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1
Kacsinta, Apollo Daniel. "Determining Biological Effectors of alpha6 Integrin Cleavage." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/193604.
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Cancer metastasis is a multi–step process that initiates with a tumor cell obtaining the ability to migrate. A multitude of changes occur in such a cell including changes to cell adhesion molecules such as integrins. In cancer cells, integrins are known to be involved in migration, invasion and metastasis. Investigation by our group of the α6 integrin led to the discovery of a cleaved form of the integrin lacking the ligand binding domain, called α6p. While it is known that the integrin is cleaved by urokinase plasminogen activator (uPA) little is known about how this process is regulated. There is a need to better understand the players involved in regulation of α6 cleavage as inhibiting this event from occurring may contribute to prolonged or increased patient survival or ultimately a cure.The existence of the integrin–actin complex has been known for many years. In this study actin was identified as a potential regulator of α6 cleavage. Using a diverse set of tumor cell lines (DU145, PC3 and MDA–MB–231) and a number of actin modifing compounds (latrunculin A, jasplakinolide and siRNA) it is reported here that disassembling actin filaments leads to an increase in α6p production. Although the increase in cleavage product did not always correlate with an increase in uPA receptor, an increase in uPAR was observed when actin was complexed by small molecule inhibitors. Taken together the results demonstrate a potential role for actin filaments to protect α6 integrin from uPA–uPAR induced cleavage via a multi–protein complex.
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Nollet, Eric A. "Integrin alpha6 Activity in Castration-Resistant Prostate Cancer." Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10289534.
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Although castration-resistant prostate cancers no longer respond to anti-androgen therapies, the androgen receptor (AR) is still required to promote tumor survival. However, the signaling pathways downstream of AR that promote this survival are not well known. We recently identified an AR-dependent survival pathway whereby AR induction of integrin α6β1 and adhesion to laminin activates NF-κB/RelA signaling and Bcl-xL. This pathway acts in parallel with the PI3K/Akt pathway in Pten-null tumor cells such that combined inhibition of both PI3K and integrin α6β1 is required to effectively kill tumor cells adherent to laminin. However, PTEN-null castration-resistant tumors were not effectively killed by this combination. I discovered that BNIP3, a hypoxia-induced BH3-only, pro-mitophagic Bcl-2 family member, is induced by androgen in castration-resistant cells through integrin α6β1 and HIF1α. Furthermore, castration-resistant cells adherent to laminin were much more efficient at inducing autophagy in response to androgen. Androgen blocked the ability of the PI3K inhibitor PX866 to kill castration-resistant tumors, but this was reversed by loss of BNIP3. Although BNIP3 was dispensable for androgen-induced autophagy, its mitophagy function was required for BNIP3 to promote resistance to PX866. Thus, enhanced hypoxia signaling in cooperation with AR/α6β1/HIF1α signaling on laminin in castration-resistant cells drives the expression of BNIP3 and enhances autophagy, both of which contribute to PX866 resistance through induction of mitophagy.
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Chang, Cheng. "Function and Regulation of the α6 Integrins in Mammary Epithelial Biology and Breast Cancer: A Dissertation." eScholarship@UMMS, 2015. http://escholarship.umassmed.edu/gsbs_diss/734.
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Integrins have the ability to impact major aspects of epithelial biology including adhesion, migration, invasion, signaling and differentiation, as well as the formation and progression of cancer (Hynes 2002; Srichai and Zent 2010; Anderson et al. 2014). This thesis focuses on how integrins are regulated and function in the context of mammary epithelial biology and breast cancer with a specific focus on the α6 integrin heterodimers (α6β1 and α6β4). These integrins function primarily as receptors for the laminin family of extracellular matrix (ECM) proteins and they have been implicated in mammary gland biology and breast cancer (Friedrichs et al. 1995; Wewer et al. 1997; Mercurio et al. 2001; Margadant and Sonnenberg 2010; Muschler and Streuli 2010; Nistico et al. 2014).
The first project investigates how alternative splicing of the α6 subunit impacts the genesis and function of breast cancer stem cells (CSCs). This work revealed that the α6Bβ1 splice variant, but not α6Aβ1, is necessary for the function of breast CSCs because it activates the Hippo transducer TAZ (Zhao et al. 2008a), which is known to be essential for breast CSCs (Cordenonsi et al. 2011). My work also led to the discovery that laminin (LM) 511 is the specific ligand for α6Bβ1 and that autocrine LM511, which is mediated by TAZ, is needed to sustain breast CSCs by functioning as a ‘ECM niche’. An important aspect of this study is the finding that surface-bound LM511 characterizes a small population of cells in human breast tumors with CSC properties.
The second project of my thesis concentrated on identifying transcription factors that regulate expression of the β4 subunit. The expression of the α6β4 integrin is repressed during the epithelial-mesenchymal transition (EMT) (Yang et al. 2009) but the contribution of specific transcription factors to this repression is poorly understood. This study revealed that Snai1 is a transcriptional repressor of β4, which is responsible for establishing the PRC2 (Polycomb complex 2)- associated repressive histone mark H3K27Me3. However, I also found that the ability of Snai1 to repress transcription is abrogated by its interaction with Id2. Specifically, I identified the biochemical mechanism for how Id2 regulates Snai1. Id2 binds the SNAG domain of Snai1 that is the docking site for several corepressors (Peinado et al. 2004; Lin et al. 2010b; Dong et al. 2012a). One important consequence of Id2 interacting with Snai1 on the β4 promoter is that it prevents repressive epigenetic modifications. This finding may explain why some epithelial cells express Snai1 and β4 because they also express Id2 (Vincent et al. 2009; Bastea et al. 2012). The repression of the α6β4 integrin during the EMT is consistent with data indicating that this integrin is not expressed in CSCs (Mani et al. 2008; Goel et al. 2012; Goel et al. 2013; Goel et al. 2014). An important question going forward is to understand how the α6β4 integrin contributes to tumor formation.
In summary, my thesis provides novel insights into the biology of the α6 integrins that has important implications for the function of these integrins in mammary gland biology and breast cancer, especially our understanding of breast CSCs.
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Hamade, Hussein. "Analyse des mécanismes moléculaires et cellulaires conduisant à une inflammation dans l'intestin et une progression tumorale induits par la perte de la sous-unité d'intégrine Alpha6 chez la souris." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ062/document.
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Le laboratoire a établi un modèle de souris α6ΔIEC qui développe une inflammation chronique intestinale associée à la formation d’adénocarcinomes colorectaux. Ce modèle correspond à une délétion ciblée à l’épithélium intestinal de l’intégrine α6β4. Mon projet de thèse a consisté à définir les mécanismes qui influencent la transformation de lésions inflammatoires en adénocarcinomes. La caractérisation du modèle α6ΔIEC a permis de mettre en évidence plusieurs altérations : détachement de l’épithélium, régénération du tissu, prolifération, augmentation de la perméabilité intestinale, hypersécrétion du mucus, ségrégation anormale des bactéries, inflammation chronique et formation de tumeurs.Pour étudier la séquence et la cinétique des mécanismes, j’ai développé un modèle de souris inductible (α6ΔIECTAM). Cette lignée présente, deux semaines après l’invalidation de l’intégrine α6,les mêmes signes d’inflammation que les souris α6ΔIEC. Mon approche a consisté à dissocier les processus impliqués dans chacune des étapes-clés de la pathologie afin de définir la contribution respective de l’infection par les bactéries et du stress mécaniqueWe generated a new mouse model, α6ΔIEC, in which the genetic ablation of α6 integrin from intestinal epithelial cells triggered the development of spontaneous colitis and colorectal cancer. My main goal was to define the mechanisms by which inflamed lesions degenerate into infiltrating adenocarcinomas. Loss of α6 integrin in this model resulted in epithelial barrier damage, enhanced permeability, altered mucus layers, abnormal bacterial segregation, chronic inflammation and tumor development.In order to define the sequence of events and the mechanisms involved at each stage of the disease, from inflamed to tumor lesions, I developed an inducible mouse model, α6ΔIECTAM, in which α6 integrin ablation was induced by tamoxifen treatment. This line recapitulates all aspects of inflammation observed in the α6ΔIEC model, as early as two weeks after tamoxifen treatment. In particular, I tried to define the respective contribution of infection by bacteria and mechanical stress during disease progression
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Mutz, Diana. "Identifizierung von Bindungspartnern des cytosolischen Teils der [alpha]3-Integrin-Untereinheit [Alpha3-Integrin-Untereinheit] und die Aufklärung ihrer Rolle bei der Funktion des [alpha]3[beta]1-Integrins [Alpha3beta1-Integrins]." [S.l. : s.n.], 2004. http://www.diss.fu-berlin.de/2004/214/index.html.
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Schaff, Mathieu. "Etude des mécanismes d'adhérence et d'activation des plaquettes sanguines appliquée à l'identification de nouvelles cibles anti-thrombotiques plus sûres." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00867777.
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L'adhérence, l'activation et l'agrégation des plaquettes sanguines sont essentielles à l'hémostase mais peuvent également conduire à la thrombose artérielle sur plaque d'athérosclérose, aujourd'hui première cause de mortalité dans le monde. Les anti-thrombotiques actuels, dirigés contre l'activation et l'agrégation plaquettaires, ont une efficacité reconnue mais ont pour inconvénient d'augmenter le risque de saignement. L'objectif de cette thèse a été d'explorer de nouvelles stratégies réduisant la thrombose tout en préservant l'hémostase. L'utilisation de souris modifiées génétiquement a mis en évidence que l'intégrine alpha6 beta1, impliquée dans l'adhérence des plaquettes aux laminines, joue un rôle critique en thrombose expérimentale mais pas en hémostase. De plus, nous avons montré dans un système de perfusion de sang qu'une protéine préférentiellement exprimée dans les plaques d'athérosclérose, la ténascine-C, permet l'adhérence et l'activation des plaquettes. En revanche, la beta-arrestine-1, une protéine de signalisation, ne contribue que modestement aux fonctions plaquettaires et à la thrombose. En conclusion, ce travail a permis de dégager deux nouvelles pistes anti-thrombotiques potentiellement capables de préserver l'hémostase, basées sur le ciblage de l'intégrine alpha6 beta1 ou de l'interaction plaquette/ténascine-C.
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Bao, Wenjie. "Role of integrin signaling in cell proliferation and survival /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-394-9/.
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Nadif, Raja. "The in vivo role of integrin alpha7 in heart integrity and function." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492878.
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Cardiovascular complications, including cardiac hypertrophy, arrhythmias and sudden death, are commonly associated with muscular dystrophies. Null mutations of the integrin alpha? gene, an essential mediator of cellular attachment to the extracellular matrix in cardiac and skeletal muscle, leads to progressive muscular dystrophy in humans, which is faithfully replicated in the integrin alpha? deficient (a7-/-) mouse model. In the latter, premature sudden death is not directly attributable to the dystrophic phenotype. We therefore analysed the cardiac phenotype in integrin a7-/- mice to determine whether their premature death is associated with altered cardiac structure and function and/or altered cardiac rhythm.
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Rahman, Abdul. "Neonatale Alloimmunthrombozytopenie die Entwicklung von rekombinanten [alpha]II-1tnb[beta]3-Integrin-Isoformen [Alpha-IIb-Beta-3-Integrin-Isoformen] (HPA-1 Antigene) und funktionelle Untersuchung einer seltenen Punktmutation auf [beta]3-Integrins [Beta-3-Integrins] (Oea-Antigen) /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968380859.
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Zargham, Ramin. "[Alpha]8[beta]1 integrin and vascular injury : role of [alpha]8[beta]1 integrin in restenosis after balloon injury." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111876.
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Restenosis is the major cause of the failure of reconstruction methods to restore the blood flow in atherosclerotic arteries. Restenosis results from neointima formation and consequent constrictive remodelling. Vascular smooth muscle cell (VSMC) migration from the tunica media toward the intima is crucial in neointima genesis. The prerequisite for VSMC migratory activity is the modulation from the differentiated (contractile) to the de-differentiated (noncontractile) phenotype. VSMC phenotype change is associated with the altered expression of integrins. alpha8beta1 integrin is upregulated in cell types with contractile properties, including myofibroblasts and mesangial kidney cells. It is one of the integrins that is intensely expressed in mature VSMCs. alpha8beta1 integrin expression during vascular injury and its role in VSMC function have not been studied so far.In this work, a rat model of carotid angioplasty was used to mimic vascular injury in humans. alpha8beta1 integrin was downregulated in the tunica media concomitantly with loss of the contractile phenotype. In vitro study revealed that it is a differentiation marker of VSMCs. To test the functional significance of the association between alpha8 integrin and the VSMC phenotype, short interference RNA was deployed to silence the alpha8 integrin gene. alpha8 integrin gene silencing heightened VSMC migratory activity as well as modulation of the VSMC phenotype in favour of the noncontractile state. In addition, alpha8 integrin overexpression induced re-differentiation of VSMCs and attenuated their migratory activity. It is, therefore, suggested that alpha8 integrin overexpression after vascular injury might control VSMC migration and neointima formation. On the other hand, alpha8 integrin gene silencing led to a reduced growth rate, which indicated a dichotomy between VSMC migration and proliferation.
In the later stages of neointima formation, constrictive remodeling plays a major role in late lumen loss. Our data demonstrated that alpha8 integrin is upregulated in the neointima during constrictive remodeling with concomitant luminal narrowing. The importance of this finding was highlighted by results showing that alpha8 integrin was required for the VSMC contractile phenotype evoked by transforming growth factor-beta (TFG-beta) and TFG-beta-induced myofibroblastic differentiation of Rat1 fibroblasts. Thus, it appears that alpha8 integrin expression blockade might reduce contractile remodeling and late lumen loss. Although the mechanism of alpha8 integrin signaling is not yet clear, our findings demonstrate that the alpha8 integrin-induced contractile phenotype is blocked by RhoA inhibitors. Furthermore, alpha8 integrin and RhoA are co-immunoprecipitated, and alpha8 integrin gene silencing reduces RhoA activity. Hence, it is postulated that alpha8-RhoA signaling might be closely intertwined.
Altogether, these studies indicate that alpha8 integrin is a contractile marker of VSMCs and a negative regulator of VSMC migration. Therefore, forced alpha8 integrin expression may be applied to reduce neointima formation. However, alpha8 integrin upregulation during constrictive remodeling concomitant with late lumen loss suggest that it could be involved in lumen narrowing. It seems likely that in therapeutic strategies to reduce restenosis the timeline of interference might be very important. Therefore, alpha8 integrin gene silencing in the later stages of neointima formation might be beneficial.
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Weiken, Claudia. "Kollagenrezeptor [alpha]2[beta]1-Integrin [Alpha-2-Beta-1-Integrin] auf humanen und tierischen Thrombozyten Heterogenität und ihre Bedeutung /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=976077981.
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Pawar, Sangita. "Regulation of Integrin Alpha 6 Cleavage in Cancer." Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/194296.
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Cancer metastasis is a multi-stage process initiated by the cancer cell acquiring the ability to migrate. The protein profile of such a cell undergoes dramatic changes including changes in integrin expression. Integrins play a major role in cell adhesion, motility, differentiation, blood clotting, tissue organization and cell growth as well as cancer cell migration, invasion and metastasis. Integrin a6, which can pair with integrin b4 or b1 is a laminin receptor and is detected in epithelial cells. Earlier studies have reported uPA mediated integrin a6 cleavage in prostate cancer resulting in loss of the ligand binding domain. Site-directed mutagenesis studies have identified the cleavage site to be at R594R595 located in the "stalk" region of the integrin a6. Prostate cancer cells PC3N-a6-RR cells, bearing a R594R595 to A594A595 mutation, engineered to express the uncleavable form of integrin a6 were found to migrate 6.4 folds lesser on Laminin-1 as compared to the PC3N-a6-WT cells which expressed the wild-type integrin a6. This result suggests that integrin a6 cleavage enhances migration. Prostate cancer is known to metastasize to the bone. Injection of the PC3N-a6-WT cells in mouse femurs resulted in increased bone destruction and pain behavior when compared to the femurs injected with PC3N-a6-RR cells indicating that the integrin a6 cleavage could affect and modify the bone microenvironment. An observation that complete conversion of integrin a6 to a6p was not observed in cell lines even in presence of excess uPA suggested a regulatory mechanism. Integrins are known to associate with many proteins including tetraspanins, which are transmembrane proteins, that function as protein adapters. Integrin a6 was found to be refractory to uPA mediated cleavage when complexed with tetraspanin CD151. The amount of integrin a6 available for cleavage increased when CD151 levels were decreased by CD151 siRNA treatment. These results suggest that the integrin a6 available and unavailable for cleavage can be modulated by interaction with CD151 and hence affect the migratory potential of the cell. Collectively these data suggest that integrin a6 cleavage can enhance cell migration, initiate signals to modify the tumor microenvironment and can be regulated by interaction with tetraspanin CD151.
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Dydensborg, Anders Bondo. "Integrin [alpha]6A[bêta]4 in colon cancer." [S.l. : s.n.], 2006.
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Dydensborg, Anders Bondo. "Integrin [alpha]6A[béta]4 in colon cancer." Thèse, Université de Sherbrooke, 2006. http://savoirs.usherbrooke.ca/handle/11143/4231.
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The expression level of the [alpha]6A[béta]4 integrin has been reported to be elevated in a number of human cancers in accordance with its known stimulatory role in several aspects of cancer progression such as promoting invasion and stimulating intracellular signaling of importance for cellular proliferation and survival. In the present work the expression levels of [béta]4 in adenocarcinomas of the human colon were evaluated at the transcript level in comparison with the expression levels in patient matched healthy colonic tissue. Not only were the expression level of the [béta]4 subunit found to be upregulated in cancerous tissue, but levels of expression of [béta]4 were found to be closely correlated to levels of expression of those of the oncogenic transcription factor MYC. This correlation was demonstrated to be of functional importance for the expression level of [béta]4, since forced expression of MYC in a colon cancer cell line stimulated transcriptional activity of various [béta]4 promoter constructs.The pre-mRNA of the [alpha]6 subunit undergo alternative splicing yielding two different variants: the A and the B variants. Their distinct intracellular domains and their distinct biochemical properties characterize these variants. As part of the characterization of the expression of the [alpha]6A[béta]4 integrin in colon cancers, the expression level of total [alpha]6 as well as the two different variants were investigated. As for the [béta]4 subunit the total level of [alpha]6 were found to be elevated in cancers as compared to their corresponding healthy resection margins. Interestingly, an alteration of the ratio of expression of two splice variants of the [alpha]6 subunit was found to be significantly altered in 81% of the cancers investigated. Thus, the expression ratio shifted from a predominant expression of [alpha]6B in the healthy resection margins to a predominant expression of [alpha]6A in the primary adenocarcinomas. Such differential expression of splice variants was also found in the normal human small intestine. Indeed, the proliferative crypts were found to express the [alpha]6A variant, while the differentiated compartments of the crypt-villus axis were found to express the [alpha]6B variant.The functional importance of this was confirmed when over-expression of the two different splice variants were demonstrated to differentially activate the [béta]-catenin/TCF4 and MYC transcriptional complexes, two well known players in intestinal proliferation and adenocarcinomas formation. On the other hand the two splice variants were not found to differentially affect differentiation of human enterocytes as assayed by monitoring the transcriptional activity from promoter constructs of sucrase-isomaltase, lactasephlorizin hydrolase, DPPIV and ALPP. Finally, it has become increasingly clear that the classic normalizing genes such as GAPD and [béta]-actin can display modulated expression levels across tissue types and during cellular differentiation. Therefore, experiments aimed at identifying and validating normalizing genes for transcript measurements during the complex cellular processes of differentiation and cancer progression in the human gut were carried out. Previously generated microarray data were screened for candidate genes of which two were selected for further analyses along with seven commonly used normalizing genes. Real time RT-PCR amplifying the nine putative normalizing genes were performed on various samples representing different differentiation stages of human enterocytes as well as on patient matched primary tumors and healthy resection margins. Using several statistical approaches, RPLP0 and B2M were found to be the two best normalizing genes for experiments aimed at assessing transcript during differentiation and in cancers respectively. These studies should serve as a paradigm for other studies aimed at validating other normalizing genes under other experimental settings.
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Chakraborty, Arup R. "Differential expression of integrin [alpha]₃[beta]₁ and [alpha]₆[beta]₄ molecules on a panel of rat esophageal cell lines." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=bgsu1131345357.
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Laplantine, Emmanuel. "Interactions au niveau des domaines intracellulaires des sous-unites alpha3a, alpha6a et beta1a des integrines." Paris 6, 2000. http://www.theses.fr/2000PA066262.
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Les adhesions focales (af) constituent un lien essentiel entre la matrice extracellulaire et le cytosquelette, ainsi que le site de transmission de signaux par les integrines. Les integrines 31 et 61, recepteurs des laminines, different dans leur specificite de reconnaissance : la laminine 1 se lie a l'integrine 61 seulement et l'adherence des cellules a ce substrat entraine la formation d'af distinctes de celles formees sur d'autres isoformes de laminine liant a la fois 31 et 61. L'integrine 31 pourrait donc reguler de maniere transdominante l'integrine 61. Afin de tester cette hypothese, des peptides representant le domaine intracellulaire des sous-unites 3a ou 6a d'integrines ont ete injectes dans des fibroblastes vivants adheres a la laminine 1. Seule la microinjection du peptide 3a entraine une reorganisation specifique des af, rappelant celles formees lors de l'activation du recepteur 31 par ses ligands. De plus, des etudes par resonance plasmonique de surface (spr) permettent de detecter une interaction directe entre les peptides correspondant aux domaines intracellulaires des sous-unites 3a et 1a d'integrine. Enfin, un criblage de banque d'adnc avec le domaine intracellulaire de la sous-unite 3a comme amorce dans le systeme double hybride chez la levure, a permis l'identification de plusieurs partenaires d'interaction. Parmi ceux-ci, la proteine dral/fhl2 interagit avec l'integrine 31 in vivo. En conclusion, differentes interactions specifiques au domaine intracellulaire de la sous-unite 3a, contribuent a la regulation de l'organisation des af par l'integrine 31. Par ailleurs, nous avons examine la contribution du domaine intracellulaire de la sous-unite 1a dans le phenomene de clustering des integrines. Des analyses en spr revelent une affinite du domaine intracellulaire de 1a pour lui-meme. Des experiences en gel filtration et en sds-page montrent que ce domaine forme des multimeres qui, d'apres des mesures en dichroisme circulaire, adoptent une structure en helice. L'oligomerisation et le changement de structure secondaire du domaine intracellulaire de la sous-unite 1a pourraient intervenir de maniere active dans l'agregation des integrines et la formation des af.
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Parks, William. "Force activation of I domain containing and lacking integrins on live cells." Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/42695.
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Cellular adhesion plays a crucial role in the biological function of cells, allowing them to communicate and signal, as well as physically anchor, by enabling them to adhere to either other cells or the extra cellular matrix (ECM). This process is regulated by several factors including intrinsic bond kinetics, internal cellular signaling, environment, force exerted on the bond, and force history of the bond. Concerning the force and force history dependence, the observation of catch bonds in integrin binding has asked as more questions than it has answered.
To explore the force and force history dependence this process, each bond was loaded to a peak force before relaxing to a much lower force that was held for the duration of the measurement. Two different integrins were studied, both of which have in previous works exhibited a catch bond. Furthermore, the effects of different metal ion conditions and an allosteric antagonist were also studied to elucidate the conformational effects on force priming of integrin. What was observed was that I domain, or αA domain, possessing integrin, whether tested against its more active or less active binding state, changed very little in terms of off rate once the priming force was applied. However in the I domain, or αA domain, lacking integrin, the observed off rate changed as well. It seems that force priming is capable of causing integrin to bind in a stronger manner regardless of the other conditions used to either activate or inhibit binding. However the way in which the binding is strengthened depends on the receptors structure.
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DiCara, Danielle. "Targeting alpha v beta 6 integrin for cancer imaging." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522319.
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Alemany, i. Boor Monica. "Domaines fonctionnels de l'intégrine plaquettaire (alpha)IIb(beta)3." Grenoble 1, 1995. http://www.theses.fr/1995GRE10023.
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Les integrines sont des recepteurs membranaires, qui interviennent dans les reactions d'adhesion entre cellules, ou entre cellules et matrice extracellulaire. Au cours de notre these, nous nous sommes interesses a l'integrine alphaiib beta3. Dans une premiere partie, nous avons etudie les domaines des deux sous-unites impliquees dans le transport de l'heterodimere. Cette etude a abouti a la production d'un complexe alphaiib beta3 soluble et fonctionnel. En consequence, il pourrait etre envisageable de le cristalliser afin de determiner la structure tridimensionnelle du recepteur alphaiib beta3. Dans la deuxieme partie de cette these, nous nous sommes interesses aux domaines de fixation des ligands presents sur la sous-unite beta3. La premiere strategie a consiste a elaborer differents fragments recombinants. Ainsi, les differentes sequences fonctionnelles de l'integrine ont pu etre isolees et leurs proprietes etablies individuellement. La deuxieme approche est basee sur la caracterisation d'un anticorps anti-beta3. La localisation precise de son epitope a permis l'identification d'un nouveau site d'interaction avec les ligands, localisee entre les acides amines beta:274-368. Ce site est fonctionnel quel que soit l'etat d'activation de l'integrine alphaiib beta3. Il interagit avec la chaine gamma du fibrinogene. Le site 274-368 de la sous-unite beta3 permet au recepteur alphaiib beta3 non stimule d'interagir rapidement avec le fibrinogene immobilise, permettant le recrutement de plaquettes non activees au niveau d'un thrombus en croissance. Ce domaine participe egalement a l'interaction du recepteur alphaiib beta3 active avec les ligands solubles. On peut en deduire que ce site est un site d'interaction primaire qui va cooperer avec les autres sites, fonctionnels uniquement apres activation, pour assurer une fixation irreversible du ligand
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Geginat, Jens. "Interdependence between adhesion and proliferation the role of the [alpha]L- [alphaL-], [beta]2-integrin [beta2-integrin] (LFA-1) in t cell antigen receptor dependent proliferation of primary human t lymphocytes /." [S.l.] : [s.n.], 1999. http://www.diss.fu-berlin.de/1999/35/index.html.
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Ni, He-Hong. "Contribution of integrin [alpha] 6 [bêta] 4 to colon cancer." Sherbrooke : Université de Sherbrooke, 2004.
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Ghannad, Farzin. "Expression of alpha v beta 6 integrin in periodontal disease." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31758.
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Integrins are the principal cell surface receptors that mediate cell-to-cell or cell-to-extracellular matrix (ECM) binding, providing adhesion for stationary cells, traction
during cell movement and, importantly, translating extracellular matrix cues into
intracellular signal transduction pathways. The ανβ6 integrin, an exclusively epithelial
integrin, exhibits limited distribution in the body. In adult tissue, ανβ6 integrin is
expressed during inflammation, carcinogenesis, and in wound healing. It is not expressed
in oral gingival epithelium but it is constitutively expressed in junctional epithelium (JE).
Its capability to bind and activate transforming growth factor-β (TGFβ) suggests immune
regulation and it could therefore play a protective role against periodontal disease. When
comparing hematoxylin and eosin stained paraffin sections of wild-type (FVB) and β6
integrin-knockout mice (β6 -/-) under the light microscope, apical migration of junctional
epithelium beyond the cemento-enamel junction (CEJ) resulting in formation of pocket
epithelium (PE) was clearly demonstrated only in specimens of β6 integrin-knockout
animals. In addition, analysis of defleshed mandibles revealed a significant increase in
alveolar bone loss and therefore enhanced exposed root surface area and furcation
involvement for knockout mice in comparison to their age matched wild-type animals
(FVB). The findings of this study suggest that ανβ6 integrin, exclusively expressed in JE,
might play an important role in the pathogenesis of periodontal disease in mice. One
possible mechanism could be through its regulatory function in the activation of TGFβ.Dentistry, Faculty of
Graduate
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Ni, He-Hong. "Contribution of integrin [alpha]6[bêta]4 to colon cancer." Thèse, Université de Sherbrooke, 2004. http://savoirs.usherbrooke.ca/handle/11143/4190.
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Integrin [alpha]6[bêta]4 is a specific laminin binding protein expressed at the base of epithelia. This integrin has been previously analyzed in colon cancers by indirect immunofluorescence using various antibodies by distinct groups, but their results have raised conflicting data. In the current study, [bêta]4 subunit expression was analyzed at the protein level in 22 primary tumors and corresponding resection margins; and at transcript level in 8 primary tumors and corresponding resection margins as well as in 6 adenocarcinoma cell lines. For immunodetection, the antibodies recognizing both the truncated and wild type intestinal forms of [bêta]4 (Basora et al., 1999) were used. In the normal colonic mucosa, both forms were detected at the base of the epithelium in the bottom and at the surface of the glands, respectively. In colon cancers, [bêta]4 staining intensity was found to be increased in 19/22 specimens as compared with their normal counterparts. Analysis of integrin [bêta]4 expression at the protein level in primary carcinomas and in the adenocarcinoma cell lines showed the presence of the [bêta]4 wild type form. The levels of transcription of the integrin [bêta]4 and [bêta]1 subunits, the transcription factors c-Myc, N-Myc and AP-1 (c-Fos, Fra-1, Fra-2, c-Jun) and the housekeeping genes S14 and [bêta]-actin were determined by RT-PCR in the 8 primary tumor paired samples. The results showed that the relative amounts of the [bêta]4 integrin and c-Myc transcripts were significantly upregulated in primary carcinomas in comparison to the resection margins (p < 0.01). Interestingly, a significant correlation was noted between integrin [bêta]4 and c-Myc transcript levels in the various samples (p < 0.005). Co-transfection studies with a c-Myc expression vector and the integrin [bêta]4 promoter linked to the luciferase reporter gene in Caco-2/15 cells showed that the integrin [bêta]4 promoter is activated by c-Myc (p < 0.05). c-Fos mRNA was reduced in colon cancers (p < 0.05), while integrin [bêta]1, Fra-1, Fra-2 and c-Jun transcript levels remained unchanged. In conclusion: (1) in vivo , the level of integrin [bêta]4A subunit expression increased in colon carcinomas relative to their normal counterparts, (2) the increased expression of integrin [bêta]4A is closely correlated with an elevated level of c-Myc as judged by RT-PCR, (3) over-expression of c-Myc activates the integrin [bêta]4 promoter in Caco2/15 cells, (4) the [bêta]4Actd-form, which was detected in the proliferative/undifferentiated compartment of the normal colonic mucosa, is lost in colon cancer cells in both primary tumors and adenocarcinoma cell lines. These finding indicate that the full length form of integrin [bêta]4A is involved in colon cancer cell proliferation and progression.
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Künneken, Kerstin. "Rekombinante Mini-Laminin-5-Proteine zur Charakterisierung der 3 1-Integrin-Bindung [Alpha-3-Beta-1-Integrin-Bindung]." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=967391334.
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Brunton, Fiona. "Targeting the osteoclast alpha v beta 3 integrin by phage display." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511761.
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Stanco, Amelia Anton Eva S. "The role of [alpha]3[beta]1 integrin in cortical development." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1789.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Neurobiology in the Curriculum of Neurobiology." Discipline: Neurobiology; Department/School: Medicine. On title page, [alpha] and [beta] appear as Greek characters.
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Woodard-Grice, Alencia V. "Hyposialylation regulates [alpha]4[beta]1 integrin binding to VCAM-1." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2009r/woodard.pdf.
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Mohazab, Leila. "The role of alpha v beta 6 integrin in enamel biomineralization." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45355.
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Tooth enamel has the highest degree of biomineralization of all vertebrate hard tissues. During the secretory stage of enamel formation, ameloblasts deposit an extracellular matrix that is in direct contact with ameloblast plasma membrane. Although it is known that integrins mediate cell-matrix adhesion and regulate cell signaling in most cell types, the receptors that regulate ameloblast adhesion and matrix production are not well characterized. Thus, we hypothesized that αvβ6 integrin is expressed in ameloblasts where it regulates biomineralization of enamel. Human and mouse ameloblasts were found to express both β6 integrin mRNA and protein. The maxillary incisors of Itgb6-/- mice lacked yellow pigment and their mandibular incisors appeared chalky and rounded. Molars of Itgb6-/- mice showed signs of reduced mineralization and severe attrition. The mineral-to-protein ratio in the incisors was significantly reduced in Itgb6-/- enamel, mimicking hypomineralized amelogenesis imperfecta. Interestingly, amelogenin-rich extracellular matrix abnormally accumulated between the ameloblast layer of Itgb6-/- mouse incisors and the forming enamel surface, and also between ameloblasts. This accumulation was related to increased synthesis of amelogenin, rather than to reduced removal of the matrix proteins. This was confirmed in cultured ameloblast-like cells, which did not use αvβ6 integrin as an endocytosis receptor for amelogenins, although it participated in cell adhesion on this matrix indirectly via endogenously produced matrix proteins. In summary, integrin αvβ6 is expressed by ameloblasts and it plays a crucial role in regulating amelogenin deposition/turnover and subsequent enamel biomineralization.
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Worst, Robinson André. "Influência da expressão da alfa-6 integrina na produção de células-tronco espermatogoniais murinas transgênicas." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/10/10131/tde-25042013-142427/.
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Ao longo da vida reprodutiva dos machos adultos, espermatozoides são formados pelas células-tronco espermatogoniais (SSCs, do inglês spermatogonial stem cells) por um processo conhecido como espermatogênese. O cultivo in vitro de SSCs abriu novas possibilidades para a transgenia, no entanto os protocolos requerem a adição de fatores de crescimento, o que encarece a manutenção dessas células por um tempo prolongado, fazendo da criopreservação de SSCs uma alternativa para esse problema. O fenótipo molecular de células-tronco espermatogoniais tem sido objeto de estudo nas últimas décadas. Uma das moléculas mais estudadas como marcador na caracterização de espermatogônias é a alfa-6 integrina. Baseado nestas informações, a seguinte hipótese foi proposta: SSCs que apresentam maior expressão de alfa-6 integrina são mais eficientes para modificações genéticas e colonização de túbulos seminíferos. Para testar essa hipótese, as SSCs murinas foram dissociadas de testículos de camundongos com 8 a 11 dias de idade. Essas células foram cultivadas in vitro, caracterizadas quanto sua morfologia, congeladas e incubadas com anticorpo anti-alfa-6 integrina para a purificação das SSCs por separação celular ativada por fluorescência (FACS). Células testiculares foram geneticamente modificadas com a inserção do gene marcador LacZ e o transplante através dos ductos eferentes foi padronizado. As Células germinativas testiculares foram dissociadas e cultivadas in vitro, porém a viabilidade foi aquém da desejada, inviabilizando as etapas de transformação, transplante e posterior avaliação histológica. Usando o marcador molecular alfa-6 integrina foi possível separar populações de células germinativas testiculares por FACS e a expressão gênica de ITGα6, GFRα1, Oct-4 e Thy-1 foi detectada por RT-PCR quantitativo. Em conclusão, não foi possível comprovar a eficiência de transdução e colonização em túbulos seminíferos por células-tronco espermatogoniais selecionadas com alfa-6 integrina.Throughout the reproductive life of adult males, spermatozoa are formed from spermatogonial stem cells (SSCs) by a process known as spermatogenesis. The in vitro culture of SSCs created new possibilities for transgenesis, however the protocols require addition of growth factors, which increases the maintenance costs of these cells for a prolonged time, making of the cryopreservation of SSCs an alternative for this problem. The molecular phenotype of spermatogonial stem cells have been target of studies in recent decades. One of the most studied marker molecule in the characterization of spermatogonia is integrin alpha-6. Based on these informations, the following hypothesis was proposed: SSCs that show increased expression of integrin alpha-6 are more efficient for genetic modification and colonization of seminiferous tubules. In order to test this hypotesis, murine SSCs were dissociated from testes of 8 to 11 days old mice. These cells were in vitro cultured, characterized based on its morphology, frozen and incubated with anti-integrin alpha-6 antibody for the purification of SSCs by activated cell sorting fluorescence (FACS). Testicular cells were genetically modified with the insertion of the marker gene LacZ and transplantation through the efferent ducts was standardized. The testicular germ cells were dissociated and in vitro cultured, however viability was below expected, precluding the steps of transformation, transplantation and subsequent histological evaluation. Using molecular marker integrin alpha-6 it was possible to separate testicular germ cell populations by FACS and gene expression of ITGα6, GFRα1, Oct-4 and Thy-1was detected by quantitative RT-PCR. In conclusion, it was not possible to prove the efficiency of transduction and colonization in the seminiferous tubules by spermatogonial stem cells selected with alpha 6 integrin.
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Leppert, Jan. "Identifizierung und Charakterisierung von Interaktionspartnern des Integrins [alpha]6[beta]4 [alpha-6-beta-4]." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=974508780.
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Zimmermann, Dunja. "Der Einfluss cyclischer RGD-Peptide auf die Wechselwirkung Fibronectin-Integrin [alpha]5[beta]1[alpha 5 beta 1]." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970414277.
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Heller, Kristin Noreen. "Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7)." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639.
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McCandless, John Richard 1954. "Alpha-6 beta-1 and alpha-6 beta-4 integrin expression and the vascularization of human prostate tumor xenografts." Thesis, The University of Arizona, 1997. http://hdl.handle.net/10150/278603.
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Growth and metastasis of tumors appear to be dependent on the ability of tumor cells to recruit blood vessels. Integrins are a class of cell adhesion molecules that may have a role in angiogenesis. In this study the effect of the expression of two integrins, α6β1 and α6β4, on microvessel density in human prostate tumor xenografts in SCID mice was evaluated. Five methods (one-person count, two-person count, digital analysis of immunostained tissues, and digital analysis of vascular corrosion casts) were used to measure microvessel density. Results indicate that alpha6 integrin expression correlates negatively with tumor vessel density. and with tumor cell proliferation but not the extent of the tumor burden. β4 integrin expression does not appear to affect tumor vessel density, tumor cell proliferation, nor tumor burden. Comparison of methods of quantitation suggest that computer-assisted vessel counting may offer advantages over optical counting or computer-assisted area measurement.
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Sun, Guobin. "The role of protein tyrosine phosphatase alpha tyrosine 789 phosphorylation in integrin signaling." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/43924.
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Focal adhesions (FA) form interfaces between the extracellular matrix and the cytoskeleton to regulate cell responses such as cell proliferation, survival, and migration. The functions and dynamic interactions of many of the ~180 molecules in this integrin-initiated FA complex network are far from fully understood. Among these is the receptor-like protein tyrosine phosphatase PTPα. In addition to the integrin-proximal action of PTPα to catalyze activation of Src family kinases, subsequent phosphorylation of PTPα at its C-terminal Tyr789 site is essential and acts in an unknown manner to promote cell spreading and migration. We used reconstitution assays in PTPα-null cells to identify and distinguish integrin signaling events that were PTPα-dependent and PTPα-Tyr789-dependent. Results show that PTPα-Tyr789 mediates the localization of PTPα and the scaffolding protein Cas to FAs where Cas interacts with and gets phosphorylated by Src to initiate Cas/Crk-Rac/Cdc42-PAK signaling. Linking these events, this study identifies the Cas-binding protein BCAR3 as a molecular connector of PTPα and Cas, with phosphoTyr789-PTPα interacting with the BCAR3 SH2 domain to recruit BCAR3-Cas to newly forming adhesion sites. These findings identify phospho-Tyr789-PTPα as the first cellular ligand for the SH2 domain of BCAR3, and reveal a role of PTPα in integrin-induced adhesion complex assembly that enables Src-mediated activation of the pivotal function of Cas in cell migration. Furthermore I extended this study into a cancer cell model by showing that the disruption of this PTPα-BCAR3-Cas-Src signaling module inhibits the invasive motility in a rhabdomyosarcoma cell line. In summary, my results in this thesis elucidate the molecular mechanism underlying the PTPα-Tyr789-dependent cell spreading and migration, and support that the PTPα-BCAR3-Cas complex is a critical regulator of cell migration as well as cancer cell invasion and metastasis.
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Rabinovitz, Isaac. "The role of alpha 6 integrin and its ligand, laminin, in prostate cancer." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187186.
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Laminin is a major component of basal lamina and binds to the cell largely through a6 integrin receptors. The continued production of laminin by a tumor cell could confer an advantage to further invasion. The endogenous production of laminin by human prostate tumor cell lines OU145 (tumorigenic) and LNCaP (non-tumorigenic) was analyzed and related to their tumorigenic potential. Both produced classical laminin and S-laminin. OU145 laminin chain ratio (A:B1:B2:S) was (1.8):(1.0):(2.5):(1.0) compared to LNCaP cells, which was (1.0):(0):(10.0):(2.5). LNCaP cells retained most of their laminin production and their secreted forms were hypoglycosylated. LNCaP cells bound little laminin to their surface. In contrast, tumorigenic OU145 cells secreted most of their laminin in mature forms which bound to their surface. These features of LNCaP cells could contribute to their low adhesiveness and non-tumorigenic phenotype. Cell adhesion to' the extracellular matrix is mediated largely by integrins and is an important component to accomplish invasion. Prostate tumor cell lines were analyzed for their integrin content and function and related to their tumorigenic potential. OU145 cells contained α6, α3, α5, av integrins. Except for α3, LNCaP cells expressed all integrins with a lower molecular weight. LNCaP cells attached to ECM substrates to a lesser extent than DU145 cells. LNCaP cell deficient production of integrins and low attachment could affect their tumorigenic potential. In contrast DU145 cells express normal integrins and laminin and are tumorigenic. The α6 integrin (laminin receptor) persists during prostate tumor progression. To examine the role of a6 integrin in invasion, DU145 cells were sorted to select high (DU-H) and low (DU-L) a6 integrin expressors. DU-H cells contained α6β1 and α6β4 heterodimers compared to DU-L that only contained a low levels of α6β4. DU-H cells were three times more mobile on laminin as compared to the low expressors. Adhesion and migration were inhibited with anti-α6 antibody. Cells were injected intraperitoneally into SCID mice to test their invasive potential. DU-H showed greater invasion than DU-L, with increased expression of α6 integrins at the invasion areas. These data suggest that α6 integrin expression may be advantageous for invading cells.
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Wray, Helen. "Characterisation of apoptotic responses in human keratinocytes expressnig alpha-6 integrin and CD44." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/372.
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a6 integrin has previously been proposed as a human keratinocyte stem cell markers. CD44-positive cells in epithelial tumours have been identified as potential cancer stem cells (CSCs) and display increased survival following chemotherapy. Keratinocytes expressing CD44 and a high level of a6 integrin (a6 integrinhigh+/CD44+ cells) displayed stem cell-like growth qualities in vitro including the formation of holoclone-like colonies and a high proliferative capacity. Irradiation with ultraviolet-B (UVB) initiated apoptosis in the total keratinocyte population. However, the a6 integrinhigh+/CD44+ cells were significantly resistant to UVB-induced apoptosis. This fraction was also resistant to apoptosis following treatment with the genotoxic agents etoposide, camptothecin and bleomycin. In contrast, the population was highly apoptotic following cisplatin treatment. Addition of the PI3 Kinase inhibitors Wortmannin and LY294002 prior to inducement increased the apoptotic sensitivity of the a6 integrinhigh+/CD44+ cells to UVB. However, pAkt was not directly involved due to the addition of a specific Akt-inhibitor not affecting the resistance of the cells to UVB. Cisplatin can induce p63-mediated apoptosis via c-abl activation. Preincubation with the c-abl kinase inhibitor imatinib significantly reduced the level of cisplatin-induced apoptosis in the a6 integrinhigh+/CD44+ population. Interestingly, the a6 integrinhigh+/CD44+ cells displayed a significantly higher level of TAp63 mRNA compared to the rest of the cell population. The nuclear expression of p63 was reduced, not increased, following cisplatin treatment and imatinib inhibited this loss. This thesis has identified a pattern of apoptotic behaviour not previously characterised in human keratinocytes. a6 integrinhigh+/CD44+ cells display a consistent apoptotic resistance to UVB, etoposide and camptothecin and a 3 sensitivity to cisplatin in vitro. Increased levels of TAp63 and evidence of PI3K and c-abl signalling have provided clues as to the pathways involved in this behaviour.
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Cheng, Suzanne Yuen Shan. "The function of protein tyrosine phosphatase alpha (PTPα) phosphorylation in integrin-mediated signaling." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45615.
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The integrin signaling network involves over 180 components and regulates a wide range of biological activities including cell adhesion, survival and migration. However, the details of the molecular mechanisms that govern these cellular processes remain unclear. Since defective integrin signaling is often associated with diseases such as cancer, a precise understanding of the molecular mechanisms underlying integrin-mediated processes may provide novel insights for developing therapeutics against cancer. Protein tyrosine phosphatase alpha (PTPα) is a receptor-like PTP that activates Src family kinases (SFKs) upon integrin stimulation. In addition, its C-terminal tail Tyr789 phosphorylation, mediated by an active Src-FAK complex, promotes integrin-induced cell spreading, focal adhesion (FA) formation, and cell migration. I hypothesized that PTPα-phosphoTyr789 serves as an SH2-domain binding site to recruit other focal adhesion proteins to regulate cell migration. Studies involving re-expression of an unphosphorylatable mutant (Y789F) of PTPα in PTPα-null cells revealed that PTPα Tyr789 promotes FA localization and tyrosine phosphorylation of Cas, a key player in cell migration. Furthermore, BCAR3 was identified as a novel binding partner of PTPα-phosphoTyr789 that mediates Cas association with PTPα, in this way localizing Cas to FAs to promote downstream signaling to regulate cell migration. The adaptor protein Grb2 also interacts with PTPα-phosphoTyr789 but its role in association with PTPα is unknown. Using a Grb2-silencing approach, I discovered that Grb2 regulates integrin-induced PTPα Tyr789 phosphorylation via two distinct mechanisms: 1) Grb2 regulates FAK autophosphorylation and thus FAK/Src complex activation and 2) the SH2 and C-terminal SH3 domains of Grb2 mediate the formation of a PTPα-Grb2-FAK complex. Together, these roles of Grb2 promote Src-FAK-mediated PTPα tyrosine phosphorylation. In summary, my results reveal both upstream molecular mechanisms that regulate PTPα Tyr789 phosphorylation and downstream PTPα Tyr789-dependent events that regulate cell migration.
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Liu, Chi-Chao. "Alpha-integrin expression and function modify chemoresistance and immunogenicity of acute lymphoblastic leukemia." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60560.
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The overall survival rate for pediatric Acute Lymphoblastic Leukemia (ALL) is >85%, achieved mainly via multi-agent chemotherapy. However, therapeutic options remain limited for those experiencing relapse, thus understanding the causes for treatment failures remains an important priority. In this thesis, I investigate the underlying mechanisms that allow leukemic cells to escape chemotherapy. Specifically, I evaluate how integrin-mediated cell adhesion promotes tumor cell survival by increased pro-survival signaling, enhanced resistance to chemotherapeutics, and decreased presentation of immunogenic cell death (ICD) markers. I show that T-lymphoblast adhesion via α4β1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Expression of α4δ, a tail-truncated α4-integrin with GFFKR as the cytoplasmic motif, promotes chemoresistance in a manner independent of integrin-mediated adhesion. The adhesion-independent chemoresistance is reproduced by expression of Tacδ, a non-integrin transmembrane receptor fused to the cytosolic GFFKR motif. Additionally, the GFFKR motif-mediated chemoresistance is associated with enhanced Akt activation, Ca²⁺ influx, and drug efflux. GFFKR is a conserved motif found in α-integrins and previously shown to interact with calreticulin, a calcium-binding endoplasmic reticulum chaperone protein. I found that α4-calreticulin interaction was enhanced by cell adhesion, while α4δ-calreticulin interaction occurred in an adhesion-independent manner. Since cell surface calreticulin is a pro-phagocytic marker for cells undergoing ICD, the impact of integrin function on surface calreticulin in lymphoblasts treated with ICD-inducing agents was evaluated. Engagement of integrins via adhesion, or expression of the minimal GFFKR motif as α4δ or Tacδ, was sufficient to reduce the levels of surface calreticulin. Furthermore, surface calreticulin was also reduced for cells co-treated with a β1-integrin activating antibody. The resulting integrin-mediated decrease in surface calreticulin significantly reduced engulfment of the target lymphoblasts by macrophages. Calreticulin expression in lymphoblasts was nullified to assess its role in integrin-mediated chemoresistance. Chemosensitivity was partially restored in calreticulin-null Tacδ cells under non-adherent conditions, and in calreticulin-null wildtype cells under adherent conditions. The affect was partly attributed to calreticulin’s role as a regulator of Ca²⁺ influx and drug efflux. Calreticulin was also implicated as a mediator of cytokine-dependent STAT proliferative signaling. This thesis provides evidence for integrin function and cell adhesion as a physiological pro-survival mediator for T-lymphoblasts.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
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Siller-Jackson, Arlene J. "Connexin 43 hemichannels are regulated by mechanical stress and [alpha]5 integrin in osteocyte-like cells : a dissertation /." San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1400962241&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Mechai, Nadja. "Untersuchungen zur biologischen Funktion der [alpha]3-cytoplasmatischen [alpha-3-cytoplasmatischen] Domäne des [alpha]3[beta]1-Integrins [Alpha-3-Beta-1-Integrins] und deren Einfluss auf die Aktivierung der kleinen GTPasen Rac1 und RhoA in PC12-Zellen." [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2005/27/index.html.
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Vignoud, Lucile. "Étude du rôle des motifs NPXY dans la fonction de l'intégrine alpha 5/beta 1." Grenoble 1, 1996. http://www.theses.fr/1996GRE10274.
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Le travail presente concerne l'etude du role joue par les deux motifs peptidiques npxy localises dans le domaine cytoplasmique de la sous-unite beta 1 des integrines. Par analogie avec le recepteur des ldl, ces deux motifs etaient assimiles au signal d'internalisation npxy permettant une association au complexe d'adaptines ha-2 et une internalisation dependante des puits a clathrine. En generant des lignees stables exprimant des integrines a sous-unite beta 1 mutees, nous avons montre que contrairement a d'autres recepteurs, les motifs npxy n'intervenaient pas dans l'internalisation de l'integrine alpha 5/beta 1. En revanche, nous avons observe que chacun des motifs npxy etait indispensable a l'assemblage des adherences focales. L'affinite pour le ligand extracellulaire n'etant pas affectee par les mutations realisees, nos resultats attribuent aux deux motifs npxy un role en tant que sites d'interaction, ou permettant la formation de sites d'interaction, avec une ou plusieurs proteines cytoplasmiques necessaires a l'assemblage des adherences focales. L'analyse de la fixation in vitro de la taline sur les chaines beta 1 mutees au niveau des sequences npxy, indique que cette proteine, pourtant necessaire a l'etablissement des adherences focales, n'est pas la proteine cible qui interagit avec les motifs npxy des integrines pour permettre leur recrutement au sein de ces adherences. La taline n'est pas suffisante a elle seule pour permettre l'assemblage des adherences focales. L'identite des proteines interagissant avec la sous-unite beta 1 de maniere dependante des motifs npxy, reste a determiner. L'immunoprecipitation des integrines a sous-unite beta 1 humaine dans des conditions menagees, a mis en evidence leur association avec diverses proteines cellulaires, controlee par le premier motif npxy (tyr 783). Ces proteines, non identifiees, pourraient jouer un role essentiel dans l'organisation des adherences focales, dependante du premier motif npxy de la sous-unite beta 1 des integrines, et/ou dans la signalisation cellulaire
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Broich, Kerstin. "Importance of [alpha]v[beta]3 [alpha-v-beta-3] integrin in arteriogenesis in the peripheral circulation of the rabbit." Giessen : DVG-Service-GmbH, 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972754466.
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Everding, Jens [Verfasser], and Michael J. [Akademischer Betreuer] Raschke. "Untersuchung des Einflusses von Integrin Alpha 2 Beta 1 auf den nativen Knochen im Alterungsprozess und die Frakturheilung anhand der Integrin-Alpha-2-Knock-out-Maus / Jens Everding. Betreuer: Michael J. Raschke." Münster : Universitäts- und Landesbibliothek der Westfälischen Wilhelms-Universität, 2013. http://d-nb.info/1034311719/34.
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YEHIA, GHASSAN. "Analyse de la fonction de la chaine integrine alpha-6 chez la souris : role des deux isoformes alpha-6a et alpha-6b." Université Louis Pasteur (Strasbourg) (1971-2008), 1996. http://www.theses.fr/1996STR13243.
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Les integrines sont des recepteurs cellulaires de la matrice extracellulaire. Ce sont des heterodimeres constitues de deux chaines transmembranaires alpha et beta. La sous-unite alpha6 integrine, associee a une chaine beta integrine (beta1 ou beta4) reconnait deux isoformes au moins de la laminine, composant majeur de la lame basale. Les deux isoformes de l'integrine alpha6, alpha 6a et alpha6b, different par leur domaine cytoplasmique. Ces deux domaines, a et b, sont hautement conserves entre plusieurs especes. Chez la souris, l'expression spatio-temporelle des deux isoformes est regulee differemment au cours du developpement embryonnaire. Ceci laisse supposer une fonction propre a chacune d'elle. Pour etudier la fonction des deux isoformes in vivo chez la souris nous avons produit, en utilisant la recombinaison homologue dans les cellules souches embryonnaires (es), deux lignees de souris alpha6b#- et alpha6a#- qui expriment selectivement une isoforme (alpha6a ou alpha6b) alors que l'autre est tronquee, sans domaine cytoplasmique. La forme tronquee alpha6b#-, analysee dans les cellules es homozygotes alpha6b#-#/#-, semble etre inactive puisqu'elle n'est ni associee a la chaine beta1 integrine, ni exprimee a la surface des cellules. Cependant, les souris homozygotes alpha6b#-#/#-, qui expriment uniquement l'isoforme alpha6a, sont viables et fertiles. Elles ne presentent pas de phenotype de decollement de l'epiderme precedemment observe chez les souris alpha6#-#/#-, ce qui indique que la presence de l'isoforme alpha6a est suffisante pour le maintien de l'integrite du tissu. Ces souris constituent un modele pour l'etude de la fonction de l'isoforme alpha6b dans le systeme nerveux. Les souris alpha6a#- sont en cours de production et d'analyse
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Saini, Asha Rani. "Expression and activation status of the [alpha]4[beta]1 integrin in human melanoma." Thesis, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338426.
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Wenke, Ann-Kathrin. "Die Rolle und Regulation von Integrin alpha10 bei physiologischen und pathophysiologischen Prozessen." kostenfrei, 2007. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/943/.
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Pinco, Karen Ann. "In vivo and in vitro analyses of the functional role of alpha4 integrin in cell migration." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080746.
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Jacquelin, Béatrice. "Etude des bases moléculaires à l'origine des variations d'expression de la sous-unité alpha2 de l'intégrine alpha2beta1." Paris 7, 2001. http://www.theses.fr/2001PA077089.
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Byström, Berit. "Laminins and alpha11 integrin in the human eye : importance in development and disease." Doctoral thesis, Umeå universitet, Oftalmiatrik, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1950.
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The extracellular matrix (ECM) offers a protective shelter for cells and provides signaling paths important for cell to cell communication. ECM consists of basement membranes (BM) and interstitial matrix. BMs provide mechanical support for parenchymal cells, influence cell proliferation, survival, migration and differentiation. They are also important for tissue integrity. Laminins (LM) are the major non-collagenous component of BMs. Cell-ECM interactions, mediated by receptors, are indispensable during embryonic development, wound healing, remodeling and homeostasis of tissues. The integrins are the major cell-adhesion receptors. The expression of alpha11 integrin chain in the cornea is of great interest, as it is part of the alpha11beta1 integrin receptor for collagen type I, the predominant component of the corneal stroma. The aims were to thoroughly characterize the ECM in the developing and adult human eye, with particular focus on the cornea, LM and alpha11 integrin chains, and to examine alpha11 integrin chain in an animal model of corneal wound healing and remodeling. Human fetal eyes, 9-20 weeks of gestation (wg), and adult human corneas with different diagnosis were treated for immunohistochemistry with specific antibodies against LM and alpha11 integrin chains. Normal and knockout (ko) mice were treated with laser surgery to create a deep wound in the corneal stroma. The wound healing process was followed at different time points. The cellular source of alpha11 integrin chain was studied in cell cultures. In the fetal eyes, the BM of the corneal epithelium, the Descemet’s membrane (DM) and the Bruch’s membrane each had their specific combinations of LM chains and time line of development, whereas the lens capsule and the internal limiting membrane showed constant LM chain patterns. The epithelial BMs of normal and diseased adult corneas contained similar LM chains. The normal morphology of the epithelial BM was altered in the different diseases, particularly when scarring was present. In the scarred keratoconus corneas there were excessive LM chains. The majority of keratoconus corneas also expressed extra LM chains in the DM. At 10-17 wg alpha11 integrin chain was present in the human corneal stroma, especially in the anterior portion, but it was scarce at 20 wg, in normal adult corneas and in Fuchs’ endothelial dystrophy. In contrast, it was increased in the anterior portion of the stroma in keratoconus corneas with scarring. Alpha11 integrin ko mice had a defective healing with subsequent thinner corneas. Alpha11 integrin expression correlated to the presence of alpha-smooth muscle actin in vivo as well as in vitro. The distinct spatial and temporal patterns of distribution for alpha11 integrin and each of the LM chains suggest that they play an important role in human ocular differentiation. The selectively affected LM composition and the novel expression of alpha11 integrin chain in scarred keratoconus corneas as well as the pathologic healing in ko mice, indicate that alpha11 integrin and LM chains also play an important role in the process of corneal healing, remodeling and scarring and might participate in the pathogenesis of corneal disease. This knowledge is of practical importance for future topical therapeutic agents capable of modulating the corneal wound healing processes.
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Welcker, Silvia. "Selektion konformationsspezifischer Aptamere sowohl gegen das aktivierte Leukozytenintegrin Mac-1 (alphaM beta 2, CD11b, CD18) als auch gegen den nicht aktivierten und aktivierten Integrin-Rezeptor alphaV Beta 3 (Vitronektin-Rezeptor, CD51,CD61)." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-44251.
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