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Results for “Phenotypic modulation”

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PubMed2002

Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies.

Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a conformational change and form amyloid fibrils, in both acquired and hereditary forms of systemic amyloidosis. More than 80 TTR mutations have been associated with autosomal dominant amyloidosis, usually presenting with peripheral and autonomic neuropathy and/or cardiomyopathy. Major areas of research in TTR amyloidosis include: molecular mechanisms leading to fibril formation; mechanisms of fibril-induced cell death; modulators of phenotypic expression of the disease; and therapeutic strategies.

Amyloid↗

PubMed1998

Two pimarane diterpenoids from Ephemerantha lonchophylla and their evaluation as modulators of the multidrug resistance phenotype.

Two new pimarane diterpenoids, lonchophylloids A (1) and B (2), were isolated from the stems of Ephemerantha lonchophylla. The structures of 1 and 2 were established predominantly through the application of extensive 1H-and 13C-NMR, 1D- and 2D-homonuclear and heteronuclear correlation NMR experiments, and X-ray diffraction methods. Consistent with structure--activity predictions, both compounds were capable of sensitizing cells that expressed the multidrug resistance phenotype to the toxicity of the anticancer drug doxorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders.

Many disease-causing point mutations do not seriously compromise synthesis of the affected polypeptide but rather exert their effects by impairing subsequent protein folding or stability of the folded protein. This often results in rapid degradation of the affected protein. The concepts of such 'conformational disease' are illustrated by reference to cystic fibrosis, phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up new therapeutic approaches.

Acyl-CoA Dehydrogenase↗

PubMed2000

Modulation of sulfated glycosaminoglycan and small proteoglycan synthesis by the extracellular matrix.

Cell culture in collagen lattice is known to be a more physiological model than monolayer for studying the regulation of extracellular matrix protein deposition. The synthesis of sulfated glycosaminoglycans (GAG) and dermatan sulfate (DS) proteoglycans by 3 cell strains were studied in confluent monolayers grown on plastic surface, in comparison to fully retracted collagen lattices. Cells were labelled with 35S-sulfate, followed by GAG and proteoglycan analysis by cellulose acetate and SDS-polyacrylamide gel electrophoresis, respectively. The 3 cell strains contracted the lattice in a similar way. In monolayer cultures, the major part of GAG was secreted into culture medium whereas in lattice cultures of dermal fibroblasts and osteosarcoma MG-63 cells but not fibrosarcoma HT-1080 cells, a higher proportion of GAGs, including dermatan sulfate, was retained within the lattices. Small DS proteoglycans, decorin and biglycan, were detected in fibroblasts and MG-63 cultures. They were preferentially trapped within the collagen gel. In retracted lattices, decorin had a higher Mr than in monolayer. Biglycan was detected in monolayer and lattice cultures of MG-63 cells but in lattice cultures only in the case of fibroblasts. In this last case, an up regulation of biglycan mRNA steady state level and down regulation of decorin mRNA was observed, in comparison to monolayers, indicating that collagen can modulate the phenotypical expression of small proteoglycan genes.

Adult↗

PubMed1997

Neuroendocrine correlates of emotional reactivity and coping in male rats from the Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance lines.

The Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance rats, originally selected and bred for rapid vs. poor acquisition of a two-way active avoidance response, differ in emotional reactivity and sensitivity to stressors in various other test situations. These behavioral differences are associated with particular neuroendocrine and neurochemical characteristics. The aim of this short review is to present data currently available on the neuroendocrine profiles of RHA/Verh and RLA/Verh rats, together with more recent findings which suggest that differences in peripheral and central hormonal responses, and in hormone action on the brain, may be closely related to emotional reactivity and coping ability. Although genetic factors certainly play a major role, there is also evidence that epigenetic factors, e.g., early environmental influences, can modulate the phenotypic expression of the basic behavioral and neuroendocrine traits characterizing these lines. These psychogenetically selected lines can therefore be used as a model to investigate interactions between genes and the environment in determining each individual's sensitivity to stress and coping abilities ("vulnerability" model). This model may prove particularly useful for studies on the etiology and pathophysiology of anxiety and affective disorders and their neuroendocrine correlates.

Adaptation, Psychological↗

PubMed1994

Epigenesis: the missing beat in biotechnology?

The range of human phenotypes/diseases for which our burgeoning bio-molecular data base is sufficient to provide understanding, diagnosis, and therapy is small. Only 2 percent of our total disease load is related to monogenic causality, and even here the final phenotype is modulated by many factors. Monogenic logic cannot, moreover, be applied to the 98 percent of our most important sources of premature disability and death. This article provides an analysis of the limits of genetic thinking in biotechnology and describes the outline for another approach to understanding complex cellular/physiological systems. In this outline, rules governing physiological regulation and cellular and higher levels of organization are located not in the genome, but in interactive epigenetic networks which themselves organize genomic response to environmental signaling.

Animals↗

PubMed2004

Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27.

Heat shock protein 27 (hsp-27) is a regulator of oestrogen receptor (ER) expression and a modulator of intracellular homeostasis. In this laboratory, Shaaban et al demonstrated the importance of ER-alpha, together with Ki67, in enhancing the progression of benign breast lesions of defined morphological types. To better understand the mechanisms by which ER-alpha promotes breast neoplasia, this study was performed to test the hypothesis that the roles of ER-alpha and hsp-27 may be defined by their quantitative expression in proliferative breast lesions of varying histological risk. The expression of hsp-27 was identified using a specific monoclonal antibody and analysed to assess the proportion of positive epithelial cells using digitised morphometric image analysis. The expression of ER-alpha was analysed by immunohistochemistry and Western blotting in a variety of benign (HUMA121) and malignant mammary cell lines, including ER-alpha(+) (MCF7, ZR-75, T47D) and ER-alpha(-) (MDA-MB 231) breast cancer cell lines. The data confirm that, during progression from normal through proliferative breast lesions to in situ cancer, there was a significant increase in both the proportion and the optical density of the epithelial cells expressing hsp-27. The mean levels of expression ranged from 7.4% of the total number of epithelial cells in normal lobules to 25.17% of epithelial cells in hyperplasias of usual type (HUT) to 61.1% of epithelial cells in ductal carcinoma in situ (P<0.001). The study has confirmed the expression of hsp-27 to be closely associated with ER-alpha(+) expression, and that its regulated expression occurs early along the mammary oncogenic pathway, supporting the initial hypothesis. It is our proposal that the differential expression of hsp-27 modulates the phenotypic behaviour of morphologically benign epithelial cells and hence may be an important determinant in initiating, or promoting, a population of human mammary cancers.

Biomarkers, Tumor↗

PubMed2006

Leukocytes in tubulointerstitial inflammation.

The work of Lange-Sperandio et al in this issue explores the differential role of beta2 integrins in promoting the macrophage infiltration characteristic of the obstructed kidneys of neonatal mice. Future work is needed to define factors that regulate macrophage death within or emigration from the kidney as well as to explore strategies to modulate macrophage phenotype. This knowledge will assist the development of novel therapeutic agents to limit injury and promote tissue repair.

Animals↗

PubMed2001

Schizophrenic women with the APOE epsilon 4 allele have a worse prognosis than those without it.

The epsilon 4 allele of APOE is generally accepted to be a risk factor in Alzheimer's disease and it has been related to other neuropsychiatric disorders, including schizophrenia. The results of several case-control studies have been inconclusive. To shed more light on this issue we carried out an association study that compared the APOE common variant in a group of 365 schizophrenia patients and 584 controls. We found no differences in the genotype distributions and allele frequencies of patients and controls. In the group of patients, we also analysed the possible influence of the epsilon 4 allele in the clinical variables. The most important findings are that the age at onset (AAO) of epsilon 4+ schizophrenic women, those that have one or two epsilon 4 alleles, is 4 years earlier than that of epsilon 4- women and their risk of suffering a negative syndrome subtype is four times greater. This was not found in schizophrenic men. Our results show that the APOE variant is not a risk factor for developing schizophrenia but that it may modulate its phenotypic expression in a sex-dependent manner.

Adult↗

PubMed2001

Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay.

Many p53 mutants found in human cancer have an altered ability to bind DNA and transactivate gene expression. Re-expression of functional p53 in cells in which the endogenous TP53 gene is inactivated has been demonstrated to restore a non-tumorigenic phenotype. Pharmacological modulation of p53 mutant conformation may therefore represent a mechanism to reactivate p53 function and consequently improve response to radio- and chemotherapy. We have recently reported that the radio- and chemoprotector Amifostine (WR2721, Ethyol) activates wild-type p53 in cultured mammalian cells. In the present study, we have used a yeast functional assay to investigate the effect of WR2721 on the transcriptional activity of p53. WR2721 restored this activity in a temperature-sensitive mutant V272M (valine to methionine at codon 272) expressed at the non-permissive temperature and it also partially restored the transcriptional activity of several other conformationally flexible p53 mutants. The results indicate that the yeast functional assay may be used to identify compounds that modulate p53 activity, with potential therapeutic implications.

Amifostine↗

PubMed2003

Genetic markers of disease susceptibility and severity in giant cell arteritis and polymyalgia rheumatica.

BACKGROUND AND OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are common and often overlapping diseases that generally occur in elderly patients. In this article, we examine the role of different genes as markers of disease susceptibility and severity in GCA and PMR. METHODS: The influence of human leukocyte antigen (HLA)-DRB1 and tumor necrosis factor alleles, as well as the different allelic polymorphisms, on the susceptibility and severity to GCA and PMR was examined. A review of the literature was conducted. RESULTS: Most studies have described an association of GCA with HLA-DRB1(*)04 alleles. However, HLA-DRB1 association in patients with PMR varies from one population to another. In Northwest Spain, patients with GCA and PMR exhibited different tumor necrosis factor microsatellite polymorphism associations. Studies of intercellular adhesion molecule-1 biallelic polymorphisms have yielded contradictory results. Interleukin 1 cluster and tumor necrosis factor alpha polymorphisms increased susceptibility to GCA and PMR slightly. In Northwest Spain, interleukin 6 promoter polymorphism at position -174 modulated the phenotypic expression of PMR in biopsy-proven GCA. In the same population, regulated upon activation, normal T cell expressed and presumably secreted gene promoter biallelic polymorphism at position -403 was a marker for PMR susceptibility but not for GCA, and corticotropin-releasing hormone polymorphism appeared to be implicated in the risk of severe ischemic complications in patients with GCA. CONCLUSIONS: The present analysis confirms that GCA and PMR are polygenic diseases. The search for additional genes is necessary to better understand the pathogenesis of these conditions.

Animals↗

PubMed2000

The endothelium and thrombosis.

Thrombosis reflects an imbalance between procoagulant and anticoagulant mechanisms. In some cases, thrombotic lesions are precipitated by gross changes in blood flow, vascular wall integrity, or systemic levels of coagulation factors. In other cases, thrombosis is induced by functional changes within the endothelium. Endothelial cells express a wide variety of factors that contribute to hemostasis, including procoagulants, anticoagulants, cell adhesion molecules, vasomotor substances, and cell survival signals. Because the endothelium displays a remarkable diversity of structure and function, the relative contribution of any one of these factors to the hemostatic balance varies between different vascular beds. In this review, we emphasize the heterogeneous nature of endothelial cell function. We then examine the role of endothelial diversity in modulating the phenotypic expression of thrombotic disorders.

Animals↗

PubMed2001

Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repair.

Nerve growth factor (NGF) is a polypeptide which, in addition to its effect on nerve cells, is believed to play a role in inflammatory responses and in tissue repair. Because fibroblasts represent the main target and effector cells in these processes, to investigate whether NGF is involved in lung and skin tissue repair, we studied the effect of NGF on fibroblast migration, proliferation, collagen metabolism, modulation into myofibroblasts, and contraction of collagen gel. Both skin and lung fibroblasts were found to produce NGF and to express tyrosine kinase receptor (trkA) under basal conditions, whereas the low-affinity p75 receptor was expressed only after prolonged NGF exposure. NGF significantly induced skin and lung fibroblast migration in an in vitro model of wounded fibroblast and skin migration in Boyden chambers. Nevertheless NGF did not influence either skin or lung fibroblast proliferation, collagen production, or metalloproteinase production or activation. In contrast, culture of both lung and skin fibroblasts with NGF modulated their phenotype into myofibroblasts. Moreover, addition of NGF to both fibroblast types embedded in collagen gel increased their contraction. Fibrotic human lung or skin tissues displayed immunoreactivity for NGF, trkA, and p75. These data show a direct pro-fibrogenic effect of NGF on skin and lung fibroblasts and therefore indicate a role for NGF in tissue repair and fibrosis.

Actins↗

PubMed1988

Purine metabolite inosine is an adrenergic neurotrophic substance for cultured chicken sympathetic neurons.

Purines are ubiquitous endogenous cellular metabolites that have been postulated as neurotransmitters or neuromodulators in the nervous system. Recently, we showed that a low-molecular-mass component present in liver-conditioned medium selectively enhances the adrenergic properties of dissociated chicken sympathetic neurons in culture. We report here that this substance is inosine, a purine metabolite. Indeed, analysis of the low-molecular-mass fraction of liver-conditioned medium by HPLC shows that the neurotrophic activity coelutes with and has the same absorption spectrum as inosine. Inosine increases incorporation of [3H]leucine into neuronal protein and stimulates catecholamine, but not acetylcholine, production by the sympathetic neurons in a dose-dependent fashion (half-maximal stimulation at 10(-6) M). This effect can be blocked by 5 x 10(-6) M dipyridamole, an inhibitor of nucleoside transport. Inosine therefore appears to be capable of modulating adrenergic phenotypic expression in cultured sympathetic neurons by acting via an as-yet-unknown intracellular pathway.

Animals↗

PubMed1994

Induction of differentiation in HL60 cells by the reduction of extrachromosomally amplified c-myc.

Oncogene amplification in tumor cells results in the overexpression of proteins that confer a growth advantage in vitro and in vivo. Amplified oncogenes can reside intrachromosomally, within homogeneously staining regions (HSRs), or extrachromosomally, within double minute chromosomes (DMs). Since previous studies have shown that low concentrations of hydroxyurea (HU) can eliminate DMs, we studied the use of HU as a gene-targeting agent in tumor cells containing extrachromosomally amplified oncogenes. In a neuroendocrine cell line (COLO 320), we have shown that HU can eliminate amplified copies of c-myc located on DMs, leading to a reduction in tumorigenicity in vitro and in vivo. To determine whether the observed reduction in tumorigenicity was due to differentiation, we next investigated whether HU could induce differentiation in HL60 cells containing extrachromosomally amplified c-myc. We compared the effects of HU, as well as two other known differentiating agents (dimethyl sulfoxide and retinoic acid), on c-myc gene copy number, c-myc expression, and differentiation in HL60 cells containing amplified c-myc genes either on DMs or HSRs. We discovered that HU and dimethyl sulfoxide reduced both c-myc gene copy number and expression and induced differentiation in cells containing c-myc amplified on DMs. These agents failed to have similar effects on HL60 cells with amplified c-myc in HSRs. By contrast, retinoic acid induced differentiation independent of the localization of amplified c-myc. These data illustrate the utility of targeting extrachromosomal DNA to modulate tumor phenotype and reveal that both HU and dimethyl sulfoxide induce differentiation in HL60 cells through DM elimination.

Cell Differentiation↗

PubMed2001

Sp3 represses the Sp1-mediated transactivation of the human COL2A1 gene in primary and de-differentiated chondrocytes.

Sp1 and Sp3 effects on the transcription of the human alpha1(II) procollagen gene (COL2A1) were investigated in both differentiated and de-differentiated rabbit articular chondrocytes. Transient transfection with constructs of deleted COL2A1 promoter sequences driving the luciferase reporter gene revealed that the region spanning -266 to +121 base pairs showed Sp1-enhancing effects, whatever the differentiation state. In contrast, Sp3 did not influence COL2A1 gene transcription. Concomitant overexpression of the two Sp proteins demonstrated that Sp3 blocked the Sp1 induction of COL2A1 promoter activity. Moreover, inhibition of Sp1/Sp3 binding to their target DNA sequence decreased both COL2A1 gene transcription and Sp1-enhancing effects. DNase I footprinting and gel retardation assays revealed that Sp1 and Sp3 bind specifically to cis-sequences of the COL2A1 gene promoter whereby they exert their transcriptional effects. Sp1 and Sp3 levels were found to be reduced in de-differentiated chondrocytes, as revealed by DNA-binding and immunochemical study. Sp1 specifically activated collagen neosynthesis whatever the differentiation state of chondrocytes, suggesting that this factor exerts a major role in the expression of collagen type II. However, our data indicate that type II collagen-specific expression in chondrocytes depend on both the Sp1/Sp3 ratio and cooperation of Sp1 with other transcription factors, the amounts of which are also modulated by phenotype alteration.

Amino Acid Motifs↗

PubMed2006

Calreticulin represses E-cadherin gene expression in Madin-Darby canine kidney cells via Slug.

Calreticulin (CRT) is a multifunctional Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. In mammals, the expression level of CRT differs markedly in a variety of organs and tissues, suggesting that CRT plays a specific role in each cell type. In the present study, we focused on CRT functions in the kidney, where overall expression of CRT is quite low, and established CRT-overexpressing kidney epithelial cell-derived Madin-Darby canine kidney cells by gene transfection. We demonstrated that, in CRT-overexpressing cells, the morphology was apparently changed, and the original polarized epithelial cell phenotype was destroyed. Furthermore, CRT-overexpressing cells showed enhanced migration through Matrigel-coated Boyden chamber wells, compared with controls. E-cadherin expression was significantly suppressed at the protein and transcriptional levels in CRT-overexpressing cells compared with controls. On the other hand, the expression of mesenchymal protein markers, such as N-cadherin and fibronectin, was up-regulated. We also found that the expression of Slug, a repressor of the E-cadherin promoter, was up-regulated by overexpression of CRT through altered Ca(2+) homeostasis, and this led to enhanced binding of Slug to the E-box element in the E-cadherin promoter. Thus, we conclude that CRT regulates the epithelial-mesenchymal transition-like change of cellular phenotype by modulating the Slug/E-cadherin pathway through altered Ca(2+) homeostasis in cells, suggesting a novel function of CRT in cell-cell interaction of epithelial cells.

Animals↗

PubMed2000

Growth factor-induced morphological, physiological and molecular characteristics in cerebral endothelial cells.

The capacity of vascular endothelial cells to modulate their phenotype in response to changes in environmental conditions is one of the most important characteristics of this cell type. Since different growth factors may play an important signalling role in this adaptive process we have investigated the effect of endothelial cell growth factor (ECGF) on morphological, physiological and molecular characteristics of cerebral endothelial cells (CECs). CECs grown in the presence of ECGF and its cofactor heparin exhibit an epithelial-like morphology (type I CECs). Upon removal of growth factors, CECs develop an elongated spindle-like shape (type II CECs) which is accompanied by the reorganization of actin filaments and the induction of alpha-actin expression. Since one of the most important functions of CECs is the creation of a selective diffusion barrier between the blood and the central nervous system (CNS), we have studied the expression of junction-related proteins in both cell types. We have found that removal of growth factors from endothelial cultures leads to the downregulation of cadherin and occludin protein levels. The loss of junctional proteins was accompanied by a significant increase in the migratory activity and an altered protease activity profile of the cells. TGF-beta1 suppressed endothelial migration in all experiments. Our data provide evidence to suggest that particular endothelial functions are largely controlled by the presence of growth factors. The differences in adhesiveness and migration may play a role in important physiological and pathological processes of endothelial cells such as vasculogenesis or tumor progression.

Actins↗