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At least 235 records · Page 13Linked to original sources
PubMed1995

A spontaneous mutation in the movement protein gene of brome mosaic virus modulates symptom phenotype in Nicotiana benthamiana.

Brome mosaic virus (BMV) is a positive-strand RNA virus with a multipartite genome that causes symptomless infection in Nicotiana benthamiana. We have isolated and characterized a strain of BMV that produced uniform vein chlorosis in systemically infected N. benthamiana. Analysis of pseudorecombinants constructed by exchanging RNA 1 and 2 and RNA 3 components between wild-type (non-symptom-inducing) and vein chlorosis-inducing strains of BMV indicated that the genetic determinant for the induction of the chlorotic phenotype is located on RNA 3. Sequence analysis of progeny RNA 3 recovered from symptomatic N. benthamiana plants revealed that vein chlorosis is due to the single nucleotide transition 887G-->887A, which changes the codon for Val-266 to Ile-266 in the movement protein gene. The mutation had no detectable effect on the accumulation of virus in either inoculated or systematically infected leaves of N. benthamiana. The vein chlorosis phenotype is the manifestation of the substitution of Ile-266 for Val-266 in the movement protein gene, since additional alterations in this region (a silent mutation, i.e., 887GUU889-->GUC, and an alteration of valine to phenylalanine, i.e., 887GUU889-->887UUU889) resulted in symptomless infections on N. benthamiana. The modulation of the symptom phenotype by the substitution of Ile-266 for Val-266 is specific for N. benthamiana, since neither movement nor the symptom phenotype in barley plants was affected.

Base Sequence↗
PubMed1994

Phenotypic and functional modulation of normal human alveolar macrophages by histamine.

Alveolar macrophages (AM) play a regulatory role in asthma. AM from asthmatics are activated, release increased amounts of cytokines, and express higher levels of the low affinity receptor for IgE (Fc epsilon RIIb/CD23b) and receptors for adhesion molecules. The bronchial microenvironment may modulate the phenotypic and functional characteristics of AM. On AM from normal subjects, the effects of histamine were studied on the expression of adhesion molecules (LFA-1, ICAM-1) and CD23b as well as on the release of fibronectin. The expression of LFA-1, ICAM-1, and CD23b was examined by immunocytochemistry using the alkaline phosphatase-anti-alkaline phosphatase technique. The expression of CD23b mRNA was studied by in situ hybridization. The release of fibronectin was measured by enzyme immunoassay. We found that histamine induced in a dose- and time-dependent fashion a significant increase of AM expressing the three membrane markers and a significant increase in the release of fibronectin. The maximum effect of histamine was observed after an incubation of 12 to 24 h and a dose of 1 microM. The histamine effects were specific, since they were significantly inhibited by an H1-blocker, pyrilamine, used at a concentration of 10 microM. The effect of an H2-blocker (ranitidine, concentration of 10 microM) was inconstant. Cycloheximide blocked the histamine effects, suggesting that it requires protein synthesis for its action. This study provides an in vitro model of cellular interaction between mast cells and AM, which might be relevant in the airway inflammation in asthma.

Adult↗
PubMed1995

Modulation of phenotypic expression of fibroblasts by alteration of the cytoskeleton.

Several studies indicate that the cytoskeleton may be involved in modulating the cellular response to environmental signals. We have studied the role of the cytoskeleton in regulating glycosaminoglycan (GAG) synthesis and secretion, hyaluronate (HA) endocytosis, the activities of hexoglycosidases, protein synthesis and secretion. Fibroblasts were treated with colchicine (1-8 microM) and nocodazole (1 or 4 microM) to alter microtubules or cytochalasin B (0.5-4 microM) to alter microfilaments. Colchicine inhibited GAG synthesis and secretion in a concentration-dependent manner. It reduced protein and sulphated GAG secretion, while HA secretion was not affected. Concentration-dependent disruption of microtubules from the periphery toward the cellular centre with nocodazole inhibited only the secretion of GAG. Centrosomal microtubles appeared to be required to promote GAG synthesis; intact microtubules promoted the transport of secretory products, intercompatmental transport of lysosomal enzymes and lysosome maturation, but not protein synthesis and HA secretion. Cytochalasin B treatment inhibited, in a concentration-dependent manner, the synthesis and secretion of GAGs and proteins, and the endocytosis of HA. Intact microfilament meshworks appeared to be required to promote synthesis and secretion of proteins and proteoglycans and to contribute to the transmembrane control of receptor-mediated endocytosis. Drug treatment of concanavalin A (Con A)-stimulated fibroblasts inhibited the stimulation of GAG synthesis. It is probable that this effect may result, in part, from drug-induced effects on Con A-mediated endocytosis.

Animals↗
PubMed2001

PKCepsilon activation induces dichotomous cardiac phenotypes and modulates PKCepsilon-RACK interactions and RACK expression.

Receptors for activated C kinase (RACKs) have been shown to facilitate activation of protein kinase C (PKC). However, it is unknown whether PKC activation modulates RACK protein expression and PKC-RACK interactions. This issue was studied in two PKCepsilon transgenic lines exhibiting dichotomous cardiac phenotypes: one exhibits increased resistance to myocardial ischemia (cardioprotected phenotype) induced by a modest increase in PKCepsilon activity (228 +/- 23% of control), whereas the other exhibits cardiac hypertrophy and failure (hypertrophied phenotype) induced by a marked increase in PKCepsilon activity (452 +/- 28% of control). Our data demonstrate that activation of PKC modulates the expression of RACK isotypes and PKC-RACK interactions in a PKCepsilon activity- and dosage-dependent fashion. We found that, in mice displaying the cardioprotected phenotype, activation of PKCepsilon enhanced RACK2 expression (178 +/- 13% of control) and particulate PKCepsilon-RACK2 protein-protein interactions (178 +/- 18% of control). In contrast, in mice displaying the hypertrophied phenotype, there was not only an increase in RACK2 expression (330 +/- 33% of control) and particulate PKCepsilon-RACK2 interactions (154 +/- 14% of control) but also in RACK1 protein expression (174 +/- 10% of control). Most notably, PKCepsilon-RACK1 interactions were identified in this line. With the use of transgenic mice expressing a dominant negative PKCepsilon, we found that the changes in RACK expression as well as the attending cardiac phenotypes were dependent on PKCepsilon activity. Our observations demonstrate that RACK expression is dynamically regulated by PKCepsilon and suggest that differential patterns of PKCepsilon-RACK interactions may be important determinants of PKCepsilon-dependent cardiac phenotypes.

Amino Acid Sequence↗
PubMed2001

Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression.

cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.

Animals↗
PubMed1989

Potential mechanisms for coordinate gene activation in the rheumatoid synoviocyte: implications and hypotheses.

Evidence is reviewed to support the concept that synovial cells in rheumatoid arthritis have undergone distinctive alterations at the cellular and subcellular level that result in their taking on some of the characteristics that are also manifest by transformed cells. These phenotypic modulations could be indirectly driven by cytokines in a paracrine or autocrine fashion. Specific regional patterns of cell phenotype modulation were used to argue against a simple widely diffusing direct inductive effect to cytokines and in favor of microenvironmental determinants. It is hypothesized that these extracellular factors induce novel activation in a coordinate manner by acting through master regulatory genes operating in cells with specific microenvironmental interactions. Two of these regulatory genes, fos and jun, are discussed in detail because of their induction by growth factors and their central role in the transactivation of genes which have been implicated in rheumatoid synovitis. A model for gene activation in the rheumatoid synovium is proposed based on the premise that fos and jun are an important link in the intracellular transduction pathways used by cytokines to induce cellular phenotypic changes.

Animals↗
PubMed1980

Tumorigenicity of human malignant melanocytes in nude mice in relation to their differentiation in vitro.

Of 16 cell lines derived from 12 human melanomas obtained from 11 patients, all were established as permanent cell lines: 7 from primary tumors and 9 from metastatic tumors. Study of the early subcultures and established cell lines showed that melanocytes passed through a phase of dedifferentiation during which they took on a fibroblast-like appearance and were hypodiploid and nontumorigenic in nude (thymus-deficient) mice. Phenotypic modulation in vitro was shown to be dependent on the culture medium. The lines varied considerably in karyologic and phenotypic expression (as assessed by morphologic appearance and 5-S-cysteinyldopa production). Fibroblast-like, epithelioid, nonpigmented, achromic, and pigmented cells were obtained from the same tumor. Heterotransplantation into nude mice revealed wide variations in tumorigenicity: The latency of the tumors, their size, and infrequent metastases bore no relationship to the phenotypic modulation of the melanocytes as expressed in vitro. Melanogenesis is therefore not related to malignancy; they are two independent characteristics.

Animals↗
PubMed1999

Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery.

The GATA-6 transcription factor is expressed in quiescent vascular smooth muscle cells (VSMCs) in culture, and levels of its transcript are rapidly downregulated on mitogen stimulation. In this study, we demonstrate that the GATA-6 transcript, protein, and DNA-binding activity are downregulated in rat carotid arteries on balloon injury. Downregulation was detected at 1 and 3 days after injury and recovered by 7 days. To assess the role of GATA-6 downregulation in injury-induced vascular lesion formation, adenoviral vectors were used to express wild-type human GATA-6 cDNA (Ad-GATA6) or an inactive mutant cDNA that lacks a portion of the zinc-finger domain (Ad-GATA6DeltaZF). Adenovirus-mediated GATA-6 gene transfer to the vessel wall after balloon injury partially restored the levels of GATA-6 protein and DNA-binding activity to before injury levels. The local delivery of Ad-GATA6 but not Ad-GATA6DeltaZF inhibited lesion formation by 46% relative to saline control and 50% relative to a control adenovirus that expressed lacZ. Local delivery of Ad-GATA6 also reversed changes in the expression patterns of smooth muscle myosin heavy chain, smooth muscle alpha-actin, calponin, vinculin, metavinculin, and proliferating cell nuclear antigen that are associated with injury-induced VSMC phenotypic modulation. These data indicate that the injury-induced downregulation of GATA-6 is an essential feature of VSMC phenotypic modulation that contributes to vessel lesion formation.

Adenoviridae↗
PubMed1990

Corneal endothelium modulation factor released by polymorphonuclear leukocytes. Partial purification and initial characterization.

Polymorphonuclear leukocytes produce a polypeptide factor that is released into the medium. This factor is partially purified 83-fold by ammonium sulfate precipitation followed by chromatography on a DEAE-Sephadex or heparin-Sepharose column. The partially purified factor is trypsin-sensitive. This factor affects a population of rabbit corneal endothelial cells by modulating them to fibroblastlike cells and by further stimulating their growth, leading to the formation of colonies of multilayered modulated cells. There is a dose-dependent phenotypic modulation of corneal endothelial cells by the partially purified corneal endothelium modulation factor (CEMF); cell shape is changed and type I collagen synthesis is increased with greater concentrations of CEMF. Since the fully modulated endothelial cells have collagen phenotypes distinct from those of normal cells, collagen synthesized by the first-passaged cells (a mixture of normal and modulated cells) was determined by immunoblot analysis with antibodies specific against types I and IV collagens. The first-passaged cells, in the presence of CEMF, contained a large amount of type I collagen (modulated phenotype) and a dramatically reduced amount of type IV collagen (physiologic type), whereas the normal endothelial cells demonstrated strongly positive staining only with antibodies to type IV collagen. Using cloned cDNA probes, the relative quantities of the transcripts of these collagens were determined by slot-blot hybridization; the first-passaged cells contained type IV collagen RNA in an amount similar to the normal cells, but a slightly larger amount of type I mRNA. These results demonstrate a functional involvement of a protein factor released by polymorphonuclear leukocytes in modulating cell shape and collagen gene expression in corneal endothelial cells.

Animals↗
PubMed1998

Airway smooth muscle cell proliferation: characterization of subpopulations by sensitivity to heparin inhibition.

Growth and maturation state of airway smooth muscle cells (SMCs) are determinants of asthma pathophysiology. Heparin reduces airway SMC proliferation and arterial SMC replication and phenotypic modulation. Distinct arterial SMC subtypes, differing in heparin sensitivity, have been characterized. We assessed the cellular mechanisms underlying the growth and phenotype of heparin-treated canine tracheal myocytes in primary culture. Heparin reduced replication by 40%. Immunoblot assay of myosin, actin, and myosin light chain kinase revealed heparin had no effect on rapid spontaneous phenotypic modulation after the cells were plated. Heparin increased cellular protein and vimentin contents in confluent cultures, suggesting that it may induce hypertrophic growth. Cell cycle analysis revealed that heparin decreased serum-stimulated replicating myocyte number by 40%. Also, G2-M transit was 20% slower for the set of SMCs that proceeded past G1 in the presence of heparin. These data indicate that heparin does not inhibit airway SMC replication by blocking modulation from the contractile state. Moreover, airway smooth muscle is composed of distinct SMC populations differing in mitogen and antiproliferative mediator responsiveness. Identification of functionally divergent subgroups suggests that distinct sets of SMCs may contribute differentially to airway physiology and pathophysiology.

Animals↗
PubMed2000

Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury.

While it is well established that phenotypic modulation of vascular smooth muscle cells (VSMCs) contributes to the development and progression of vascular lesions, little is known regarding the molecular mechanisms of phenotypic modulation in vivo. Here we show that vascular injury reduces transcription of VSMC differentiation marker genes, and we identify cis regulatory elements that may mediate this decrease. Using a carotid wire-injury model in mice carrying transgenes for smooth muscle alpha-actin, smooth muscle myosin heavy chain, or a SM22alpha promoter-beta-gal reporter, we collected arteries 7 and 14 days after injury and assessed changes in endogenous protein and mRNA levels and in beta-gal activity. Endogenous levels for all markers were decreased 7 days after injury and returned to nearly control levels by 14 days. beta-gal staining in all lines followed a similar pattern, suggesting that transcriptional downregulation contributed to the injury-induced decreases. To begin to dissect this response, we mutated a putative G/C-rich repressor in the SM22alpha promoter transgene and found that this mutation significantly attenuated injury-induced downregulation. Hence, transcriptional downregulation contributes to injury-induced decreases in VSMC differentiation markers, an effect that may be partially mediated through a G/C-rich repressor element.

Actins↗
PubMed1992

Modulation of phenotype and cytoskeleton architecture by interleukin-1 alpha in human osteoblast-like cells in vitro.

Interleukin-1 alpha, a growth factor produced by macrophages as well as many other types of cells, is able to modulate biosynthetic activities in bone cells. In this work, the authors show that the administration of interleukin-1 alpha to osteoblast-like cells in vitro induces a marked change in cell morphology, which becomes dendritic, with a smaller cellular body and numerous prolongations. The morphological changes are also accompanied by an altered expression in the pattern of cytoskeleton proteins.

Cells, Cultured↗
PubMed1990

Effect of interleukin-1 beta on the production of cathepsin B by rabbit articular chondrocytes.

Rabbit articular chondrocytes in monolayer culture were stimulated with human recombinant interleukin-1 beta. Under the influence of the cytokine the intracellular pool of the cysteine endopeptidase cathepsin B was increased by a 2-4-fold factor, while enzyme secretion was not stimulated at a significant level. Under the same conditions, the secretion of collagenase, measured as an internal control, was stimulated about 6-fold. The effects of interleukin-1 beta were compared to those caused by phenotypic modulation. Chondrocytes modulated by serial subcultures in monolayer secreted more cathepsin B, but less collagenase than differentiated cells (cultured within collagen gels). Thus, interleukin-1 beta and phenotypic modulation affected differently two endopeptidases which are relevant in the pathogenesis of osteoarthritis.

Animals↗
PubMed2003

Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis development.

During atheromatous plaque formation or restenosis after angioplasty, smooth muscle cells (SMCs) migrate from the media toward the intima, where they proliferate and undergo phenotypic changes. The mechanisms that regulate these phenomena and, in particular, the phenotypic modulation of intimal SMCs have been the subject of numerous studies and much debate during recent years. One view is that any SMCs present in the media could undergo phenotypic modulation. Alternatively, the seminal observation of Benditt and Benditt that human atheromatous plaques have the features of a monoclonal or an oligoclonal lesion has led to the hypothesis that a predisposed, medial SMC subpopulation could play a crucial role in the production of intimal thickening. The presence of a distinct SMC population in the arterial wall implies that under normal conditions, SMCs are phenotypically heterogeneous. The concept of SMC heterogeneity is gaining wider acceptance, as shown by the increasing number of publications on this subject. In this review, we discuss the in vitro studies that demonstrate the presence of distinct SMC subpopulations in arteries of various species, including humans. Their specific features and their regulation will be highlighted. Finally, the relevance of an atheroma-prone phenotype to intimal thickening formation will be discussed.

Animals↗
PubMed2006

Bordetella bronchiseptica modulates macrophage phenotype leading to the inhibition of CD4+ T cell proliferation and the initiation of a Th17 immune response.

Bordetella bronchiseptica is a Gram-negative bacterium equipped with several colonization factors that allow it to establish a persistent infection of the murine respiratory tract. Previous studies indicate that B. bronchiseptica adenylate cyclase toxin (ACT) and the type III secretion system (TTSS) synergize to drive dendritic cells into an altered phenotype to down-regulate the host immune response. In this study, we examined the effects of B. bronchiseptica ACT and TTSS on murine bone marrow-derived macrophages. We demonstrate that ACT and TTSS are required for the inhibition of Ag-driven CD4+ T cell proliferation by bacteria-infected macrophages. We identify PGE2 as the mediator of this inhibition, and we show that ACT and the TTSS synergize to increase macrophage production of PGE2. We further demonstrate that B. bronchiseptica can modulate normal macrophage function and drive the immune response toward a Th17 phenotype classified by the significant production of IL-17. In this study, we show that B. bronchiseptica-infected macrophages can induce IL-17 production from naive CD4+ splenocytes, and that lung tissues from B. bronchiseptica-infected mice exhibit a strong Th17 immune response. ACT inhibited surface expression of CD40 and CD86, suppressed TNF-alpha production, and up-regulated IL-6 production. TTSS also synergized with ACT to up-regulate IL-10 and PGE2 secretion. These findings indicate that persistent colonization by B. bronchiseptica may rely on the ability of the bacteria to differentially modulate both macrophage and dendritic cell function leading to an altered adaptive immune response and subsequent bacterial colonization.

Adenylate Cyclase Toxin↗
PubMed2006

[The role of SM22 alpha in cytoskeleton organization and vascular remodeling].

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a key role in vascular remodeling diseases, such as atherosclerosis, hypertension and restenosis. Recent researches have focused on the expression regulation of VSMC-specific marker genes and cytoskeleton organization in association with phenotypic modulation of VSMCs. Smooth muscle 22 alpha (SM22 alpha) is a novel differentiated VSMC marker, which is characterized by its smooth muscle tissue-specific and VSMC phenotype-specific expression pattern, and serves as an actin-association protein to participate in VSMC cytoskeleton organization and vascular remodeling. This article reviews recent advances in the characterization of SM22 alpha structure and its mechanism in VSMC cytoskeleton organization and vascular remodeling.

Cells, Cultured↗
PubMed1983

Sézary cells with an unusual phenotype, their modulation with 12-O-tetradecanoyl phorbol-13-acetate (TPA) in vitro, and their relationship to T-cell development.

Leukemic cells from a patient with Sézary syndrome were studied with a panel of monoclonal antibodies. Despite their typical morphology, the cells expressed an unusual surface phenotype. They simultaneously expressed OKT4 and OKT8 reactivity, indicating a more immature origin of the neoplastic cells than what has previously been observed in Sézary syndrome, but they were OKT6 negative. In response to 12-O-tetradecanoyl phorbol-13-acetate (TPA) the cells underwent phenotypic alterations, as the OKT4 reactivity was significantly reduced and the OKT8 expression was retained. Thus, following TPA, the cells expressed a surface phenotype consistent with the cytotoxic/suppressor T-cell subset in normal peripheral blood. The findings are discussed in relation to normal T-cell maturation and differentiation processes.

Aged↗
PubMed2006

Alpha 8 integrin expression is required for maintenance of the smooth muscle cell differentiated phenotype.

OBJECTIVE: Vascular smooth muscle cell (VSMC) de-differentiation is a prerequisite for migration from the tunica media to the intima after vascular injury. Integrin cell adhesion molecules participate in VSMC phenotype modulation. Alpha 8 beta 1 integrin is a differentiation marker of VSMCs and its knockdown heightens migration. In the present study, we examined whether or not alpha 8 integrin is required for the maintenance of VSMC differentiated phenotype. METHODS: Alpha 8 integrin in rat VSMC was knocked down by short interference RNA (siRNA) targeting alpha 8 integrin in comparison to a non-silencing siRNA. Cytoskeletal and morphological changes in VSMC were examined by immunofluorescence staining. The expression of phenotype-dependent markers was analyzed by immunoblotting. RESULTS: Alpha 8 integrin gene silencing evoked drastic changes in characteristics of the VSMC differentiated phenotype, including VSMC morphology, actin fibre organization, focal adhesion assembly and the expression of phenotype-dependent markers in favor of de-differentiation. Then, we investigated whether or not phenotype modulation induced by alpha 8 integrin gene silencing could be reversed by an inducer of VSMC differentiation. Transforming growth factor-beta (TGF-beta) failed to upregulate smooth muscle-myosin heavy chain as well as the assembly of parallel actin fibres in VSMCs transfected by siRNA-alpha 8. In addition, TGF-beta-induced vinculin localization at the tip of the cells was impaired by alpha 8 integrin gene silencing. CONCLUSION: These data suggest that alpha 8 integrin expression is required for maintenance of the VSMC differentiated phenotype, a state that is crucial for non-motile VSMCs.

Actins↗