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  • 1
    Abstract: Glioblastoma multiforme (GBM) is the most common malignant brain tumour in adults. One main source of its high malignancy is the invasion of isolated tumour cells into the surrounding parenchyma, which makes surgical resection an insufficient therapy in nearly all cases. The invasion is triggered by several cell surface receptors including receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), TGF-beta receptor, integrins, immunoglobulins, tumour necrosis factor (TNF) family, cytokine receptors, and protein tyrosine phosphatase receptors. The cross-talk between cell-surface receptors and the redundancy of downstream effectors make analysis of invasive signals even more complex. Therapies involving inhibition of single receptors do not give promising outcomes and a thorough knowledge of invasive signals of common and exclusive signalling components is required for design of best combinatory treatment schemes to fight the disease.
    Type of Publication: Journal article published
    PubMed ID: 19688773
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  • 2
    Abstract: Activation of the epidermal growth factor receptor (EGFR) has been shown to occur by ligand-dependent and ligand-independent mechanisms. Different molecular mechanisms have been found to be responsible for ligand-independent receptor transactivation. Here, we show that hyperosmolar concentrations of sorbitol activate the EGFR in human keratinocytes. Experiments using specific inhibitors of EGFR phosphorylation show that the increased amount of activated receptors is the result of a decreased rate of dephosphorylation. Furthermore, sorbitol treatment results in a strong activation of stress kinase p38. Treatment of the cells with SB203580, a known inhibitor of p38 alpha and beta kinases, results in impairment of receptor activation, indicating that the stress kinase is involved in receptor activation modulation. This is further reinforced by experiments showing that addition of Toxin B, known to be an inhibitor of the small Rho GTPases rac1, cdc42, and Rho A/B, to the cells results in a strong induction of EGFR activation. Our results point, therefore, to a mechanism by which osmotic shock activates EGFR through the small Rho GTPases-p38 stress kinase pathway.
    Type of Publication: Journal article published
    PubMed ID: 12115730
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  • 3
    Keywords: DIFFERENTIATION ; radiation ; IN-SITU HYBRIDIZATION ; INSTABILITY ; DOUBLE-STRAND BREAKS ; immortalization ; CELLULAR SENESCENCE ; HIGH-LET ; HUMAN-SKIN FIBROBLASTS ; LUNG FIBROBLASTS
    Abstract: To assess why during in vitro aging of fibroblasts the maintenance of chromosomal stability is effective or occasionally fails, a detailed cytogenetic analysis was performed in normal human IMR-90 fetal lung fibroblasts. The onset of senescence was inferred from proliferation activity, expression pattern of cell cycle regulating proteins, activity of beta-galactosidase, and morphological features. Over the period of proliferation, a moderate increase of non-transmissible structural chromosomal aberrations was observed. In addition, using fluorescence in situ hybridization (mFISH and mBAND) techniques, we detected clonally expanding translocations in up to 70% of the analyzed metaphases, all involving one homolog of chromosome 9 as an acceptor. Notably, chromosomes are randomly involved as donor-chromosomes of the translocated terminal acentric fragments. These fragments result from duplication because the donor chromosomes are apparently unchanged. Interstitial telomeric signals were detectable at fusion sites, most likely belonging to chromosome 9. Quantitative fluorescence in situ hybridization (QFISH) detecting telomere sequences, followed by mFISH technique revealed that already in young cells the respective telomeres of one chromosome 9 were particularly short. For the first time, we have observed dysfunctional telomeres of one specific chromosome in normal human cells that have been stabilized by duplicated terminal sequences.
    Type of Publication: Journal article published
    PubMed ID: 21732364
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  • 4
    Abstract: With an increasing number of endosomal cargo molecules studied, it is becoming clear that endocytic routes are diverse, and the cell uses more pathways to adjust expression of cell surface proteins. Intracellular itinerary of integral membrane proteins that avoid the early endosomal recycling route is not enough studied. Therefore, we studied endocytic trafficking of empty Ld (eLd ) molecules, an open form of murine MHC-I allele, in fibroblast-like cells. Pulse labeling of cell surface eLd with mAbs and internalization kinetics suggest two steps of endosomal recycling: rapid and late. The same kinetics was also observed for human open MHC-I conformers. Kinetic modeling, using in-house developed software for multicompartment analysis, colocalization studies and established protocols for enriched labeling of the late endosomal (LE) pool of eLd demonstrated that the late step of recycling occurs from an LE compartment. Although the majority of eLd distributed into pre-degradative multivesicular bodies (MVBs), these LE subsets were not a source for eLd recycling. The LE recycling of eLd did not require Rab7 membrane domains, as demonstrated by Rab7-silencing, but required vectorial LE motility, suggesting that LE recycling occurs from dynamic tubulovesicular LE domains prior segregation of eLd in MVBs. Thus, our study indicates that LE system should not be simply considered as a feeder for loading of the degradative tract of the cell but also as a feeder for loading of the plasma membrane and thereby contribute to the maintenance of homeostasis of plasma membrane proteins. J. Cell. Physiol. 232: 872-887, 2017. (c) 2016 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 27438986
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  • 5
    Keywords: APOPTOSIS ; EXPRESSION ; GROWTH ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; transcription ; IMPACT ; DOWN-REGULATION ; PROGRESSION ; METASTASIS ; E-cadherin ; TGF-BETA ; BREAST-CANCER CELLS ; MESENCHYMAL TRANSITION ; REPRESSORS ZEB1
    Abstract: The Forkhead family of transcription factors comprises numerous members and is implicated in various cellular functions, including cell growth, apoptosis, migration and differentiation.In this study we identified the Forkhead factor FoxQ1 as increased in expression during TGF-beta1 induced changes in epithelial differentiation, suggesting functional roles of FoxQ1 for epithelial plasticity.The repression of FoxQ1 in mammary epithelial cells led to a change in cell morphology characterized by an increase in cell size, pronounced cell-cell contacts and an increased expression of several junction proteins (e.g. E-cadherin). In addition, FoxQ1 knock-down cells revealed rearrangements in the actin-cytoskeleton and slowed down cell cycle G1-phase progression.Furthermore, repression of FoxQ1 enhanced the migratory capacity of coherent mammary epithelial cells.Gene expression profiling of NM18 cells indicated that FoxQ1 is a relevant downstream mediator of TGF-beta1 induced gene expression changes. This included the differential expression of transcription factors involved in epithelial plasticity, e.g. Ets-1, Zeb1 and Zeb2.In summary, this study has elucidated the functional impact of FoxQ1 on epithelial differentiation.
    Type of Publication: Journal article published
    PubMed ID: 20717954
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  • 6
    Keywords: EXPRESSION ; PROSTATE-CANCER ; BINDING-PROTEIN ; ESTERS ; ESTERIFICATION ; ISOMEROHYDROLASE ; PUTATIVE RECEPTOR ; REDUCED LECITHIN ; RETINOIC ACID RECEPTORS ; VISUAL CYCLE
    Abstract: Disturbance in vitamin A metabolism seems to be an important attribute of cancer cells. Retinoids, particularly retinoic acid, have critical regulatory functions and appear to modulate tumor development and progression. The key step of vitamin A metabolism is the esterification of all-trans retinol, catalyzed by lecithin/retinol acyltransferase (LRAT). In this work, we show that malignant melanoma cells are able to esterify all-trans retinol and subsequently isomerize all-trans retinyl esters (RE) into 11-cis retinol, whereas their benign counterparts-melanocytes are not able to catalyze these reactions. Besides, melanoma cell lines express lecithin/retinol acyltranseferase both at the mRNA and protein levels. In contrast, melanocytes do not express this enzyme at the protein level, but mRNA of lecithin/retinol acyltransefrase could still be present at mRNA level. RPE65 is expressed in both melanocytic counterparts, and could be involved in the subsequent isomerization of RE produced by lecithin/retinol acyltransefrase to 11-cis retinol. Cellular retinol-binding protein 2 does not appear to be involved in the regulation of all-trans retinol esterification in these cells. Expression of LRAT and RPE65 can be modulated by retinoids. We propose that the post-transcriptional regulation of lecithin/retinol acyltransefrase could be involved in the differential expression of this enzyme. Besides, activities of LRAT and RPE65 may be important for removal of all-trans retinal which is the substrate for retinoic acid production in skin cells. Consequently, the decreasing cellular amount of retinoic acid and its precursor molecules could result in a change of gene regulation. J. Cell. Physiol. (c) 2011 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 21465477
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  • 7
    Keywords: CANCER CELLS ; EXPRESSION ; RAT ; HEALTH ; DEFICIENCY ; secretion ; CALCIUM-SENSING RECEPTOR ; ZnR, GPR39, zinc signaling, s100A4, epithelial cells ; CA2+-SENSING RECEPTOR ; EXTRACELLULAR ZINC ; TRIGGERS
    Abstract: Zinc signaling is mediated by the zinc sensing receptor, ZnR, recently suggested to be the same receptor as G-protein coupled receptor 39, GPR39. However it is unknown if GPR39 is mediating Zn2+-dependent signaling in prostate and salivary tissue where changes in zinc concentrations are frequent and of physiological significance. Here, we show that GPR39 is mediating Zn2+-dependent Ca2+ responses and is regulating activity of MAP and PI3 pathways in prostate cancer cells, PC3, and ductal salivary gland cells, HSY. We next ask whether ZnR/GPR39 interacts with other GPCR family members. We find that endogenous ZnR/GPR39 activity is regulated by the expression and activity of another cation sensing GPCR, the Ca2+-sensing receptor (CaSR). Although CaSR is not activated by Zn2+, co-expression of CaSR and ZnR/GPR39 ynergistically enhances Ca2+ responses in PC3 and HSY cells. Silencing of the CaSR using siRNA or a dominant negative construct reduces the Zn2+-dependent signaling. Importantly, overexpression of GPR39 in HEK293 cells is sufficient to trigger Zn2+-dependent responses. Nevertheless, application of the CaSR agonist spermine, at concentration below its threshold, enhanced Zn2+-dependent Ca2+ response. Our results suggest that the CaSR interacts with ZnR/GPR39 and thereby regulates its activity. Finally, we show that in PC3 cells ZnR/GPR39 is required for mediating the Zn2+-dependent activation of MAPK and PI3K, pathways leading to enhanced cell growth. Importantly, Zn2+-dependent activation of ZnR/GPR39 also enhances the expression of the Ca2+- binding protein S100A4 that is linked to invasion of prostate cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 24264723
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  • 8
    Abstract: Bradykinin (BK), a well known mediator of pain and inflammation, is also known to be involved in the process of bone resorption. The present study therefore evaluated the role of BK in osteoblast lineage commitment. Our data showed that BK inhibits the migration of bone marrow mesenchymal stem cells, but does not affect their viability. Moreover, BK also inhibits osteoblastic differentiation by significantly downregulating the levels of mRNAs for osteopontin, runX2, col24, osterix, osteocalcin genes and bone mineralization (P 〈 0.05). Further, BK was found to elicit the BK receptors (BDKR1 and BDKR2) mediated activation of ERK1/2 and Akt pathways, which finally led to the activation of NFkappaB. BK also promoted the osteoclast differentiation of bone marrow derived preosteoclast cells by upregulating the expression of c-fos, NFATC1, TRAP, clcn7, cathK, and OSCAR genes and increasing TRAP activity through NFkappaB pathway. In conclusion, our data suggest that BK decreases the differentiation of osteoblasts with concomitant increase in osteoclast formation and thus provides new insight into the mechanism of action of BK in modulating bone resorption.
    Type of Publication: Journal article published
    PubMed ID: 24825463
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  • 9
    Keywords: ANGIOGENESIS, APOPTOSIS, ARTERY, BINDING, BIOLOGY, BLOOD, CELL, CELLS, DIFFERENTIATION, EXPRESSION,
    Abstract: Endothelial cells are constantly exposed to high or low shear stress in arteries and veins by the flowing blood. Angiopoietin-2 (Ang-2) is acting as a critical regulator of vessel maturation and endothelial cell quiescence. In this study, flow-dependent regulation of Ang-2 was analyzed in vitro and in vivo. Ang-2 mRNA, protein expression and release was upregulated by 24 h of low (1 dyne/cm(2)), but downregulated by high flow (30 dyne/cm(2)) in human endothelial cells. Increased endothelial NO synthase expression and NO formation was not affecting regulation of Ang-2 by low or high flow. Low and high flow increased VEGF-A expression. Inhibition of VEGFR-2 prevented upregulation of Ang-2 by low flow, but not downregulation of Ang-2 by high flow. Furthermore, upregulation of Ang-2 by VEGF was reduced by application of high flow. Forkhead box 0 (FOXO) transcription factor FOXO1 has been shown to regulate Ang-2 expression in endothelial cells. FOXO1 binding activity was reduced by high flow. Nuclear localization of transcription factor FOXO1 was not changed by low flow, but reduced by high flow. In vivo, Ang-2 was higher expressed in veins compared to arteries. Arterial ligation augmented Ang-2 expression in distal arterial low flow areas. Our results support a VEGF-dependent induction of Ang-2 in low flow areas, and FOXO1-dependent downregulation of Ang-2 in high flow areas. These data suggest a new mechanism of flow-dependent regulation of vessel stability and differentiation
    Type of Publication: Journal article published
    PubMed ID: 17960565
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  • 10
    Keywords: ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; VITRO ; SYSTEM ; transcription ; TISSUE ; ANTIGEN ; BIOLOGY ; BONE-MARROW ; antibodies ; ASSAY ; leukemia ; ADHESION ; MIGRATION ; TNF-ALPHA ; DEFICIENCY ; RE ; ASSAYS ; USA ; BONE ; BOMBAY PHENOTYPE ; VENULES
    Abstract: During the initiation of tumor associated angiogenesis endothelial cells migrate, adhere to extracellular matrix and form cell-cell contacts. Humoral factors of malignant cells conduct this process. We investigated whether cell surface expression of the carbohydrate blood group determinant Lewis(y)(CD 174) and its precursor structure H2 (CD 173) on endothelial cells is influenced by soluble factors of tumor cells. Using a bone marrow derived endothelial cell line we observed an enhanced expression of CID 173/CD 174 and transcription of FUT1, the key enzyme for their synthesis, after treatment with tumor necrosis factor-alpha (TNF-alpha) or conditioned supernatants of the leukemia cell line KG I a. CID 173/CD 174 are concentrated on pseudopodial extensions responsible for initial contacts between endothelial cells. Endothelial migration induced by TNF-alpha, could be diminished by antibodies to CD 174 as well as by siRNA induced downmdulation of FUTI transcription. Endothelial FUTI-siRNA-transfectants displayed impaired in vitro angiogenesis when cultivated on extracellular matrix and in spheroid assays. In vivo upregulation of CD 174 expression was observed immunocytologically in capillaries of tumor-infiltrated tissue. Together, our observations point to a tumor induced transcription of endothelial FUT I and consequently an enhanced expression of CID 174 which is involved in migration and early cell-cell contacts during tumor associated angiogenesis
    Type of Publication: Journal article published
    PubMed ID: 18205178
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