86 resultados para cell signalling
em QUB Research Portal - Research Directory and Institutional Repository for Queen's University Belfast
Resumo:
Internalization of cargo proteins and lipids at the cell surface occurs in both a constitutive and signal-regulated manner through clathrin-mediated and other endocytic pathways. Clathrin-coated vesicle formation is a principal uptake route in response to signalling events. Protein-lipid and protein-protein interactions control both the targeting of signalling molecules and their binding partners to membrane compartments and the assembly of clathrin coats. An emerging aspect of membrane trafficking research is now addressing how signalling cascades and vesicle coat assembly and subsequently disassembly are integrated.
Resumo:
Endogenous electric fields (EF) have long been known to influence cell behaviour during development, neural cell tropism, wound healing and cell behaviour generally. The effect is based on short circuiting of electrical potential differences across cell and tissue boundaries generated by ionic segregation. Recent in vitro and in vivo studies have shown that EF regulate not only cell movement but orientation of cells during mitosis, an effect which may underlie shaping of tissues and organs. The molecular basis of this effect is founded on receptor-mediated cell signalling events and alterations in cytoskeletal function as revealed in studies of gene deficient cells. Remarkably, not all cells respond directionally to EF in the same way and this has consequences, for instance, for lens development and vascular remodelling. The physical basis of EF effect may be related to changes induced in 'bound water' at the cell surface, whose organisation in association with trans-membrane proteins (e.g. receptors) is disrupted when EF are generated. Copyright © 2007 S. Karger AG.
Resumo:
Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic.
Resumo:
Radiotherapy is commonly planned on the basis of physical dose received by the tumour and surrounding normal tissue, with margins added to address the possibility of geometric miss. However, recent experimental evidence suggests that intercellular signalling results in a given cell's survival also depending on the dose received by neighbouring cells. A model of radiation-induced cell killing and signalling was used to analyse how this effect depends on dose and margin choices. Effective Uniform Doses were calculated for model tumours in both idealised cases with no delivery uncertainty and more realistic cases incorporating geometric uncertainty. In highly conformal irradiation, a lack of signalling from outside the target leads to reduced target cell killing, equivalent to under-dosing by up to 10% compared to large uniform fields. This effect is significantly reduced when higher doses per fraction are considered, both increasing the level of cell killing and reducing margin sensitivity. These effects may limit the achievable biological precision of techniques such as stereotactic radiotherapy even in the absence of geometric uncertainties, although it is predicted that larger fraction sizes reduce the relative contribution of cell signalling driven effects. These observations may contribute to understanding the efficacy of hypo-fractionated radiotherapy.
Resumo:
CCN3, a founding member of the CCN family of growth regulators, was linked with hematology in 2003(1) when it was detected in human serum. CCN3 is expressed and secreted by hematopoietic progenitor cells in normal bone marrow. CCN3 acts through the core stem cell signalling pathways including Notch and Bone Morphogenic Protein, connecting CCN3 with the modulation of self-renewal and maturation of a number of cell lineages including hematopoietic, osteogenic and chondrogenic. CCN3 expression is disrupted in Chronic Myeloid Leukemia as a consequence of the BCR-ABL oncogene and allows the leukemic clone to evade growth regulation. In contrast, naive cord blood progenitors undergo enhanced clonal expansion in response to CCN3. Altered CCN3 expression is associated with numerous solid tumors including glioblastoma, melanoma. adrenocortical tumours, prostate cancer and bone malignancies including osteosarcoma. Mature CCN3 protein has five distinct modules and truncated protein variants with altered function are found in many cancers. Regulation by CCN3 is therefore cell type and isoform specific. CCN3 has emerged as a key player in stem cell regulation, hematopoiesis and a crucial component within the bone marrow microenvironment. (c) 2008 Elsevier Ltd. All rights reserved.
Resumo:
TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T-ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T-ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T-ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T-ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology.
Resumo:
PURPOSE: FKBPL and its peptide derivative, AD-01, have already demonstrated tumour growth inhibition and CD44 dependent anti-angiogenic activity. Here we explore the ability of AD-01 to target CD44 positive breast cancer stem cells (BCSCs). EXPERIMENTAL DESIGN: Mammosphere assays and flow cytometry were utilized to analyse the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anti-cancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples and xenografts. Delays in tumour initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, qPCR and immunofluorescence. RESULTS: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere forming efficiency (MFE) and ESA+/CD44+/CD24- or ALDH+ cell subpopulations in vitro and tumour initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism appears to be due to AD-01-mediated BCSC differentiation demonstrated by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4 and Sox2, were also significantly reduced. Furthermore, we demonstrated additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signalling. CONCLUSIONS: AD-01 has dual anti-angiogenic and anti-BCSC activity which will be advantageous as this agent enters clinical trial.
Resumo:
Peptidyl prolyl isomerases (PPIases) are proteins belonging to the immunophilin family and are characterised by their cis-trans isomerization activity at the X-Pro peptide bond, in addition to their tetratricopeptide repeat (TPR) domain, important for interaction with the molecular chaperone, Hsp90. Due to this unique structure these proteins are able to facilitate protein-protein interactions which can impact significantly on a range of cellular processes such as cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis. Malfunction and/or dysregulation of most members of this class of proteins promotes cellular damage and tissue/organ failure, predisposing to ageing and age-related diseases. Many individual genes within the PPIase family are associated with several age-related diseases including cardiovascular diseases (CVDs), atherosclerosis, type II diabetes (T2D), chronic kidney disease (CDK), neurodegeneration, cancer and age-related macular degeneration (AMD), in addition to the ageing process itself. This review will focus on the different roles of PPIases, and their therapeutic/biomarker potential in these age-related vascular diseases.