共查询到20条相似文献,搜索用时 15 毫秒
1.
D. Nikitovic M. Mytilinaiou Ai. Berdiaki N.K. Karamanos G.N. Tzanakakis 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
The solid melanoma tumor consists of transformed melanoma cells, and the associated stromal cells including fibroblasts, endothelial cells, immune cells, as well as, soluble macro- and micro-molecules of the extracellular matrix (ECM) forming the complex network of the tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are an important component of the melanoma tumor ECM. Importantly, there appears to be both a quantitative and a qualitative shift in the content of HSPGs, in parallel to the nevi–radial growth phase–vertical growth phase melanoma progression. Moreover, these changes in HSPG expression are correlated to modulations of key melanoma cell functions.Scope of review
This review will critically discuss the roles of HSPGs/heparin in melanoma development and progression.Major conclusions
We have correlated HSPGs' expression and distribution with melanoma cell signaling and functions as well as angiogenesis.General significance
The current knowledge of HSPGs/heparin biology in melanoma provides a foundation we can utilize in the ongoing search for new approaches in designing anti-tumor therapy. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. 相似文献2.
Background
Thyroid hormone receptors TRα1, TRβ1 and TRβ2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function.Scope of review
The purpose of the review is to discuss two puzzling issues:- –
- The isoform specificity problem: the different functions of TRα1, TRβ1 and TRβ2 might reflect either their different distribution in tissues or differences in the receptor intrinsic properties.
- –
- The cell-specificity problem: one would expect that different cell types share a common repertoire of TR target genes, but current knowledge does not support this assumption. How TR function is affected by the cellular context is an unsolved question.
Major conclusions
Mouse genetics support a balanced contribution of expression pattern and receptor intrinsic properties in defining the receptor respective functions. The molecular mechanisms sustaining cell specific response remain hypothetical and based on studies performed with other nuclear receptors.General significance
The isoform-specificity and cell-specificity questions have many implications for clinical research, drug development, and endocrine disruptor studies. This article is part of a Special Issue entitled Thyroid hormone signalling. 相似文献3.
Winnok H. De Vos Frederik Houben Ron A. Hoebe Raoul Hennekam Baziel van Engelen Erik M.M. Manders Frans C.S. Ramaekers Jos L.V. Broers Patrick Van Oostveldt 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
The nuclear lamina provides structural support to the nucleus and has a central role in defining nuclear organization. Defects in its filamentous constituents, the lamins, lead to a class of diseases collectively referred to as laminopathies. On the cellular level, lamin mutations affect the physical integrity of nuclei and nucleo-cytoskeletal interactions, resulting in increased susceptibility to mechanical stress and altered gene expression.Methods
In this study we quantitatively compared nuclear deformation and chromatin mobility in fibroblasts from a homozygous nonsense LMNA mutation patient and a Hutchinson–Gilford progeria syndrome patient with wild type dermal fibroblasts, based on the visualization of mCitrine labeled telomere-binding protein TRF2 with light-economical imaging techniques and cytometric analyses.Results
Without application of external forces, we found that the absence of functional lamin A/C leads to increased nuclear plasticity on the hour and minute time scale but also to increased intranuclear mobility down to the second time scale. In contrast, progeria cells show overall reduced nuclear dynamics. Experimental manipulation (farnesyltransferase inhibition or lamin A/C silencing) confirmed that these changes in mobility are caused by abnormal or reduced lamin A/C expression.Conclusions
These observations demonstrate that A-type lamins affect both nuclear membrane and telomere dynamics.General significance
Because of the pivotal role of dynamics in nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development. 相似文献4.
Background
The small GTPase Ran, Ras-related nuclear protein, plays important roles in multiple fundamental cellular functions such as nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, by binding to either GTP or GDP as a molecular switch. Although it has been clinically demonstrated that Ran is highly expressed in multiple types of cancer cells and specimens, the physiological significance of Ran expression levels is unknown.Methods
During the long-term culture of normal mammalian cells, we found that the endogenous Ran level gradually reduced in a passage-dependent manner. To examine the physiological significance of Ran reduction, we first performed small interfering RNA (siRNA)-mediated abrogation of Ran in human diploid fibroblasts.Results
Ran-depleted cells showed several senescent phenotypes. Furthermore, we found that nuclear accumulation of importin α, which was also observed in cells treated with siRNA against CAS, a specific export factor for importin α, occurred in the Ran-depleted cells before the cells showed senescent phenotypes. Further, the CAS-depleted cells also exhibited cellular senescence. Indeed, importin α showed predominant nuclear localisation in a passage-dependent manner.Conclusions
Reduction in Ran levels causes cytoplasmic decrease and nuclear accumulation of importin α leading to cellular senescence in normal cells.General significance
The amount of intracellular Ran may be critically related to cell fate determination, such as malignant transformation and senescence. The cellular ageing process may proceed through gradual regression of Ran-dependent nucleocytoplasmic transport competency. 相似文献5.
Background
Chondroitin sulfate proteoglycans (CSPGs) are principal pericellular and extracellular components that form regulatory milieu involving numerous biological and pathophysiological phenomena. Diverse functions of CSPGs can be mainly attributed to structural variability of their polysaccharide moieties, chondroitin sulfate glycosaminoglycans (CS-GAG). Comprehensive understanding of the regulatory mechanisms for CS biosynthesis and its catabolic processes is required in order to understand those functions.Scope of review
Here, we focus on recent advances in the study of enzymatic regulatory pathways for CS biosynthesis including successive modification/degradation, distinct CS functions, and disease phenotypes that have been revealed by perturbation of the respective enzymes in vitro and in vivo.Major conclusions
Fine-tuned machineries for CS production/degradation are crucial for the functional expression of CS chains in developmental and pathophysiological processes.General significance
Control of enzymes responsible for CS biosynthesis/catabolism is a potential target for therapeutic intervention for the CS-associated disorders. 相似文献6.
7.
Manaswini Sivaramakrishnan Abhishek S. Kashyap Beat Amrein Stefanie Saenger Sonja Meier Christian Staudenmaier Zee Upton Friedrich Metzger 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some of these functions involve regulation by the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, the functions and exact nature of these interactions remain incomplete.Methods
IGF-I variants PEGylated at lysines K27, K65 and K68, were assessed for binding to IGFBPs using BIAcore, and for phosphorylation of the IGF-IR. Furthermore, functional consequences of PEGylation were investigated using cell viability and migration assays. In addition, downstream signaling pathways were analyzed using phospho-AKT and phospho-ERK1/2 assays.Results
IGF-I PEGylated at lysines 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) was employed. Receptor phosphorylation was similarly reduced 2-fold with PEG-K65 and PEG-K68 in 3T3 fibroblasts and MCF-7 breast cancer cells, whereas PEG-K27 showed a more than 10- and 3-fold lower activation for 3T3 and MCF-7 cells, respectively. In addition, all PEG-IGF-I variants had a 10-fold reduced association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes, whereas cell viability was fully preserved. Analysis of downstream signaling revealed that AKT was preferentially affected upon treatment with PEG-IGF-I variants whereas MAPK signaling was unaffected by PEGylation.Conclusion
PEGylation of IGF-I has an impact on cell migration but not on cell viability.General significance
PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on receptor interaction as well as key extracellular proteins such as VN and IGFBPs. 相似文献8.
Background
Hematopoietic stem cell (HSC) niche of the BM provides a specialized microenvironment for the regulation of HSCs. The strict control of HSCs by the niche coordinates the balance between the proliferation and the differentiation of HSCs for the homeostasis of the blood system in steady states and during stress hematopoiesis. The osteoblastic and vascular niches are the classically identified constituents of the BM niche.Scope of review
Recent research broadens our understanding of the BM niche as an assembly of multiple niche cells within the BM. We provide an overview of the HSC niche aiming to delineate the defined and possible niche cell interactions which collectively modulate the HSC integrity.Major conclusions
Multiple cells in the BM, including osteoblasts, vascular endothelia, perivascular mesenchymal cells and HSC progeny cells, function conjunctively as niche cells to regulate HSCs.General significance
The study of HSC niche cells and their functions provides insights into stem cell biology and also may be extrapolated into the study of cancer stem cells. This article is part of a Special Issue entitled Biochemistry of Stem Cells. 相似文献9.
Background
Snake venoms are rich in Kunitz-type protease inhibitors that may have therapeutic applications. However, apart from trypsin or chymotrypsin inhibition, the functions of most of these inhibitors have not been elucidated. A detailed functional characterization of these inhibitors may lead to valuable drug candidates.Methods
A Kunitz-type protease inhibitor, named DrKIn-II, was tested for its ability to inhibit plasmin using various approaches such as far western blotting, kinetic analyses, fibrin plate assay and euglobulin clot lysis assay. In addition, the antifibrinolytic activity of DrKIn-II was demonstrated in vivo.Results
DrKIn-II potently decreased the amidolytic activity of plasmin in a dose-dependent manner, with a global inhibition constant of 0.2 nM. Inhibition kinetics demonstrated that the initial binding of DrKIn-II causes the enzyme to isomerize, leading to the formation of a much tighter enzyme-inhibitor complex. DrKIn-II also demonstrated antifibrinolytic activity in fibrin plate assay and significantly prolonged the lysis of the euglobulin clot. Screening of DrKIn-II against a panel of serine proteases indicated that plasmin is the preferential target of DrKIn-II. Furthermore, DrKIn-II treatment prevented the increase of FDP in coagulation-stimulated mice and significantly reduced the bleeding time in a murine tail bleeding model.Conclusion
DrKIn-II is a potent, slow and tight-binding plasmin inhibitor that demonstrates antifibrinolytic activity both in vitro and in vivo.General significance
This is the first in-depth functional characterization of a plasmin inhibitor from a viperid snake. The potent antifibrinolytic activity of DrKIn-II makes it a potential candidate for the development of novel antifibrinolytic agents. 相似文献10.
Junyan Han Myung Shin Han Ching-Hsuan Tung 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Mitochondria, powerhouses of cells, are responsible for many critical cellular functions, such as cell energy metabolism, reactive oxygen species production, and apoptosis regulation. Monitoring mitochondria morphology in live cells temporally and spatially could help with the understanding of the mechanisms of mitochondrial functional regulation and the pathogenesis of mitochondria-related diseases.Methods
A novel non-cytotoxic fluorogenic compound, AcQCy7, was developed as a mitochondria-specific dye.Results
AcQCy7 emitted no fluorescent signal outside of cells, but it became fluorescent after intracellular hydrolysis of the acetyl group. The hydrolyzed fluorescent product was well retained in mitochondria, enabling long-lasting fluorescence imaging of mitochondria without cell washing. A 2-day culture study using AcQCy7 showed no sign of cytotoxicity, whereas a commonly used mitochondria-staining probe, Mitochondria Tracker Green, caused significant cell death even at a much lower concentration. Apoptosis-causing mitochondria fission was monitored clearly in real time by AcQCy7.Conclusions
A simple add-and-read mitochondria specific dye AcQCy7 has been validated in various cell models. Bright mitochondria specific fluorescent signal in treated cells lasted several days without noticeable toxicity.General Significance
The probe AcQCy7 has been proofed to be a non-toxic agent for long-term mitochondria imaging. 相似文献11.
Aims
The aim of the present study was to identify the potential therapeutic effects of BH3-mimetic gossypol on melanoma cells with acquired resistance to BRAF inhibitors.Main methods
The IC50 values of gossypol were determined using MTT assays in three melanoma cell lines with different resistances to BRAF inhibitor. The effects of gossypol on three melanoma cell lines were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. The functional role of autophagy in gossypol-induced growth inhibition was investigated using siRNA-mediated knockdown of Beclin-1.Key findings
Gossypol retained its efficacy in BRAF-V600E melanoma clones with acquired resistance to BRAF inhibitors through a mechanism independent of MEK–ERK inhibition. Gossypol caused G2/M arrest in both BRAF mutant A375P and A375P/Mdr cells with high expression of p21Cip1, regardless of their drug resistance. Interestingly, we determined that the lack of gossypol-induced mitotic arrest in BRAF-WT-harboring SK-MEL-2 cells was associated with a low level of p21Cip1 expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol-sensitive cells and not in the gossypol-resistant SK-MEL-2 cells. In particular, alleviation of autophagy by knockdown of Beclin-1 partially caused a resistance to gossypol-induced cell cycle arrest at G2/M in BRAF-V600E cells with a concomitant decreased induction of apoptosis.Significance
Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor-resistant tumors, but a functional p21Cip1 is a prerequisite for a positive response to its clinical application. 相似文献12.
13.
Background
Mitochondria, essential to the cell homeostasis maintenance, are central to the intrinsic apoptotic pathway and their dysfunction is associated with multiple diseases. Recent research documents that microRNAs (miRNAs) regulate important signalling pathways in mitochondria, and many of these miRNAs are deregulated in various diseases including cancers.Scope of review
In this review, we summarise the role of miRNAs in the regulation of the mitochondrial bioenergetics/function, and discuss the role of miRNAs modulating the various metabolic pathways resulting in tumour suppression and their possible therapeutic applications.Major conclusions
MiRNAs have recently emerged as key regulators of metabolism and can affect mitochondria by modulating mitochondrial proteins coded by nuclear genes. They were also found in mitochondria. Reprogramming of the energy metabolism has been postulated as a major feature of cancer. Modulation of miRNAs levels may provide a new therapeutic approach for the treatment of mitochondria-related pathologies, including neoplastic diseases.General significance
The elucidation of the role of miRNAs in the regulation of mitochondrial activity/bioenergetics will deepen our understanding of the molecular aspects of various aspects of cell biology associated with the genesis and progression of neoplastic diseases. Eventually, this knowledge may promote the development of innovative pharmacological interventions. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. 相似文献14.
Yi Liang Jia Cheng Lin Kun Wang Yi Jie Chen Hong Hong Liu Rong Luan Shuai Jiang Tao Che Yong Zhao De Feng Li Da Cheng Wang Lin Guo Hui Sun 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
We have previously reported a novel fungal galectin Agrocybe aegerita lectin (AAL) with apoptosis-induced activity and nuclear migration activity. The importance of nuclear localization for AAL's apoptosis-induced activity has been established by mutant study. However, the mechanism remains unclear.Methods
We further investigated the mechanism using a previously reported carbohydrate recognition domain (CRD) mutant protein H59Q, which retained its nuclear localization activity but lost most of its apoptotic activity. The cell membrane-binding ability of recombinant AAL (rAAL) and H59Q was analyzed by FACS, and their cellular partners were identified by affinity chromatography and mass spectroscopy. Furthermore, the interaction of AAL and ligand was proved by mammalian two-hybrid and pull down assays. A knockdown assay was used to confirm the role of the ligand.Results
The apoptotic activity of AAL could be blocked by lactose. Mutant H59Q retained comparable cell membrane-binding ability to rAAL. Four cellular binding partners of AAL in HeLa cells were identified: glucose-regulated protein 78 (GRP78); mortality factor 4-like protein 1 (MRG15); elongation factor 2 (EEF2); and heat shock protein 70 (Hsp70). CRD region of AAL was required for the interaction between AAL/mutant AAL and MRG15. MRG15 knockdown increased the cells' resistance to AAL treatment.Conclusion
MRG15 was a nuclear ligand for AAL in HeLa cells. These data implied the existence of a novel nuclear pathway for the antitumor activity of fungal galectin AAL.General significance
These findings provide a novel explanation of AAL bioactivity and contribute to the understanding of mushroom lectins' antitumor activity. 相似文献15.
Steven B. Levery Catharina Steentoft Adnan HalimYoshiki Narimatsu Henrik ClausenSergey Y. Vakhrushev 《Biochimica et Biophysica Acta (BBA)/General Subjects》2015
Background
Global analyses of proteins and their modifications by mass spectrometry are essential tools in cell biology and biomedical research. Analyses of glycoproteins represent particular challenges and we are only at the beginnings of the glycoproteomic era. Some of the challenges have been overcome with N-glycoproteins and proteome-wide analysis of N-glycosylation sites is accomplishable today but only by sacrificing information of structures at individual glycosites. More recently advances in analysis of O-glycoproteins have been made and proteome-wide analysis of O-glycosylation sites is becoming available as well.Scope of review
Here we discuss the challenges of analysis of O-glycans and new O-glycoproteomics strategies focusing on O-GalNAc and O-Man glycoproteomes.Major conclusions
A variety of strategies are now available for proteome-wide analysis of O-glycosylation sites enabling functional studies. However, further developments are still needed for complete analysis of glycan structures at individual sites for both N- and O-glycoproteomics strategies.General significance
The advances in O-glycoproteomics have led to identification of new biological functions of O-glycosylation and a new understanding of the importance of where O-glycans are positioned on proteins. 相似文献16.
Aliza Hariton-Shalev Moran Shalev Noam Adir Edurad Belausov Miriam Altstein 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The pyrokinin/pheromone biosynthesis-activating neuropeptide (PK/PBAN) plays a major role in regulating a wide range of physiological processes in insects. The ubiquitous and multifunctional nature of the PK/PBAN peptide family raises many questions regarding the mechanisms by which these neuropeptides elicit their effects and the nature of the receptors that mediate their functions.Methods
A sex pheromone gland receptor of the PK/PBAN family from Heliothis peltigera female moth and a Spodoptera littoralis larval receptor were cloned and stably expressed, and their structural models, electrostatic potentials and cellular functional properties were evaluated.Results
Homology modeling indicated highly conserved amino-acid residues in appropriate structural positions as experimentally shown for class A G-protein coupled receptors. Structural differences could be proposed and electrostatic potentials of the two receptor models revealed net charge differences. Calcium mobilization assays demonstrated that both receptors were fully functional and could initiate extracellular calcium influx to start PK/PBAN signal transduction. Evaluation of the signaling response of both receptors to PBAN and diapause hormone (DH) revealed a highly sensitive, though differential response. Both receptors responded to PBAN whereas only Spl-PK/PBAN-R exhibited a high response toward DH.Conclusions
The structural, electrostatic and cellular functional differences indicate that different PK/PBAN in vivo functions may be mediated by different PK/PBAN receptors and elicited by different peptide(s).General significance
The results advance our understanding of the mode of action of the PK/PBAN family, and might help in exploring novel high-affinity receptor-specific antagonists that can serve as a basis for the development of new families of insect-control agents. 相似文献17.
Isotta Chimenti Elvira Forte Francesco Angelini Elisa Messina Alessandro Giacomello 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Cardiac regenerative medicine is a rapidly evolving field, with promising future developments for effective personalized treatments. Several stem/progenitor cells are candidates for cardiac cell therapy, and emerging evidence suggests how multiple metabolic and biochemical pathways strictly regulate their fate and renewal.Scope of review
In this review, we will explore a selection of areas of common interest for biology and biochemistry concerning stem/progenitor cells, and in particular cardiac progenitor cells. Numerous regulatory mechanisms have been identified that link stem cell signaling and functions to the modulation of metabolic pathways, and vice versa. Pharmacological treatments and culture requirements may be exploited to modulate stem cell pluripotency and self-renewal, possibly boosting their regenerative potential for cell therapy.Major conclusions
Mitochondria and their many related metabolites and messengers, such as oxygen, ROS, calcium and glucose, have a crucial role in regulating stem cell fate and the balance of their functions, together with many metabolic enzymes. Furthermore, protein biochemistry and proteomics can provide precious clues on the definition of different progenitor cell populations, their physiology and their autocrine/paracrine regulatory/signaling networks.General significance
Interdisciplinary approaches between biology and biochemistry can provide productive insights on stem/progenitor cells, allowing the development of novel strategies and protocols for effective cardiac cell therapy clinical translation. This article is part of a Special Issue entitled Biochemistry of Stem Cells. 相似文献18.
Aldo Olivieri Keith F. Tipton Jeff O'Sullivan 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Primary-amine oxidase (PrAO) catalyzes the oxidative deamination of endogenous and exogenous primary amines and also functions, in some tissues, as an inflammation-inducible endothelial factor, known as vascular adhesion protein-1. VAP-1 mediates the slow rolling and adhesion of lymphocytes to endothelial cells in a number of inflammatory conditions, including inflammation of the synovium.Methods
Glucosamine binding to the enzyme was assessed spectrofluorometrically and the kinetics of inhibition of PrAO were determined spectrophotometrically through the use of direct or coupled assays, in the presence of different substrates.Results
Glucosamine is not a substrate for PrAO, but acts as a time-dependent inhibitor of PrAO activity, displaying mixed inhibition kinetics. The observed inhibition and binding were augmented in the presence of H2O2.Conclusions
Significant in vitro effects on PrAO require glucosamine in the millimolar concentration range and it is not clear at this stage whether a low but persistent level of PrAO inhibition might contribute to the anti-arthritic response.General significance
This work was aimed at characterizing the interactions of PrAO/VAP-1 with glucosamine, a widely used “over-the-counter” supplement for the treatment of osteoarthritis. 相似文献19.
Salomé S. Pinho Joana Figueiredo Joana Cabral Sandra Carvalho Joana Dourado Ana Magalhães Fátima Gärtner Ana Maria Mendonça Tomoya Isaji Jianguo Gu Fátima Carneiro Raquel Seruca Naoyuki Taniguchi Celso A. Reis 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013