ablation of the amnioserosa leads to clear defects in dorsal closure and, thus, directly demonstrate a role for the amnioserosa in dorsal closure. We also show that DJNK (Drosophila Jun N-terminal kinase) signaling, an epidermal trigger of closure, is unaffected by amnioserosal ablation. These data, together with our demonstration that amnioserosal ablated and Dpp signaling mutant embryos exhibit shared loss-of-function phenotypes, point to a requirement for the amnioserosa in dorsal closure that is downstream of Dpp, perhaps as part of a paracrine response to this signaling cascade.

Amnion↗
PubMed2005

Nicastrin controls aspects of photoreceptor neuron specification and differentiation in the Drosophila eye.

Nicastrin is a component of the Notch signaling pathway involved in proteolytic release of the Notch receptor intracellular domain. It has been postulated that intracellular Notch is required within the nucleus of fly eye progenitor cells to enhance (pro-neural enhancement) and then repress (lateral inhibition) transcription of pro-neural genes. We present here an analysis of Nicastrin function during eye development and find that Nicastrin is essential to early photoreceptor neuron development. Nicastrin mutant tissue displays neuronal loss or hyperplasia; these phenotypes can be rescued by targeted expression of an intracellular form of Notch. Thus, nuclear translocation of Notch and its direct regulation of gene expression appear to be critical to pro-neural enhancement as well as lateral inhibition. In addition, we show that Nicastrin as well as Notch are required to maintain normal R-cell morphology, because the nuclei of mutant photoreceptor neurons cannot maintain their proper position. Thus, Notch signaling plays a role, not only in cell fate specification, but also in differentiation of photoreceptor neurons.

Amyloid Precursor Protein Secretases↗
PubMed1990

The effect of mutations in the MHC class I peptide binding groove on the cytotoxic T lymphocyte recognition of the Kb-restricted ovalbumin determinant.

The H-2Kb-restricted cytotoxic T lymphocyte (CTL) response directed against ovalbumin (OVA) is specific for a region contained within the sequence OVA253-276. In this study we have characterized this response by examining the class I-restricted presentation of OVA peptides by the naturally occurring Kb mutant (Kbm) glycoproteins Kbm1, Kbm3, Kbm5, Kbm8, Kbm10, Kbm11 and Kbm23. To facilitate this study we derived a series of somatic cell hybrid targets expressing the various Kbm class I molecules. Experiments using bulk OVA-specific CTL from C57BL/6 mice demonstrated that all the Kbm molecules except for Kbm1 and Kbm8 could present OVA peptides for effective T cell recognition. Clonal analysis revealed a more complex and relatively diverse pattern of CTL recognition of the Kbm/peptide combinations. This diversity is unlikely to result from the existence of multiple, independent Kb-restricted T cell determinants within OVA, since all CTL tested were specific for a single region between residues 259 and 273. Examination of the fine specificity of Kbm presentation identified individual changes at residues 77, 80 and 116 which affected T cell recognition. The results imply that these changes do not inhibit peptide binding since some clones could recognize peptide presented by a particular Kbm molecule, while other clones could not. All three residues reside within the peptide-binding cleft of the class I protein and are not expected to directly contact the T cell receptor. Although we did not formally demonstrate that OVA binding by Kbm vs. Kb is quantitatively identical, our results are best explained by postulating that the changes at residues 77, 80 and 116 indirectly affect T cell recognition by altering peptide conformation. Taken together our results suggest that changes within the class I binding site can profoundly modify peptide presentation without significantly inhibiting peptide-class I association.

Animals↗