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1
Rossdeutsch, A. "The role of thymosin β4 in vascular development." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1333963/.
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Thymosin β4 (Tβ4) is a 43 amino acid peptide encoded by the Tmsb4x gene located on the X-chromosome. It has previously been shown to act as a secreted factor from the myocardium to the overlying epicardium of the developing murine heart, to mediate transformation of epicardial derived progenitor cells (EPDCs) into the coronary vasculature. This PhD project seeks to build on these studies and characterises the function of Tβ4 in the developing systemic vasculature, using the mouse as a model system. Expression analyses demonstrated specific localisation of Tβ4/Tβ4 in the endothelial cells of the embryonic vasculature. In order to ascertain the function of vascular Tβ4, global and endothelial cell specific in vivo Tβ4 loss of function models were examined. Both global and endothelial-specific Tβ4 mutant embryos displayed a reduced recruitment of vascular mural cells to developing blood vessels. Detailed phenotypic examination revealed that the mural cell deficit could be attributed to impaired differentiation of mature mural cells from undifferentiated mesoderm. This process was modelled in vitro, and it was discovered that treatment of the mural progenitor cell lines 10T1/2 and A404 with exogenous Tβ4 could promote their differentiation into mural cells. This process correlated with an increase in Smad phosphorylation and increased activity of the TGF-β pathway. Decreased levels of TGF-β target genes in vivo in Tβ4β null embryos indicated that TGF-β signalling was perturbed in the absence of Tβ4. These findings suggest a model whereby Tβ4 is secreted by the developing endothelium to stimulate the differentiation of uncommitted mesoderm into mature peri-vascular mural cells, via activation of the TGF-β pathway in the target cell population. As a consequence, Tb4 plays an essential role in vascular stability through mural cell support which has implications for vascular dysfunction in disease.
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Lowe, Martin David. "Functional characterisation of the cardiac putative β4-adrenergic receptor." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619730.
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Ruban, Emily L. "PLC-β4 signalling & function in human squamous cell carcinoma." Thesis, Queen Mary, University of London, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612569.
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Martin, R. K. "Exploring the role of centaurin β4 in a melanoma cell line." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501277.
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Melanoma is a cancer of the epidermal pigment cells, melanocytes. It is characterised by its metastatic ability and resistance to chemotherapy and radiotherapy. Centaurin β4 expression was recently shown to be upregulated in advanced stages of uveal melanoma and also in breast, colon and prostate cancer. Centaurin β4 is involved in the cyclic activation of ADP Ribosylation Factors (Arfs) which are activated at membranes. Arfs are involved in clathrin and COPI/Il vesicle formation and budding and therefore control protein trafficking between membranes. They are also involved in control of the actin cytoskeleton and their cyclic activation promotes protrusions such as invadopodia. Centaurin β4 is a multi-domain protein whose interaction with cortactin promotes invasion and metastasis specifically in tumour cells. Knock-down of centaurin β4 expression reduces invasion and motility of breast cancer cell lines sussesting an important role in carcinogenesis.
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Harrington, Lauriane. "The role of β4-containing nicotinic acetylcholine receptors in nicotine addiction." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066328/document.
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Le tabac est consommé par environ un milliard de personnes. D'après l'Organisation Mondiale de la Santé, le tabagisme est la première cause évitable de mortalité dans le monde, provocant six millions de morts par an. La nicotine est le composant neuro-actif principal dans le tabac, et exerce ses effets neurologiques via une activation directe des récepteurs nicotiniques de l’acétylcholine (nAChR). Ces récepteurs transmembranaires sont composés de sous-unités alpha, ou alpha plus beta, créant une variété de canaux ioniques ligand-dépendants activés par le neurotransmetteur ACh. Les études génétiques chez l’homme ont mis en évidence des variants dans le cluster génomique CHRNA5-CHRNA3-CHRNB4, codant pour les sous-unités α5, α3 et β4, comme facteurs influençant le tabagisme. Cette thèse a étudié le rôle des nAChRs contenant la sous-unité β4 (β4*) dans l’addiction à la nicotine. En collaboration, nous avons montré que les souris déficientes pour la sous-unité β4 (β4 KO), sont moins sensibles aux effets récompensant et aversifs de la nicotine. En générant un lentivirus exprimant la séquence murine d'ADN complémentaire de β4, j’ai pu restaurer son expression dans des régions d’intérêt du cerveau, sur un fond génétique β4KO. Ceci a permis de mettre en évidence le rôle du réseau habénulo-interpedonculaire dans la contribution des β4* nAChRs à la consommation de nicotine. Ceci a également démontré le rôle modulateur de ces récepteurs dans les réponses de la voie mésolimbique à la nicotine, voie centrale dans l'effet renforçant des droguesTobacco is consumed by an estimated 1 billion people world-wide. The World Health Organization names tobacco consumption the primary cause of preventable morbidity and mortality, causing six million deaths per year. Nicotine is the principal neuro-active compound in tobacco, and exerts neurological effects by binding to nicotinic acetylcholine receptors (nAChRs). These transmembrane receptors are composed of alpha or alpha plus beta subunits, forming a diverse variety of ligand-gated ion channels endogenously activated by ACh. Human genetic studies have highlighted variants in the CHRNA5-CHRNA3-CHRNB4 genomic cluster, coding for subunits α5, α3 and β4, as altering smoking behaviours. The present thesis investigated the role of β4-containing (β4*) nAChRs in nicotine addiction. In collaboration, we showed that β4 knockout (KO) mice are less sensitive to nicotine reward and nicotine aversion. Generating a lentivirus for the expression of mouse β4 nAChR subunit complementary DNA, I was able to restore receptor expression to brain regions of interest on a KO background, locating the role of β4* nAChR in nicotine reward and aversion to the habenulo-interpedunular pathway. This also demonstrated the receptor’s modulation of nicotinic responses of the mesolimbic system, central hub of drug reinforcement
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Knop, Jana [Verfasser], and Ewald [Akademischer Betreuer] Hannappel. "Die enzymatische und chemische Vernetzung von Thymosin β4 mit Proteinen. Charakterisierung der Vernetzung und Auswirkung auf die biologischen Funktionen von Thymosin β4 / Jana Knop. Betreuer: Ewald Hannappel." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1036305317/34.
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Viltard, Mélanie. "Mise en évidence de nouveaux gènes impliqués dans la néphrogenèse : Thymosine β4 [Bêta 4]." Paris 6, 2005. http://www.theses.fr/2005PA066364.
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Zhao, Yanan. "The role of thymosin β4 during embryonic wound healing and tail regeneration in Xenopus." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-thymosin-4-during-embryonic-wound-healing-and-tail-regeneration-in-xenopus(7578b7d2-c63a-4a89-992c-16ab8bf1e24c).html.
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At the outset of my PhD, my aim was to investigate the mechanisms responsible for the directed migration of primitive myeloid cells (PMCs) to wounds in Xenopus embryos. PMCs are the first blood cells to differentiate and become functional in Xenopus embryos, and have a notable migratory ability to be recruited by embryonic wounds before a functional vasculature is established. To find the mechanism underlying PMCs migration toward embryonic wounds, I first performed a screen to identify candidate cytoskeleton related genes, which might be responsible for facilitating the inflammatory response to injury in embryos. In situ hybridization and RT-PCR showed that coronin1a and l-plastin were specifically expressed in PMCs. I carried out loss-of-function experiments for coronin 1a and l-plastin in Xenopus embryos. Unfortunately neither knockdown affected the ability for PMCs to migrate during embryonic development or during the wound healing process. Loss-of-function experiments on coronin 1a and l-plastin also did not affect epidermal wound closure speed. Thus, although coronin 1a and l- plastin are expressed specifically in PMCs, they do not appear to be necessary for the migration of PMCs during development and during wound healing in Xenopuos embryos. Since my initial aim failed to provide insight into the mechanisms that mediate 9the inflammatory response to embryonic wounds, I decided to investigate the function of a previously identified monomeric actin protein during embryonic wound healing and appendage regeneration: namely Thymosin beta4 (Tβ4). In situ hybridization experiments showed that Tβ4 is expressed exclusively in the epidermis of developing frog embryos. Tβ4 knockdown embryos resulted in a significantly delay in the speed of wound closure during the early phase of wound healing. This delay correlated with a decrease in the actin contractile ring at the wound margin. Furthermore I found that the cell shapes of epidermal cells in the Tβ4 knockdown embryos were different from epidermal cells in control embryos. I hypothesize that this reduction caused the actin filaments changes in the epidermal cells, and were responsible for the failure of the cells to form an actin contractile ring, thus delaying the initial speed of wound closure. I tried to confirm that most of these defects specific to Tβ4, by performing rescue experiments with Tβ4 mRNA injections. Furthermore, I discovered that Tβ4 knockdown embryos displayed defects in tail development, including the absence of blood vessel branching within the fin of the tail. Finally, I found that the tails in Tβ4 knocked-down tadpoles failed to regenerate, while tails in control embryos regenerated completely following amputation. Both in situ hybridization and real-time PCR showed that Tβ4 was up regulated in the regenerated part of the tail in Xenopus tadpoles. Together with the tail amputation results, Tβ4 might be important for tail development and regeneration. These findings suggest that Tβ4 might play an important roles in the modulation of the actin cytoskeleton, which are essential for the proper behavior of epidermal cells during wound healing and appendage regeneration.
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Lexow, Jonas Maximilian. "Inducible depletion of cardiac thymosin β4 : development and shortcomings of a popular technique in cardiac research." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11091.
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In reference to recent studies highlighting the importance of Thymosin beta 4 (Tβ4) during embryonic development and its therapeutic potential, an inducible cardiac-specific knockdown of Tβ4 was established to investigate the outcomes of loss of function in adult mammalian hearts. Tβ4shRNAflox/MerCreMer mice were generated with the aim of depleting cardiac Tβ4 expression by RNA interference in a tamoxifen-dependent fashion. In vivo, in vitro and ex vivo approaches showed that tamoxifen treatment of Tβ4shRNAflox/MerCreMer mice does not result in significant down-regulation of Tβ4 mRNA or protein in the heart. Interestingly, higher levels of Tβ4 were identified in cardiac fibroblasts compared to cardiomyocytes. The above analyses suggest that an inducible knockout of Tβ4 would be a more direct, more reliable and more effective means to study loss of function in the adult mammalian heart. In the course of the study, an adverse cardiac phenotype was observed in tamoxifen-treated MerCreMer-positive animals, consisting of perivascular and interstitial fibrosis, decreased cardiac function, a marked inflammatory response and increased expression of factors involved in cardiac remodelling and hypertrophy. This was not related to MerCreMer gene copy number (homo/heterozygosity) but found to be associated with tamoxifen dose, mode of delivery and genetic background. A thorough analysis of related literature revealed that a number of recent publications have failed to include tamoxifen-treated αMHC/MerCreMer controls and some of the presented data may be affected by Cre toxicity. In conclusion, αMHC/MerCreMer mice should be included as controls in the analysis of future studies or alternative inducible systems considered. Recent analyses revealed that IGF-1Ea overexpression in the heart improves the outcome of myocardial infarction in mice. This process has been described on the molecular level but a comprehensive analysis of the subcellular structure of αMHC/IGF-1Ea hearts had not previously been performed. A detailed transmission electron microscope analysis of αMHC/IGF-1Ea hearts revealed previously not described large electron-dense structures inside αMHC/IGF-1Ea cardiomyocytes. The structures resembled large autophagolysosomes although markers of autophagy were neither found to be associated with the structures nor upregulated in the hearts of αMHC/IGF-1Ea mice. Intriguingly lysosomes were identified in the proximity of the structures potentially implying a role in turnover of intracellular material. These results provide further insights into the diverse roles of IGF-1Ea in the heart.
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Bon, Emeline. "Implication de la sous-unité B4 des canaux sodiques dépendants du voltage dans l'invasivité des cellules cancéreuses mammaires et régulation de son expression par l'acide docosahexaènoïque." Thesis, Tours, 2015. http://www.theses.fr/2015TOUR3310/document.
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La perte de l’expression de la sous-unité β4 des canaux sodiques dépendants du voltage NaV dans les tumeurs mammaires est associée à un grade cancéreux élevé et au développement des métastases. L’extinction de son expression dans les cellules MDA-MB-231 augmente de plus de deux fois leur invasivité. Au cours de cette thèse, nous avons montré que la sous-expression de β4 favorise la transition mésenchymato-amoeboïde et augmente l’invasion cancéreuse indépendante de NaV. Cette transition se caractérise par l’acquisition d’une morphologie plus arrondie, par la présence de blebs à la surface cellulaire et par une augmentation de l’activité RhoA-GTPase. Cette transition est inhibée par la surexpression du domaine intracellulaire C-terminal de la sousunité β4. L’expression de β4 peut être augmentée par un apport en acide docosahexaènoïque (22:6n-3), qui augmente l’activité du promoteur de son gène SCN4B. Le DHA augmente également l’expression de β4 en modulant l’expression des récepteurs nucléaires PPAR, sensibles aux lipidesThe loss of voltage gated sodium channel NaVβ4 subunit expression in breast cancer biopsies is associated with high grade tumors and metastatic development. The inhibition of β4 expression in MDA-MB-231 breast cancer cells enhanced their invasiveness by two fold. During this thesis, we have shown that β4 underexpression promotes mesenchymal-amoeboid transition and increases NaV-independent invasion. This transition is characterized by rounded morphology, the presence of blebs at the cell surface and an increased RhoAGTPase activity. This transition is inhibited by β4 C-terminal intracellular domain overexpression. Expression of β4 can be enhanced by a DHA supplementation that increases the encoding SCN4B promoter activity. DHA also increases β4 expression through the modulation of PPARs lipid-sensitive nuclear receptors expression
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Slimak, Marta Anna [Verfasser]. "Molecular determinants of the β4 nAChR subunit in channel function and nicotine-mediated behavior / Marta Anna Slimak." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1029954895/34.
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Kirchner, Lennart Kaan [Verfasser], and Tobias [Akademischer Betreuer] Lange. "Einfluss des Integrin β4 auf das Wachstum des Adenokarzinoms des Pankreas / Lennart Kaan Kirchner ; Betreuer: Tobias Lange." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2019. http://d-nb.info/118744488X/34.
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Labitzky, Vera [Verfasser], and Udo [Akademischer Betreuer] Schumacher. "Bedeutung von Integrin β4 für die intraperitoneale Metastasierung des Ovarialkarzinoms im Xenograftmodell / Vera Labitzky ; Betreuer: Udo Schumacher." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1169358411/34.
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Howard, S. "The regulation of Wt1 in the epicardium by the SWI/SNF-like BAF complex and thymosin β4." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1419273/.
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During development, cells of the epicardium undergo epithelial-mesenchymal transition (EMT) to generate multipotent progenitor cells (epicardium-derived cells, EPDCs) that contribute to multiple lineages of the cardiovascular system. Critical to this process is the epicardially-expressed Wilms’ tumour 1 (Wt1) gene. In the adult, the epicardium is largely quiescent and no longer expresses Wt1. Upon myocardial infarction (MI), however, the adult epicardium is reactivated; it re-expresses Wt1, reverts to its embryonic potency, and contributes to cardiac repair. Previous work showed that this reactivation is enhanced by ‘priming’ mice with the G-actin-binding protein thymosin β4 (Tβ4), although the molecular mechanisms were not defined. Here we investigated Wt1 regulation in the epicardium during development and post-MI and found Wt1 to be regulated by the SWI/SNF chromatin remodelling complex in combination with Tβ4. During development, Wt1-expressing cells in the epicardium expressed the SWI/SNF ATPases, Brg1 and Brm. Both Wt1 and SWI/SNF were largely absent from the uninjured adult epicardium, but the re-expression of Wt1 post-MI was accompanied by substantial upregulation of both Brg1 and Brm. Exogenous Tβ4 in the form of priming increased the post-MI expression of Wt1, Brg1 and Brm, whilst endogenous Tβ4 was found to be required for maximal Wt1 reactivation. Furthermore, we found that Tβ4 physically interacts with the SWI/SNF complex and that it potentiates SWI/SNF-mediated activation of specific regulatory regions of the Wt1 promoter and intron 1, suggesting that this interaction is functional. Loss of Brg1 in the epicardium using Gata5Cre;Brg1flox embryos showed that Brg1 is not required for Wt1 expression, which we postulate is due to compensation from Brm, whilst loss of Brg1 in Wt1-expressing lineages (using the tamoxifen-inducible Wt1CreERT2) caused no obvious phenotype. Further understanding of the mechanisms underlying Wt1 expression, during both development and epicardial reactivation post-MI, is essential in our quest to utilise resident-cell-based therapy in cardiac repair.
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App, Christine [Verfasser], and Ewald [Akademischer Betreuer] Hannappel. "Markierung von Thymosin β4 mit UV-aktivierbaren Crosslinkern und molekulare Charakterisierung der Derivate / Christine App. Betreuer: Ewald Hannappel." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1038871298/34.
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Schetler, Daniela [Verfasser], and Tobias [Akademischer Betreuer] Lange. "Bedeutung von Integrin β4 und E-/P-Selektin für dasTumorwachstum im Prostatakarzinom-Xenograftmodell / Daniela Schetler ; Betreuer: Tobias Lange." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2019. http://d-nb.info/1188818694/34.
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Sun, Huayan. "Function of the β4 Integrin in Cancer Stem Cells and Tumor Formation in Breast Cancer: A Masters Thesis." eScholarship@UMMS, 2001. http://escholarship.umassmed.edu/gsbs_diss/814.
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The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Integrin β4 is important for the organization and maintenance of epithelial architecture in normal cells. Particularly, β4 is shown to be essential for mammary gland development during embryogenesis. Integrin β4 also plays important roles in tumor formation, invasion and metastasis in breast cancer. However, the mechanism of how integrin β4 mediates breast tumor formation has not been settled. A few studies suggest that integrin β4 is involved in cancer stem cells (CSCs), but the mechanism is not clear. To address this problem, I examined the expression of β4 in breast tumors and its potential role involved in regulating CSCs. My data shows that β4 is expressed heterogeneously in breast cancer, and it is not directly expressed in CSCs but associated with a basal epithelial population. This work suggests that β4 can regulate CSCs in a non-cell-autonomous manner through the interactions between β4+ non-CSC population and β4- CSC population. My data also shows that β4 expression is associated with CD24+CD44+ population in breast tumor. To further study the role of β4 in breast cancer progression, I generated a β4 reporter mouse by inserting a p2A-mCherry cassette before ITGB4 stop codon. This reporter mouse can be crossed with breast tumor models to track β4+ population during tumor progression.
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Sun, Huayan. "Function of the β4 Integrin in Cancer Stem Cells and Tumor Formation in Breast Cancer: A Masters Thesis." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/814.
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The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Integrin β4 is important for the organization and maintenance of epithelial architecture in normal cells. Particularly, β4 is shown to be essential for mammary gland development during embryogenesis. Integrin β4 also plays important roles in tumor formation, invasion and metastasis in breast cancer. However, the mechanism of how integrin β4 mediates breast tumor formation has not been settled. A few studies suggest that integrin β4 is involved in cancer stem cells (CSCs), but the mechanism is not clear. To address this problem, I examined the expression of β4 in breast tumors and its potential role involved in regulating CSCs. My data shows that β4 is expressed heterogeneously in breast cancer, and it is not directly expressed in CSCs but associated with a basal epithelial population. This work suggests that β4 can regulate CSCs in a non-cell-autonomous manner through the interactions between β4+ non-CSC population and β4- CSC population. My data also shows that β4 expression is associated with CD24+CD44+ population in breast tumor. To further study the role of β4 in breast cancer progression, I generated a β4 reporter mouse by inserting a p2A-mCherry cassette before ITGB4 stop codon. This reporter mouse can be crossed with breast tumor models to track β4+ population during tumor progression.
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Ehrhardt, Vincent Henrique [Verfasser], and Udo [Akademischer Betreuer] Schumacher. "Der Einfluss von Integrin β4 auf die Metastasierung des humanen Magenkarzinoms im Xenograftmodell / Vincent Henrique Ehrhardt ; Betreuer: Udo Schumacher." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1172880468/34.
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Ehrhardt, Vincent Henrique Verfasser], and Udo [Akademischer Betreuer] [Schumacher. "Der Einfluss von Integrin β4 auf die Metastasierung des humanen Magenkarzinoms im Xenograftmodell / Vincent Henrique Ehrhardt ; Betreuer: Udo Schumacher." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://nbn-resolving.de/urn:nbn:de:gbv:18-94311.
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Driffort, Virginie. "Rôle du canal sodique NaV1.5 et de la sous-unité auxiliaire β4 dans l’invasivité des cellules cancéreuses mammaires in vitro et in vivo." Thesis, Tours, 2014. http://www.theses.fr/2014TOUR3310.
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L’expression anormale du canal sodique Nav1.5 dans le cancer du sein est corrélée au développement métastatique et à une mortalité augmentée. Le canal Nav1.5 est localisé dans les invadopodes des cellules cancéreuses mammaires humaines MDA-MB-231 et augmente leur activité protéolytique par une modulation allostérique de l’échangeur NHE-1 et l’activation de protéases acides. In vivo, dans un modèle de xénogreffe sur souris NMRI nude, l’expression de Nav1.5 potentialise la colonisation des poumons par les cellules cancéreuses mammaires humaines. Cette colonisation métastatique est inhibée par un traitement à la ranolazine, un inhibiteur pharmacologique des canaux Nav1.5. La sous-unité β4, auxiliaire des canaux Nav, voit son expression diminuer au cours de la progression cancéreuse, ce qui est associé in vitro à une augmentation de l’invasivité cellulaire. Cette augmentation d’invasivité semble indépendante du canal Nav1.5 et pourrait être associée à une transition des cellules vers un phénotype amiboïde. En conclusion, l’expression de Nav1.5 et la perte d’expression de β4 semblent jouer des rôles complémentaires dans l’invasivité des cellules cancéreusesThe abnormal expression of sodium channel Nav1.5 in breast cancer is correlated with metastatic development and an increased mortality. The Nav1.5 channel is located in invadopodia in human breast cancer cells MDA-MB-231, where it increases proteolytic activity by allosteric modulation of exchanger NHE-1 and activation of acidic proteases. In vivo, in a xenograft model in nude NMRI mice, the expression of Nav1.5 potentiates lung colonization by human breast cancer cells. Metastatic colonization is inhibited by treatment with ranolazine, a pharmacological inhibitor of Nav1.5. The β4 subunit, an auxiliary subunit of Nav channels, is expressed at low levels or lost when tumors are more aggressive, and its suppression in vitro increases celI invasiveness. This increase seems to be independent of Nav1.5 and could be associated with the transition of cells to an amoeboid phenotype. In conclusion, Nav1.5 expression and the loss of β4 expression seem to play complementary roles in the invasiveness of cancer cells
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Hsiao, Hung-Liang, and 蕭宏良. "Analyzing the Promoter Activity of Thymosin β4 Gene and the Effect of Overexpressing Thymosin β4 on Apoptosis of SW480 Colon Cancer Cells." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/28020986877092889997.
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博士國立陽明大學
藥理學研究所
94
Thymosin β4 (Tβ4), a small peptide originally isolated from calf thymus, modulates the formation of F-actin microfilaments by sequestering the monomeric G-actin. Recent studies have shown that overexpression of the Tβ4 gene occurs in many human tumors. However, little is known about the regulation of Tβ4 gene expression and the effects of Tβ4 on tumor. Our present study analyzed in details of the promoter of the mouse thymosin β4 (mTβ4) gene. This study found that the first exon of mTβ4 gene spans 56 bp with its cap site situated in a putative initiator highly similar to the consensus mammalian sequence. In addition, a TATA box-like motif and two consecutive downstream promoter elements were found and their locations are in agreement with the ones present in a variety of other genes. This study showed that the expression level of reporter gene driven by the -118 to +56 region of mTβ4 gene was approximately 8-fold higher than that directed by the SV40 promoter and significant promoter activity was found to be associated with the -57 to +56 fragment. A silencer that was bound by a nuclear protein was located in the region between the -168 to -119 and an enhancer whose effect did not seem to be dependent on protein binding was identified in the -118 to -89 region of this gene. Interestingly, neither of the regulatory sequences affected reporter expression directed by a heterologous viral promoter. Unexpectedly, the mTβ4 promoter functioned effectively in HeLa cervical carcinoma cells. Since a downregulation of Fas in the Tβ4 overexpressing SW480 colon cancer cells and a reduction in their susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) have been demonstrated in our previous study. Effects of Tβ4 overexpressing on the apoptosis of SW480 cells induced by other cytotoxic agents were assessed. As expected, Tβ4 overexpressers were also more resistant to the toxic effect of the FasL-bearing Jurkat cells. However, pretreating these cells with an MMP inhibitor not only increased Fas levels but also abolished their resistance to CH-11. Interestingly, even though the susceptibilities of the Tβ4 overexpressers to 5-FU and irinotecan remained the same, these cells were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspase-9 and caspase-3 by the two aforementioned topoisomerase II inhibitors was diminished in the Tβ4 overexpressers accounted possibly by an increased expression of Survivin, an anti-apoptotic factor whose expression was upregulated by β-catenin. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody. Taken together, this study provide crucial information for further elucidation of the transcriptional regulation of mTβ4 gene as well as for designing a better approach for colon cancer treatment by targeting Tβ4 expression.
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Huang, Yung-Chin, and 黃詠勤. "Folding study of intrinsically disordered proteins, recombinant Thymosin β4." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/26612434032735559733.
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Tseng, Hui-Yuan, and 曾暉元. "The interaction between focal adhesion kinase (FAK) and integrin β4 in carcinoma cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/71056181565987161914.
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碩士國立臺灣大學
植物病理與微生物學研究所
95
A numerous studies have shown that integrin β4 involved in tumor progression and clustering of integrin β4 might lead to the activation of focal adhesion kinase (FAK) and its downstream signaling. These findings are consistent with the roles of FAK in cell proliferation, migration and tumor development. Hence, we were further pursuing the possibility of direct interaction between integrin β4 and FAK. Indeed, we demonstrated that in several tumor cell lines, such as MDA-MB-231 and HCT116 but not HeLa, MCF7 and A549, integrin β4 could co-immuoprecipitate FAK protein endogenously. Besides, this integrin β4-FAK interaction is independent of FAK activity. It implicated the participation of this interaction in tumorigenesis. Moreover, the interaction required an 11-amino-acids motif within FAK’s amino-terminus. By using the in vitro binding assay and competition approach, this association is further confirmed. Among them, two out of 11 amino acids exhibited a critical role in interaction with integrin β4. And the further observations showed that this interaction existed only as cells are adherent.Our data resolved for the first time a physical interaction between integrins and FAK, suggesting a strong link regarding integrin-FAK signaling events. Future work will decipher the signaling pathway(s) and biological significance through the integrin β4-FAK interaction, which will shed a light on better strategies for cancer therapies.
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Zimmermann, Moritz [Verfasser]. "Thymosin β4 [Beta-4] in humanem Speichel : Quellen und Einflussfaktoren / vorgelegt von Moritz Zimmermann." 2011. http://d-nb.info/1011334445/34.
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Bodendorf, Sabine [Verfasser]. "Thymosin-β4 [Thymosin-beta-4] in postoperativer Wundflüssigkeit : eine Verlaufsstudie / vorgelegt von Sabine Bodendorf." 2010. http://d-nb.info/1008785547/34.
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Chan, Li-Chuan, and 詹立全. "Elucidation of the mechanism underlying thymosin β4 induced migration of SW480 colon cancer cells." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/8rk8v3.
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碩士國立陽明大學
生物藥學研究所
97
Thymosin β4 (Tβ4) is a 5 kDa intracellular G-actin sequestering peptide which regulates F-actin formation. Previous studies have shown that overexpression of Tβ4 gene occurs not only in human colorectal carcinomas (CRC) but also in their liver metastases. In fact, increased migration and invasion were found in several Tβ4-overexpressing stable clones derived from SW480 human colon cancer cells. Although the latter could be attributed in part to an upregulation of MMP-7 in these cells, the underlying mechanism for the former is largely unknown at present. In this study, transwell migration assay was used to analyze the influence of Tβ4 upregulation on the migration ability of SW480 cells. Our data showed that Tβ4-overexpressing stable clones Tb3 and Tb4 migrated better than the parental SW480 and vector-transfected (BK2) cells. Accordingly, knockdown of Tβ4 expression in Tb3 and Tb4 cells by its shRNA reduced their migration ability in a dose-dependent manner. Interestingly, even though higher levels of active Rac1 were found in Tb3 and Tb4 cells, treating them with a Rac1 inhibitor, NSC23766, did not diminish their migration, suggesting that guanine nucleotide exchange factors (GEFs) Trio and Tiam1 are not responsible for Rac1 activation in these cells. Surprisingly, higher RNA and protein levels of IQGAP1, a positive regulator of Rac1, were found in Tb3 and Tb4 cells whose knockdown resulted in a drastic reduction in the motility of these cells. Furthermore, co-immunoprecipitation assay showed that IQGAP1 could form a complex with integrin-linked kinase (ILK), and the latter has previously been shown to be upregulated in Tb3 and Tb4 cells. Together, our data suggest that Tβ4 can facilitate the migration of SW480 cells by activating Rac1 via upregulating IQGAP1 expression.
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Shen, Yi-Ting, and 沈逸婷. "Assessment of the effects of downregulated thymosin β4 expression on the viability of HeLa cells." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/15920065370420738473.
Full textAbstract:
碩士國立陽明大學
生物藥學研究所
94
In our previous studies, the growth rate, colony formation in soft agar, cell motility, and invasion capability, all good indicators for malignant progression of SW480 colon carcinoma cells were shown to be dramatically increased by enforced expression of Tβ4 gene. Upregulation of Tβ4 gene was also observed in the liver metastases of several colorectal carcinoma (CRC) patients. On the other hand, Tβ4 downregulation has also been reported in the apoptotic cancer cells treated with tamoxifen or taxol. More recently, downregulation of Tβ4 expression in HeLa human cervical carcinoma cells not only suppressed their growth but also enhanced their susceptibility to paclitoxel. To assess the influence of Tβ4 downregulation on the growth and survival of various cancer cells, recombinant adenoviruses carrying the antisense Tβ4 gene (Ad-asTβ4) were generated and used to infect different cancer cells. Expression of the endogenous Tβ4 gene in HeLa cells was indeed decreased after Ad-asTβ4 infection. Downregulation of Tβ4 resulted in a drastic viability reduction and a morphological change in both HeLa and SW480 colon cancer cells. However, a slight viability decrease and a minor shape alteration were found in virus-infected human SaOS-2 osteosarcoma cells. By contrast, no effect was seen in human MDA-MB-231 breast cancer cells, human HepG2 hepatoma cells, and human BJ-1 foreskin fibroblast cells. In addition, both the growth and survival of HeLa cells were suppressed by the viruses in a dose- and time-dependent manner. Altered cell cycle progression as well as increased sub-G1 population were also detected in Ad-asTβ4-infected HeLa cells. Interestingly, death of HeLa cells induced by Ad-asTβ4 infection was partially suppressed by both caspase-8 and caspase-9 inhibitors. Although a severe disruption of the F-actin was observed in HeLa cells 24 hr post-infection, no gross change in G-actin were found. On the other hand, intratumoral injection of Ad-asTβ4 failed to suppress tumor growth in nude mice. Taken together, our results suggest that Tβ4 plays an important role in the survival of HeLa cells.
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Tien, Yu-Shan, and 田玉珊. "Elucidating the role of integrin-linked kinase in thymosin β4 induced migration of SW480 colon cancer cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/36630717141051924201.
Full textAbstract:
碩士國立陽明大學
生物藥學研究所
99
Thymosin β4 (Tβ4) is a 5 kDa intracellular G-actin sequestering peptide which regulates F-actin formation. Aberrant expression of Tβ4 has been found not only in many malignant tumors but also to contribute to certain malignant phenotypes including mobility increase. Previous study done by others has reported that Tβ4 facilitates the migration of endothelial cells via its interaction with a lamellipodia-localized integrin-linked kinase (ILK) which in turn induces MMP-2 synthesis through activating Akt2. On the other hand, recent work from our laboratory provided evidence that Tβ4 can stimulate the migration of SW480 cells by activating Rac1 via upregulating ILK-IQGAP1 complex formation. However, contribution of the enzyme activity of ILK in this process in unclear. To address this question, genes encoding a hyperactive and a kinase-dead ILK were introduced respectively into SW480 cells via adenovirus infection. Results from transwell migration and wound healing assays showed that hyperactive ILK enhanced whereas kinase-dead ILK reduced Tβ4-induced cell migration. Accordingly, the levels of active Rac1 was increased and decreased respectively by hyperactive and kinase-dead ILK. Interestingly, shRNA-mediated knockdown of IQGAP1 expression in Tβ4-overexpression stable clone (Tb3) reduced not only their migration, but also Rac1 activation and the complex of IQGAP1/active Rac1. Meanwhile, upregulation of hyperactive ILK in IQGAP1-knockdowned Tb3 cells could partially restore their migration ability, suggesting that the residual IQGAP1 might be modified by ILK to sustain the activity of Rac1, leading to elevated migration. More intriguingly, higher RNA and protein levels of αPIX, a guanine nucleotide exchanger factor (GEFs) for Rac1 activation, were found in Tb3 cells whose knockdown resulted in a drastic reduction in the motility of these cells. Finally, we also found an involvement of MMPs in Tβ4-induced migration of SW480 cells since not only were the RNA levels and activities of MMP-2 and MMP-9 increased in Tb3 cells and in cells transiently overexpressing Tβ4 but also the migration ability of the former was partially abolished by GM6001, a broad-spectrum MMP inhibitor. Furthermore, the activities of MMP-2 and MMP-9 were decreased in Tb3 cells by ILK knockdown or by expressing a kinase-dead ILK. Besides, Tβ4-induced cell migration could be diminished by AKTi-1/2, an inhibitor for both AKT1 and AKT2, via reducing MMP-2 and MMP-9 activities as well as Rac1 activation. Taken together, our data demonstrate that in addition to ILK kinase activity, αPIX, AKT and MMPs are also crucial for Tβ4-facilitated migration of SW480 cells.
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Ρομποτή, Αγγελική. "Μεθοδολογία απομόνωσης θυμοσίνης β4 απο ιστούς, σύνθεση αντιγονικών επιτόπων, ανάπτυξη αντισωμάτων και αξιολόγηση αυτών με σύστημα elisa." Thesis, 1996. http://nemertes.lis.upatras.gr/jspui/handle/10889/2772.
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Chen, Ke-Jie, and 陳科傑. "Elucidating the mechanism underlying abnormal DNA replication induced by thymosin β4 knockdown in IEC-6 normal intestinal epithelial cells." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/44026058637220236226.
Full textAbstract:
碩士國立陽明大學
生物藥學研究所
98
Thymosin β 4 (Tβ4) is a highly conserved, water-soluble, acidic polypeptide with molecular weight of 5 kDa which regulates F-actin formation by sequestering the intracellular G-actin. According to several previous studies, upregulated expression of the Tβ4 gene has been found to correlate with the malignant progression of colorectal carcinomas (CRC), a highly fatal tumor due to its high metastatic ability and drug resistance mainly. Overexpression of Tβ4 has been demonstrated to enhance both the in vitro and in vivo invasion as well as drug resistance of SW480 human CRC cells. On the other hand, knockdown of Tβ4 expression in both SW480 cells and IEC-6 rat small intestinal epithelial cells by its shRNA resulted in a significant growth suppression. Flow cytometric analysis demonstrated that Tβ4 knockdown not only caused a dramatic decrease in the G0/G1 population but also a remarkable elevation of the polyploid population. These findings suggested that Tβ4 downregulation in IEC-6 cells induce an abnormal DNA replication. DNA replication licensing regulates chromosome duplication by limiting the loading of Pre-replication complex (Pre-RC) on the replication origin (ori) at S phase. When this mechanism operates aberrantly via uncontrolled formation of Pre-RC and chromosome reduplication (DNA rereplication) will occur. It has been shown that Emi1 (early mitotic inhibitor 1) regulates Pre-RC formation by inhibiting the Anaphase promoting complex/cyclosome (APC/C) activity which in turn prevents the degradation of Geminin to ensure a constant copy number of chromosomes. To examine whether Tβ4 knockdown in IEC-6 cells might affect the expression of DNA replication licensing molecules, real-time RT-PCR was first performed. My results showed that Emi1 expression was downregulated when Tβ4 levels were knocked down by its shRNA. In the meantime, I also found that RNA levels of two DNA licensing molecules, Cdc6 and Cdt1. An increase in Cdc6 protein levels 24 hr post - Tβ4 knockdown than those infecting by AdLacZ was demonstrated by Western blotting. To verified the occurrence of DNA rereplication in these cells, we measured the incorporation of bromodeoxyuridine (BrdU) into DNA by flow cytometry. Marked increases in BrdU incorporation were observed in Tβ4-knockdowned IEC-6 cells within 12 hours, suggesting that DNA synthesis, most likely DNA replication was induced by such a reaction. The result showed that endogenous Tβ4 inhibited in IEC-6 cells 0 to 12 hours, cells incorporated bromodeoxyuridine at a much higher level than AdLacZ group. The results suggested endogenous Tβ4 inhibited in IEC-6 cells that induce DNA rereplication. In addition, cyclin A and cyclin B1 protein levels were elevated from 6 hours to 24 hours after Tβ4 knockdown in IEC-6 cells. These findings suggested that Tβ4 downregulation in IEC-6 cells might interfere with their cell cycle progression by keeping them at S phase to continue DNA synthesis. Interestingly, the levels of phoso-CHK1, a DNA damage marker and r-H2AX, a marker for double strand break were also increased in these cells 12hr post Tβ4 knockdown. These observations suggested that an abnormal DNA replication triggered by Tβ4 knockdown could induce DNA replication stress in IEC-6 cells. I also transduced the gene encode Emi1 into the IEC-6 cells with the introduction of Tβ4 shRNA or influence only by a recombinant adenovirus. However, we did not see the growth suppression and morphological change was restored in IEC-6 cells by these treatments which might explain the failure of exogenous Emi1 to suppress DNA rereplication due to some unknown mechanisms. I also analyzed the effects of Tβ4 knockdown in Madin-Darby canine kidney (MDCK) epithelial cells and found that such a treatment induced a significant growth suppression. Flow cytometric analysis also demonstrated that Tβ4 knockdown caused a remarkable elevation of the polyploid population. Finally, detailed mechanisms underlying of Tβ4 induce DNA rereplication in IEC-6 are still under investigation.
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Burzer, Klaus [Verfasser]. "Modulation der Expression von Integrin-β4 [Integrin-Beta-4], Interleukin-1β [Interleukin-1-Beta] und HMGA in humanen kolorektalen Karzinomzellen durch Butyrat / vorgelegt von Klaus Burzer." 2004. http://d-nb.info/970170297/34.
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Jackson, James O. II. "β4 Peptide Mediated Voltage-gated Sodium Channel Resurgent Currents of Human Nav1.5 Sodium Channel Expressed in Hek293 Cells Increase after Exposure to Pyrethroid Insecticides Permethrin and Cypermethrin." Thesis, 2018. http://hdl.handle.net/1805/17423.
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Voltage-gated sodium channels (VGSCs) are transmembrane proteins responsible for the initiation of action potentials in excitable tissues by selectively allowing sodium ions (Na+) to flow through the cell membrane. VGSC resurgent currents occur when an open channel blocker from the β4 subunit interacts with the α subunit, transiently blocking the movement of Na+ across the membrane. VGSC subtype Nav1.5 channels are expressed in cardiac tissue and irregularities in their activity can lead to pathophysiological conditions like arrhythmias that can lead to death. Pyrethroid insecticides have been used widely in agriculture, vector control and households around the world for decades and since this is the case, human exposure to these products has increased dramatically. It is important to understand the effects of these insecticides on humans, including how these insecticides affect the heart. This thesis highlights the effects of pyrethroids on β4 peptide mediated Nav1.5 VGSC resurgent currents. The aims of this thesis were to 1) determine Nav1.5 channel activity and if activity changes with exposure to the vehicle (DMSO) used to dilute pyrethroids; 2) investigate the β4 peptide’s effect on these Nav1.5 currents and if resurgent currents are produced; 3) investigate Nav1.5 channel activity when exposed to pyrethroids; and 4) investigate β4 peptide mediated VGSC resurgent current activity after exposure to pyrethroids. Standard whole-cell electrophysiology was used to determine electrophysiological and pharmacological properties of WT Nav1.5 currents. Results from these experiments showed that 1) Nav1.5 channel activity follows established understanding of VGSC: when depolarized a rapid and transient inward current is produced followed by a rapid inactivation; 2) DMSO did not affect activation and inactivation pattern; 3) the β4 peptide produced resurgent currents in Nav1.5; 4) pyrethroids alter electrophysiological
properties of Nav1.5 by prolonging inactivation; and 5) β4 peptide mediated resurgent currents are larger after exposure to pyrethroids. Overall, this thesis answers important questions regarding effects of pyrethroids on the cardiac VGSC and has implications for effects on health and highlights the necessity to be mindful of how pyrethroids are used in the future.
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Vay, Christian [Verfasser]. "Untersuchung zur Expression der Integrin-Untereinheiten α2 [alpha 2], α3 [alpha 3], {α6 [alpha 6], {β1 [beta 1] und {β4 [beta 4] beim Plattenepithelkarzinom des Ösophagus / vorgelegt von Christian Vay." 2006. http://d-nb.info/980905303/34.
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Helmstädter, Victor [Verfasser]. "Der Einfluss von 17-β-Estradiol [17-beta-Estradiol], Tamoxifen und ICI 182,780 (Faslodex) auf die mRNA-Expression der Integrinuntereinheiten {α6 [alpha6], {β1 [beta1] und {β4 [beta4] in den Plattenepithelkarzinomzelllinien UM-SCC 14A, 14B und 14C / von Victor Helmstädter." 2006. http://d-nb.info/980872987/34.
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