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Bünemann, Christoph Lars. "Molekulare Mechanismen der Inhibition TGF-[beta]-induzierter [TGF-beta-induzierter] Apoptose in Hepatomzellen." [S.l. : s.n.], 2000. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB8560503.
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Ouyang, Nengtai. "Effects of TGF-[beta]1 [TGF-beta-1] in ischemia, reperfusion injury and chronic allograft nephropathy." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972198628.
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Köhler, Heike Christine. "Die TGF-[beta] [TGF-beta] vermittelte Suppression der antigenspezifischen Immunantwort kann durch CD28 Kostimulation überwunden werden." München Verl. Dr. Hut, 2008. http://d-nb.info/992163080/04.
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Mecha, Ezekiel Onyonka [Verfasser]. "Characterization of the TGF-beta signalosome and of TGF-beta-dependent endometrial cell proliferation / Ezekiel Onyonka Mecha." Gießen : Universitätsbibliothek, 2014. http://d-nb.info/1068590459/34.
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Choi, Won Seon 1975. "Involvement of TGF-beta in skin photoaging." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33842.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005.<br>Vita.<br>Includes bibliographical references.<br>The goal of this thesis study was to understand the role of TGF-[beta] in skin photoaging, especially in solar elastosis. Solar elastosis, the accumulation of elastotic material in the dermal extracelluar matrix, is a major hallmark of photoaging. However, the mechanisms by which UV radiation causes solar elastosis are poorly understood. TGF-[beta] is a multifunctional cytokine involved in the regulation of extracelluar matrix and is known to be up-regulated by UVR. Involvement of reactive oxygen species (ROS) in the development of solar elastosis has been demonstrated by many studies using antioxidants and anti-inflammatory agents in the mouse skin in vivo. We hypothesized that ROS produced by TGF-[beta] are key components in the tropoelastin (TE, a soluble precursor of elastin) up-regulation in dermal fibroblasts, and that TGF-[beta] is a major regulator in the photoaging processes. Using human skin fibroblasts system in vitro, we found that ROS generated from NADPH oxidase and mitochondria are involved in the TGF-[beta] induced elastin production, and intracellular sources of ROS vary with time. We showed that both Smad and non-Smad pathways, e.g. MAPK and PKC pathways, are required for TE mRNA up-regulation by TGF-[beta].<br>(cont.) However, ROS were not involved in some of the important steps in these pathways, such as phosphorylations of p38 or ERK or Smad2, suggesting that ROS acts downstream of these pathways. The in vivo chronic UVB irradiation study using a Skh- 1 hairless mouse model with a small molecule inhibitor for the TGF-[beta] type I receptor showed that the TGF-[beta] receptor inhibitor increased the number of mast cells, but decreased the levels of active TGF-[beta] protein, and mRNA levels for collagen III and IV, MMP-2 and 9, and TE in the chronically UVB irradiated mouse skin. However, those responses did not result in the changes in the collagen and elastin content, or the wrinkle formation. Overall, this work indicates that TGF-[beta] contributes to the solar elastosis, through the effects on the TE mRNA level in skin. Implication of this role of TGF-[beta] in the elastin fiber deposition or visible changes of photoaged skin requires further investigation.<br>by Won Seon Choi.<br>Ph.D.
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Dudu, Veronica. "TGF-beta signaling at the cellular junctions." [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11878497.
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Peri, Francesca. "The role of EGF and TGF-[beta] [TGF-beta] signaling specifying the polarity of the Drosophila egg and embryo." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963638386.
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Kroner, Antje. "Klonierung und Charakterisierung von Rezeptorkinasen der EGF- und TGF[beta]-Familie [TGF-Beta-Familie] des kleinen Fuchsbandwurmes Echinococcus multilocularis." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969749481.
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Möller, Antje. "Proliferation von Lungenfibroblasten in vitro unter dem Einfluss von ionisierender Strahlung bzw. von TGF-[beta]1 [TGF-beta-1]." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974672165.
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Serwe, Annegret. "Hemmung der Angiogenese und Tumorprogression durch Blockierung der TGF-[beta]-Signaltransduktion [TGF-Beta-Signaltransduktion] durch neue Wirkstoffe isoliert aus Pilzen." Duisburg Köln WiKu, 2007. http://d-nb.info/987489674/04.
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Chen, Feng. "Phosphorylation and activation of transforming growth factor beta (TGF-[beta]) receptor kinases." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/41406.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1996.<br>On t.p., "[beta]" appears as the lower case Greek letter. Vita.<br>Includes bibliographical references (leaves 166-207).<br>by Feng Chen.<br>Ph.D.
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Galliher, Amy Jo. "[Beta]₃ integrins enhance TGF-[beta]-mediated tumor progression in mammary epithelial cells /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2007.<br>Typescript. Non-Latin script record Includes bibliographical references (leaves 112-128). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Scharrer, Eva. "Consequences of HtrA1 deficiency on TGF-Beta signaling." Diss., Ludwig-Maximilians-Universität München, 2015. http://nbn-resolving.de/urn:nbn:de:bvb:19-185742.
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Patel, Vyomesh. "TGF-#beta# signal transduction mechanisms in epithelial carcinogenesis." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386229.
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Gu, Ye. "Homo & heterodimeric TGF-[beta] family growth factors." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610106.
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Sennett, Kristyn. "TGF-beta Receptors and Alcohol Sensitivity in Drosophila." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2695.
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Clic proteins influence ethanol-related behavior in flies and other species and also mediate TGF-β signaling. These findings suggest that Clics and the TGF-β signaling pathway might work together to modulate behavioral responses to ethanol. I used the Drosophila model to address the hypothesis that TGF-β signaling is important for ethanol sensitivity. Ethanol sensitivity was blunted by multiple transposon insertions in the TGF-β receptor gene thickveins. Collectively, however, I found no consistent correlation between expression of thickveins and altered ethanol sensitivity in flies harboring transposons. I therefore also assessed ethanol sensitivity in flies with loss of function point mutations in thickveins. Ethanol sensitivity was not altered in these additional thickveins genotypes, contrary to my major hypothesis. My analysis of thickveins suggests that TGF-β signaling might influence ethanol sensitivity, but if so there must be a complex relationship between the function of this pathway and sensitivity to alcohol.
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Moosmann, Nicolas. "TGF-beta und Empfindlichkeit für NO-abhängige Apoptose." [S.l. : s.n.], 2002. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10316263.
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Haase, Oliver. "Strahleninduzierte Aktivierung von TGF-[beta]1 [TGF-Beta-1] und Phosphorylierung von Smad2 im Prozess der terminalen Differenzierung von humanen Hautfibroblasten." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973220317.
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Lam, Sze-man Joyce. "Expression of transforming growth factors (TGF-alpha and TGF-beta 1) on postmortem skin wounds /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38480566.
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林詩敏 and Sze-man Joyce Lam. "Expression of transforming growth factors (TGF-alpha and TGF-beta 1) on postmortem skin wounds." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011400.
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Isken, Frank. "Entwicklung und Anwendung einer HPLC-gestützten quantitative RNA-Analyse von drei Isoformen der TGF-[beta]-Familie [TGF-beta-Familie] in humanem Knochen." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961894806.
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Karagiannidis, Christian. "Activin A und TGF-[beta]1 [TGF-Beta-1] bei Asthma bronchiale: differentielle Expression und gemeinsame Funktionen sowie deren Regulation durch Glukokortikoide." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974673056.
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Sevilla, Sánchez Pablo. "Functionalization of titanium surfaces with TGF-beta inhibitor peptides." Doctoral thesis, Universitat Politècnica de Catalunya, 2013. http://hdl.handle.net/10803/129568.
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Esta tesis queda enmarcada en el ámbito de los biomateriales metálicos, concretamente en superficies de titanio desarrolladas para la regeneración ósea. Las aplicaciones más habituales del titanio como biomaterial son los implantes dentales y las prótesis de cadera y rodilla. Estos componentes requieren, en servicio, buena estabilidad y fijación al hueso a largo plazo. El titanio es un material idóneo para el cumplimiento de estos requisitos gracias a su alta resistencia mecánica, tenacidad, resistencia a la corrosión y, sobre todo, por su alta capacidad de osteointegración.
En general, el titanio es un biomaterial bioinerte donde, una vez implantado, el tejido vivo genera una fina capa de tejido fibroso alrededor del implante la cual separa el hueso del implante. Un espesor excesivo de esta capa de tejido fibroso puede comprometer la estabilidad e integración del implante y conllevar el fracaso del tratamiento.
El objetivo principal de esta tesis es el desarrollo de una nueva superficie de titanio que sea capaz de controlar e inhibir la generación de tejido fibroso en la superficie del implante. De esta manera, tratamos de mejorar la osteointegración de implantes y prótesis mediante la mejora de la respuesta celular sobre la superficie del implante. Para el control del crecimiento de tejido fibroso en la superficie se han desarrollado nuevas superficies de titanio donde se han inmovilizado dos tipos de péptidos cortos capaces de inhibir la interacción de la citoquina TGF-β, la cual incrementa la producción de este tipo de tejido por parte de las células fibroblásticas. Estos péptidos, llamados P17 y P144 han sido desarrollados por el equipo de nuestro colaborador el Dr. Francisco Borrás-Cuesta, en el Centro de Investigación Médica aplicada de la Universidad de Navarra.
Esta tesis está dividida en 6 capítulos donde se describe el desarrollo y caracterización de las superficies de titanio funcionalizadas con péptidos inhibidores del TGF-β: • Capítulo 1: Introducción a los ámbitos y conceptos importantes de la tesis. • Capítulo 2: Diseño y desarrollo de un método de inmovilización covalente de péptidos cortos sobre superficies de titanio. • Capítulo 3: Estudio de los factores que intervienen en la inmovilización de péptidos cortos sobre las superficies de titanio. • Capítulo 4: Caracterización físico-química de las superficies de titanio funcionalizadas con el péptido P17. • Capítulo 5: Caracterización físico-química de las superficies de titanio
funcionalizadas con el péptido P144. • Capítulo 6: Respuesta biológica in vitro de las superficies de titanio funcionalizadas con P17 y P144.
Los resultados más relevantes en el desarrollo de esta tesis han sido: • El desarrollo de un nuevo método de inmovilización covalente de péptidos sobre superficies de titanio obteniendo una alta densidad de péptido en superficie con una buena estabilidad mecánica y termoquímica. • La consecución de superficies de titanio capaces de inhibir la acción del TGF-β. • Las nuevas superficies desarrolladas son capaces de incrementar la diferenciación osteoblástica y así, potencialmente mejorando la capacidad de osteointegración de implantes y prótesis de titanio.
Este trabajo de investigación contribuye a aumentar el conocimiento sobre la inmovilización covalente y no covalente de péptidos cortos en superficies de titanio. También contribuye en aumentar el conocimiento de la acción e inhibición del TGF-β en células fibroblasticas y osteoblásticas, estas últimas sembradas sobre superficies de titanio. El material desarrollado es un excelente candidato para su aplicación en implantología y traumatología ósea.<br>This thesis is framed in the field of metallic biomaterials, specifically on titanium surfaces developed for bone regeneration. The most common applications of titanium as a biomaterial are dental implants and hip and knee prostheses. These components clinically require good stability and fixation to the bone in the long term. Titanium is an ideal material for these applications as it has high mechanical strength, toughness,
corrosion resistance and, above all, a high capacity for osseointegration.
In general, titanium is a bioinert material where, once implanted, the living tissue generates a thin layer of fibrous tissue around the implant which separates the bone to the implant. An excessive thickness of this layer of fibrous tissue can compromise the stability and integration of the implant leading to the failure of the biomedical treatment.
The main objective of this thesis is the development of a new titanium surface with control and inhibition of the generation of fibrous tissue on the surface of the implant. We aim improving the osseointegration of implants and prostheses by benefiting cellular responses on the surface of the implant. For the control of the formation of fibrous tissue on the surface we have developed new biofunctional titanium surfaces by covalently immobilizing two different short peptides on the metallic substrate. These two peptides are inhibitors of the effect of
the cytokine TGF-β1, which increases the production of fibrous tissue by the activity of fibroblastic cells. These peptides, P17 and P144, have been developed by the team of our collaborators at the Dr. Francisco Borrás-Cuesta’s lab, in the Centro de Investigación Médica Aplicada of the Universidad de Navarra This thesis is divided into 6 chapters describing the development and characterization of titanium surfaces functionalized with TGF-β inhibitor peptides: * Chapter 1: Introduction to the areas and important concepts of the thesis.
• Chapter 2: Design and development of a method of covalent immobilization of short peptides on titanium surfaces. • Chapter 3: Study of the factors involved in the immobilization of short peptides on the titanium surfaces. • Chapter 4: Physical-chemical characterization of titanium surfaces functionalized with the P17 peptide. • Chapter 5: Physical-chemical characterization of titanium surfaces functionalized with the P144 peptide. • Chapter 6: In vitro biological response of titanium surfaces functionalized with P17 and P144.
The most relevant results in the development of this thesis are: • The development of a new method of covalent immobilization of peptides on
titanium surfaces with a high density of peptide on the surface and with a good mechanical and thermal-chemical stability. • The development of titanium surfaces with inhibitory action of TGF-β activity. • The developed new surfaces are able to increase osteoblast differentiation,
thereby potentially enhancing osseointegration of the biofunctionalized titanium implants and prostheses.
This research work contributes to increase the knowledge on covalent and noncovalent immobilization of short peptides on titanium surfaces. It also helps in increasing the knowledge of the action and inhibition of TGF-β on fibroblastic and osteoblastic cells; the later seeded on titanium surfaces. The developed material is an excellent candidate for its application in implantology and orthopedics.
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Chou, Yu-Ting. "Cited2, an autoregulated transcriptional modulator, in TGF-beta signaling." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1147147222.
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Sarkar, Oliver. "Expression und Funktion der TGF-Beta-Isoformen in Hypophysentumorzellen." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-67306.
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Rusholme, Sarah Ann Buchanan. "Strain-dependent variation in developmental TGF#beta# knockout phenotypes." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361011.
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Jonker, Leon. "TGF-#beta# signalling : the roles of endoglin and TAKI." Thesis, University of Newcastle Upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270892.
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Lee, Jen Yee. "TGF-beta family ligands in autophagy and muscle wasting." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/24910.
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Chronic Obstructive Pulmonary Disease (COPD) is a collective term for emphysema, chronic bronchitis, and obstructive bronchiolitis, which is caused by chronic tobacco smoke exposure. COPD is a multi-system disease; skeletal muscle is one such system that is dysfunctional in a significant proportion of COPD patients. Muscle weakness and wasting is observed in COPD patients, with fibre type changes as well as fibre atrophy reported. Skeletal muscle as a target for pharmacotherapy in COPD as exercise training improves life expectancy and quality of life in patients. Loss of protein contributes to muscle atrophy; however, the mechanisms and signalling pathways involved in protein degradation are not fully understood. Autophagy is a protein degradation pathway implicated in muscle atrophy. Additionally, the TGF-β superfamily member -myostatin and FHL1 are signalling molecules of interest. The cytokine myostatin is a recognised inhibitor of muscle growth, whilst FHL1 is an adaptor protein usually associated with hypertrophy in muscle. The data presented herein focuses on three aspects: the effect of myostatin on autophagy, the interaction between myostatin and FHL1 in atrophy and the effect of smoke exposure on autophagy. Furthermore, the effects of other atrophy associated signalling molecules (growth differentiation factor 15, GDF-15 and angiotensin-II, ang-II) on these themes were examined. The data show that myostatin is a novel inducer of autophagy indicating that myostatin can induce protein degradation through autophagy. FHL1 augmented myostatin induced signalling in vitro and in vivo, suggesting a potential mechanism by which type II fibres are more susceptible to atrophy than others and helping to account for the fibre type changes and atrophy in COPD. The role of smoke exposure of autophagy remains unclear; however, GDF-15 may be involved in muscle atrophy. Ang-II did not induce autophagy in vivo and inhibition of angiotensin signalling had no effect on autophagy in COPD patients.
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Petrel, Trevor Alan. "TGF-[beta] and estrogen signaling interactions in breast cancer /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486572165278522.
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Shumaker, Stephanie D. "Improved methodology for refolding functional TGF-beta Superfamily ligands." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465086.
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Thesis (M.S.)--University of California, San Diego, 2009.<br>Title from first page of PDF file (viewed June 22, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 35-37).
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Clarke, David Chisholm. "The quantitative analysis of TGF-beta/Smad signaling dynamics." Connect to online resource, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3315795.
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Fisichella, Vincenzo. "TGF-beta 1 pathway and age-related macular degenertion." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/3870.
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Purpose: To set up a retinal degenerative model in rat that mimics pathologic conditions such as age-related macular degeneration (AMD) using amyloid-beta (Abeta) oligomers, and assess the effect of TGF-beta 1. Furthermore a topical formulation of transforming growth factor 1 (TGF-beta 1) was developed; and TGF-beta 1 ocular pharmacokinetics profile was assessed.
Methods: Sprague-Dawley male rats were used. Human Abeta 1-42 oligomers were intravitreally (ITV) injected in the presence or in the absence of recombinant human TGF-beta 1. The apoptotic markers Bax and Bcl-2 were assessed by western blot analysis in retina lysates. TGF-beta1 has been formulated as encapsulated in small unilamellar liposomes(SUV). Ocular bioavailability of TGF-beta 1 was assesed in the vitreous of New Zealand rabbits at different time points (30, 60, 120, 180 and 240 min) after a single administration of eye drops by a commercial ELISA kit. Ocular tolerability was also assessed by a modified Draize s test.
Results: Treatment with Abeta oligomers induced a strong increase in Bax protein levels and a significant reduction in Bcl-2 protein. Co-injection of TGF-beta 1 triggered a significant reduction of Bax protein induced by Abeta oligomers. The pharmacokinetics profile of TGF-beta 1 lipid formulation demonstrated remarkable levels of TGFbeta-1 in the posterior segment of the eye. In particular, high levels of TGFbeta-1 were detected in the vitreous after 240 minutes (Tmax) from the topical application of the eye drops. The tested formulation was well tolerated and the score for each parameter was zero at all time of observations.
Conclusions: Overall, these data indicate that ITV injection of Abeta1-42 oligomers in rat induced molecular changes associated with apoptosis in rat retina, highlighting a potential pathogenetic role of Abeta oligomers in AMD. Abeta1-42 oligomers damage was counteracted by intreavitreal injection of TGF-beta1. Furthermore, the novel formulation was able to deliver remarkable levels of TGFbeta-1 into the back of the eye. Therefore, this TGFbeta-1 delivery system may be useful in clinical practice to manage ophthalmic conditions such as age-related macular degeneration avoiding invasive intraocular injections.
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Daig, Ute. "NO-vermittelte Effekte der Aminosäure L-Arginin auf die TGF-[beta]-Überexpression [TGF-Beta-Überexpression] im Modell der akuten Anti-Thy-1-Glomerulonephritis." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976619776.
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Kadlec, Nicole [Verfasser]. "Optimierung der Transfektion pankreatischer Sternzellen mit TGF-beta-1-Antisense-Oligonukleotiden : ein Beitrag zum Nachweis autokriner Stimulationsmechanismen über TGF-beta-1 / Nicole Kadlec." Ulm : Universität Ulm. Medizinische Fakultät, 2005. http://d-nb.info/1015472060/34.
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Mead, Anna Louise. "Modulation of transforming growth factor beta (TGF beta) and conjunctival scarring after glaucoma filtration surgery." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444824/.
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The conjunctival wound healing response remains the major barrier to achieving long term intraocular pressure control after glaucoma filtration surgery (GFS). Current anti-scarring agents improve the outcome of surgery but act by causing widespread cell death and can be associated with potentially blinding complications. In addition, some individuals still fail surgery. A more physiological and targeted approach to wound healing control and scarring prevention is required. Of all the growth factors, TGF beta has been shown to play a pivotal role in wound healing throughout the body, and has been identified as a potent stimulant of the scarring process in the eye. Modulation of TGF beta has been highlighted as a possible mechanism by which ocular scarring may be reduced. This thesis has investigated the role of TGF p modulation as a potential anti-scarring strategy in glaucoma surgery. In vitro, I have demonstrated that the anti-TGF beta2 monoclonal antibody, CAT-152, inhibits Tenon's fibroblast collagen production and myofibroblast transformation at physiological concentrations. It appears that these are the key histological changes associated with bleb failure following experimental GFS. In vivo, subconjunctival administration of CAT-152, given at the time of surgery and in the immediate post-operative period, successfully improves surgical outcome, reduces subconjunctival fibrosis and is safe and well tolerated. Isolated post-operative administration of subconjunctival CAT-152 can prevent late bleb failure and prolonged dosing with CAT-152 appears to modulate the long-term scarring response after GFS. In addition, the anti-scarring effects of CAT-152 have compared favourably to one of the gold standard anti-scarring agents in clinical use. Finally, I have shown that antisense oligonucleotides directed against TGF beta may also have a role in the prevention of conjunctival scarring. In summary, the work supports the hypothesis that TGF beta modulation may represent a novel potential anti-scarring strategy in glaucoma surgery.
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Parker, Wendy Lynne. "TGF-[beta] receptors on human chondrocytes : hetero-oligomerization and function." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19424.
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Human cartilage does not have the capacity for parent-like regeneration; instead, following injury, there is a programmed attempt at regeneration that ultimately results in fibrocartilage formation. This lack of intrinsic repair has been attributed to the avascular state of the tissue and chondrocyte dedifferentiation towards a cell incapable of type II collagen production and with altered responsiveness to the structural and regulatory mediators within its microenvironment. For several decades, debate has existed regarding the role Transforming Growth Factor-Beta (TGF-P) plays in modulating articular cartilage. Blocking of TGF-p signaling in mice by a dominant negative type II TGF-p receptor and transgenic knockouts of Smad 3, a central mediator of TGF-p signaling, result in osteoarthritic-like phenotypes, whereas local up-regulation of TGF-p promotes cartilage healing in degenerative joint disease models. Despite TGF-p being implicated as a key player In the regulation of chondrocyte phenotype and extracellular matrix (ECM), little is known about TGF-p action in human chondrocytes. These investigations have established a critical link between variation in TGF-p receptor expression at the cell surface and TGF-p action in cartilage. In addition to the TGF-p signaling receptors, the presence of betaglycan and RIIB (a spliced variant of the type II signaling receptor) was confirmed on human chondrocytes. Moreover, the expression of three novel TGF-p receptors was identified, namely Sol RI (a soluble form of the type I receptor), Alk-l, and endoglin. These receptors formed a variety of heteromeric complexes and regulated TGF-p signaling. More importantly, RIIB and endoglin were demonstrated to regulate type II collagen levels and evidence was provided that they likely represent chondrocyte phenotypic markers. A critical link between endoglin expression, cell phenotype, TGF-~ responsiveness, and ECM was established. These results demonstrate the formation of TGF-~ receptor heteromeric complexes of various subtype composition on chondrocytes suggesting that such complexes may regulate TGF-~ signaling pathways in those cells. Cell surface TGF-~ binding proteins, acting as phenotypic markers in human cartilage, are potential modulators of complex interactions between the cell and its microenvironment. Therefore, novel TGF-~ receptors may provide an avenue to regulate the effects ofTGF-~ locally and establish new insights into cartilage regeneration or repair.
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Bolton, L. W. Y. T. "Recombinant TGF-beta type I and type II receptor domains." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596753.
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Transforming growth factor-β (TGF-β) is a multifunctional cytokine that signals by binding to two related transmembrane serine/threonine kinases called the type I and type II receptors. The <I>in vitro</I> binding properties of these receptors for the TGF-β1 and TGF-β3 isoforms were investigated by developing expression systems for recombinant extracellular domains (ECDs) of the type I and type II receptors, which also enabled the interaction of the two receptor domains to be examined. 1. A variety of vectors were constructed incorporating the fusion protein glutathione S transferase (GST) and peptide tags to promote purification of the ECDs from bacterial lysates (<I>E.coli</I> TG1 and BL21 (DE3) strains). 2. The optimum conditions for purification and yield of the recombinant proteins from lysed bacteria were examined for vector and bacterial systems for both type I and type II ECDs. 3. The ECD of the type I receptor was found to bind TGF-β1 <I>in vitro</I>, in the absence of the type II receptor. Binding was retained in an ECD cleaved from the GST domain and therefore did not depend on the presence of the fusion protein or other peptide tags. 4. The ECD of the type II receptor bound both TGF-β1 and TGF-β3 isoforms, consistent with previous <I>in vitro</I> data, whereas the type I receptor ECD did not bind TGF-β3. 5. Attempts to develop an ELISA for TGF-β1 using the type I and II receptor ECDs as capture and detection agents revealed that the two receptor ECDs associate with each other in the absence of TGF-β1. 6. A mammalian cell expression system to produce TGF-β3 was developed to enable biochemical and structural interactions of TGF-β3.
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Ruf, Doris Anne. "Die Entwicklung der Pankreasfibrose im TGF-beta-1-transgenen Tiermodell." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-57128.
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Lee, Ellen. "Characterization of TGF-beta regulation during chronic infection with LCMV." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1467915.
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Thesis (Ph. D.)--University of California, San Diego, 2009.<br>Title from first page of PDF file (viewed September 15, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 44-51).
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Rafiei, Shahrzad. "Talin : a novel inducible antagonist of transforming growth factor-beta 1 (TGF-[beta]1) signal transduction." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100203.
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The survival of breast cancer patients declines when tumors are invasive and have an increased possibility of metastasizing to distal sites. Transforming Growth Factor-beta (TGF-beta) suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells. However, at late stage of mammary carcinogenesis, due to genetic and epigenetic alterations, TGF-beta loses its cytostatic actions, and contributes to tumor invasion by promoting cell proliferation, Actin cytoskeletal reorganization, as well as Epithelial to Mesenchymal Transition (EMT). Despite the key role of TGF-beta1 in tumor suppression as well as tumor progression, the molecular mechanisms underlying the conversion of TGF-beta form an inhibitor of proliferation in mammary breast cancer cells to an inducer of their cell growth and EMT have not been fully elucidated. Thus, acquiring a basic knowledge on the mechanism of TGF-beta regulating its target genes and its contribution to cancer progression may highlight new avenues for cancer therapy development. This prompted us to further investigate and identify TGF-beta-inducible genes that may be involved in TGF-beta biological responses during tumorigenesis.<br>In this thesis, we identified Talin as a novel TGF-beta1 target gene that acts as an antagonist to inhibit TGF-beta-mediated cell growth arrest and transcriptional activity in mammary cancer cell line, MCF-7. Searching for new partners of activated Smads, we found that TGF-beta1 induces Talin translocation from cytosol to the plasma membrane where Talin physically interacts with the TGF-beta1 signaling components, the Smads and the receptors. Furthermore, we observed that TGF-beta1 stimulation leads to the formation of Actin stress fibers where Talin was detected at the end of these stress fibers. Taken all together, the obtained data show that TGF-beta1 positively induced expression of Talin and suggests a role for Talin, which acts as a negative feedback loop to control TGF-beta biological responses.
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Henning, Kirsten [Verfasser]. "TGF-β-induzierte [TGF-beta-induzierte] Expression extrazellulärer Matrixproteine durch Herzmuskelzellen der adulten Ratte / eingereicht von Kirsten Henning". Giessen : VVB Laufersweiler, 2009. http://d-nb.info/1000412865/34.
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Rose, Aidan Michael. "Transforming growth factor-beta signalling in human cutaneous squamous cell carcinoma." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/51b1a1c1-ac43-4f60-aa77-9002af3f2186.
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There is an urgent need to define the key pathological driving events in human cutaneous squamous cell carcinoma (cSCC) in order to identify novel therapeutic targets. Already the second most common form of human non-melanoma skin cancer, the incidence of cSCC has continued to rise at epidemic proportions over the past two decades. Rarely, cSCC can be highly aggressive, causing significant soft-tissue defects in sun-exposed areas of skin and progressing to metastatic disease, which is usually associated with poor survival. The transforming growth factor-β (TGF-β) signalling pathway is known to play key regulatory roles in skin homeostasis and wound repair. Murine studies indicate that loss of TGF-β signalling is sufficient to drive cSCC, but conclusive evidence for a similar role in human cSCC remains elusive. Combining immunohistochemical and genetic studies of the TGF-β signalling pathway on human cSCC tissue, with a thorough examination of TGF-β responses in human primary cSCC cell lines in-vitro, this thesis aims to investigate the complex role of TGF-β signalling in human cSCC. An extensive tissue micro-array analysis demonstrated the consistent reduction of endogenous TGF-β signalling activity in human primary cSCC. This intriguingly correlated with higher risk thick tumours pathologically, indicating that TGF-β is likely to act primarily as a tumour suppressor in human cSCC and its reduction or loss may impart a significant growth advantage for cSCC tumour cells. This tumour suppressor effect was reflected in-vitro, whereby the majority of primary cSCC cell lines remained sensitive to TGF-β mediated growth arrest. Resistance to TGF-β tumour suppression was also identified, and mechanistically its main protagonist in cSCC cell lines appeared to be mutational loss of TGF-β receptors. Consolidating in-vitro findings, both whole exome sequencing and 454 pyrosequencing of human cSCC tissue revealed frequent functionally damaging mutations of both TGF-β type 1 and type 2 receptors, indicating that mutational loss of the TGF-β pathway may be a key driving event in human cSCC tumourigenesis. Perhaps most interestingly, mutational loss of TGF-β type 2 receptors in cSCC cell lines appeared to result in a novel pro-oncogenic dependence on TGF-β type 1 receptor kinase activity, highlighting not only the important paradoxical role of TGF-β mediated tumour promotion in cSCC, but also the potential for signalling crosstalk between alternative TGF-β superfamily members, namely Activin signalling, to drive tumourigenesis in the absence of active TGF-β signalling. Although further mechanistic studies are required to support this hypothesis, the mutational status of TGF-β type 2 receptors may not only provide a powerful prognostic tool for patients with cSCC, but also represent an important biomarker for the targeted use of TGF-β inhibitors in potentially aggressive disease where pro-tumourigenic responses could be driving disease progression.
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Byrom, Daniel. "Synthesis of TGF-Beta inhibitors and compounds for spatiotemporal drug release." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/665149.
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During this doctoral thesis, we have synthesised hundreds of grams of the TGF-β inhibitor LY2157299 (Galunisertib). This product was used by the group of Eduard Batlle in their investigations into the roles that TGF-β plays in colorectal cancer. During the initial synthesis and subsequent scale up, we overcame hurdles including optimisation of the penultimate step of the reaction - giving reproducible results - as well as optimising conditions of the final solid form to provide a product which is suitable for formulation for the in vivo experiments. After discovering some of the drawback of LY2157299, we designed and synthesised a novel TGF-β inhibitor which we named HOLY (3-10). HOLY proved to be nearly 10x more potent than the original compound and shows a very significant reduction in the negative physical effects that were observed when administering LY2157299 at a therapeutic dose in vivo. HOLY was designed to be a compound which could be transformed into a prodrug, and therefore modulation of various properties could be achieved with careful modification of the structure. This was demonstrated by modification of the phenol of HOLY to give a substituted carbamate inspired by the structure of Irinotecan and was subsequently named IrinOLY. It was hypothesised that this carbamate would be enzymatically cleaved in vivo, releasing the active TGF-β inhibitor. When tested in vivo, this IrinOLY was shown to be a potent TGF-β inhibitor as well as a compound much more comfortable to formulate when compared to LY2157299. Other potential advantages of this novel compound, such as infusion via an osmotic pump, are yet to be explored and will be done so in the near future.
We then moved on to a separate project where we designed a molecule which was capable of being cleaved at a specific point by an exogenous enzyme (LigF), releasing the active compound 4-hydroxy tamoxifen. After the cleavage, 4-OHT would then be able to activate the Cre toolkit and therefore performing specific genetic modifications to cells in the vicinity from where the 4-OHT was released. In order for the 4-hydroxytamoxifen to be released, a beta ether bond needed to be cleaved by the enzyme LigF. The fragment containing the beta ether bond had various points in which modifications could be possible to modulate properties such as solubility and bioavailability, however specificity for the LigF enzyme needed to be maintained. In order to synthesise the optimum compound(s), first a structure activity relationship study was performed on the recognition fragment of the part of the desired compound that LigF would cleave. A small library of compounds bearing on one side various strategic modification of the original ligand to LigF, and on the other side the reporter 4methylumberliferone. This enabled us to perform modifications on the recognition fragment, test the new modifications in front of the LigF enzyme, and then perform further modifications based upon these results. A synthesis the optimised recognition fragment covalently bound to 4-hydroxy tamoxifen was then designed, synthesised, and tested both in vitro. The tests showed that 4-OHT was indeed cleaved in all three of the aforementioned settings, and so we sought to synthesise the target compound in its pure isomeric form. Following many attempts at complex coupling reactions, we eventually reached our target compound isomerically-pure following preparative HPLC of a key intermediate of the initial synthesis. The corresponding isomers were then transformed successfully into both the E and the Z isomers of Guaymoxifen.<br>Durante esta tesis doctoral, se han sintetizado cientos de gramos del inhibidor de TGF-Beta LY2157299 (Galunisertib). Este producto ha sido utilizado por el grupo de Dr. Eduard Batlle en sus investigaciones de cáncer colorrectal. Antes de llevar a cabo la síntesis a grande escala, se ha optimizado cada paso a pequeña escala– mejorando la síntesis para que sea más reproducible. Para superar algunas dificultades durante la formulación de LY2157299, se ha decidido diseñar y a continuación sintetizar un nuevo inhibidor de TGF-Beta para mejorar dichas desventajas. Después de realizar los experimentos in vivo, se demostró que el nuevo inhibidor es 10 veces más potente que LY2157299. Más adelante, este nuevo inhibidor de TGF-Beta ha sido transformado en un profármaco para mejorar sus propiedades como por ejemplo la solubilidad en agua. El segundo proyecto de esta tesis doctoral ha sido el diseño y la síntesis de una molécula para liberar 4hidroxitamoxifeno únicamente cuando esté en presencia de una enzima exógena especifica - LigF. Una vez liberado, el 4-hidroxitamoxifeno puede activar el sistema/la enzima Cre para llevar a cabo ciertas modificaciones genéticas como activar o silenciar un gen en específico. El enlace que rompe LigF para liberar el 4-OH es de tipo beta éter. Se sintetizó una librería de moléculas con modificaciones en sus estructuras para optimizar el fragmento que LigF reconozca. Mas adelante se llevó a cabo la síntesis de que Guaymoxifen – una molecula basada en 4-hidroxitamoxifeno y el fragmento que LigF reconozca. Se realizó ensayos en células para confirmar la hipótesis de activar Cre en células en el alrededor de células que contiene LigF.
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Bizet, Albane. "Mechanisms of action of CD109, a novel TGF-beta co-receptor." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104617.
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Transforming Growth Factor β (TGF-β) is a multifunctional cytokine that plays a critical role in cell growth, differentiation and extracellular matrix deposition. Dysregulation of its pathway has been implicated in tissue fibrosis and cancer. TGF-β signals via the type I (TGFBR1) and type II (TGFBR2) receptor complex, which phosphorylates their intracellular substrates, SMAD2 and SMAD3. The phosphorylated SMAD2/3 then forms a complex with SMAD4 and regulates target gene expression. Alternatively to the SMAD2/3 (canonical) pathway, TGF-β also elicits signalling via non-canonical pathways, such as the ERK and p38 MAPK pathways. TGF-β receptors internalize via the clathrin-coated pits route, which facilitates SMAD2/3 signalling, and via the caveolae route, which is associated with receptor degradation and with MAPK activation. Little is known regarding the factors regulating TGF-β receptor compartmentalization and turnover. Previously, CD109 was identified in our lab as a GPI-anchored protein that binds TGF-β and forms a heteromeric complex with the TGF-β receptors. The results presented here demonstrate that CD109 inhibits SMAD2/3-dependent signalling and responses, such as TGF-β-induced growth inhibition. Together, these results suggest that CD109 is a novel TGF-β co-receptor that negatively regulates TGF-β signalling. I then explored the mechanism by which CD109 regulates TGF-β action. My results indicate that CD109 increases TGF-β receptor internalization via the caveolar pathway and enhances TGF-β receptor degradation by the E3 ubiquitin ligase Smurf2, leading to inhibition of TGF-β signalling.Because TGF-β is a potent inducer of epithelial-mesenchymal transition (EMT), a process involved during cancer invasion and metastasis, I next investigated the role of CD109 in this process. CD109 inhibits TGF-β-induced EMT in both non-tumorigenic keratinocytes and squamous cell carcinoma cells via the SMAD and ERK and p38 MAPK pathways. Indeed, CD109 modulates TGF-β-induced MAPK activation, in a caveolin-1 dependent manner. Collectively, these data suggest that CD109 exerts its function by promoting TGF-β receptor localization to caveolae, thereby accelerating their degradation and modulating TGF-β canonical and non-canonical signalling. Thus, CD109 may play a critical role in pathologies where TGF-β signalling is dysregulated, such as cancer progression.<br>Le TGF-β (facteur de croissance transformant β) est une cytokine multifonctionnelle jouant un rôle important dans la croissance, la différentiation cellulaire et la déposition de la matrice extracellulaire. La dérégulation de la cascade de signalisation du TGF-β peut engendrer la fibrose des tissus ou des cancers. Le TGF-β transmet son signal grâce aux récepteurs de type I (TGFBR1) et de type II (TGFBR2), qui phosphorylent leurs substrats intracellulaires, SMAD2 et SMAD3. Les SMAD2/3 phosphorylées s'associent à SMAD4 et régulent l'expression de gènes cibles. En plus de la voie canonique de SMAD2/3, le TGF-β transmet aussi son signal par des voies non-canoniques, telle les voies des MAPKs p38 et ERK. Les récepteurs du TGF-β sont internalisés dans des puits recouverts de clathrine (ce qui facilite la voie des SMAD2/3) et dans les cavéoles (ce qui entrainent la dégradation des récepteurs et l'activation des MAPKs). Peu de choses sont connues sur les facteurs régulant la compartimentalisation et la dégradation des récepteurs du TGF-β. CD109 a été identifié précédemment dans notre laboratoire en tant que protéine à ancre GPI capable de se lier au TGF-β et de former un complexe avec les récepteurs du TGF-β. Les résultats présentés ici démontrent que CD109 inhibe la voie des SMAD2/3 et leurs réponses associées, telles l'arrêt de la croissance cellulaire. Tout ceci suggère que CD109 est un nouveau co-récepteur du TGF-β régulant de manière négative le signal du TGF-β. J'ai ensuite exploré les mécanismes par lesquels CD109 régule l'action du TGF-β. Mes résultats indiquent que CD109 augmente l'internalisation dans les cavéoles des récepteurs du TGF-β et leur dégradation par l'E3-ubiquitine ligase Smurf2, conduisant ainsi à l'inhibition du signal du TGF-β.Comme le TGF-β induit l'EMT (transition épithélium-mésenchyme), j'ai examiné le rôle de CD109 dans ce processus impliqué dans les métastases cancéreuses. CD109 inhibe l'EMT dans les keratinocytes non tumorigéniques et dans les cellules de carcinomes squameux, via les voies des SMADs et des MAPKs p38 et ERK. CD109 régule l'activation des MAPKs, par un processus qui dépend de la cavéoline-1. L'ensemble de ces données suggèrent que CD109 exerce ses fonctions en facilitant la localisation des récepteurs dans les cavéoles, accélérant ainsi leur dégradation et modulant les voies canoniques et non canoniques du TGF-β. CD109 pourrait donc jouer un rôle crucial dans les pathologies où l'action du TGF-β est dérégulée, comme la progression des cancers.
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Marcoux, Anne 1978. "Characterization of a novel TGF-[beta] accessory receptor in human keratinocytes." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84058.
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Transforming growth factor-beta (TGF-beta) signaling is involved in a wide array of cellular responses in both physiological and pathological conditions. Dysregulation of TGF-beta action can lead to impaired tissue homeostasis and several developmental defects. Mechanisms regulating TGF-beta signal transduction include modulation of TGF-beta signaling receptor activity by accessory receptors. Our group has recently identified a GPI-anchored TGF-beta1 binding protein, r150, and has shown that it is implicated in the regulation of TGF-beta signaling in keratinocytes. Recent molecular cloning of r150 in our laboratory shows that it represents CD109, a novel member of the alpha2-macroglobulin/complement (AMCOM) gene family.<br>We provided evidence showing that r150 contains an intact internal thioester bond, which is one of the defining characteristics of almost all members of the alpha2M/complement family, including CD109. Using affinity labeling, immunoprecipitation and Western blot analysis, we demonstrated that r150 binds TGF-beta1 with high affinity and associates with the TGF-beta receptors indicating that it is a component of the TGF-beta signaling complex. In addition, overexpression of r150 resulted in a significant decrease in TGF-beta-induced wound closure and TGF-beta-mediated growth inhibition. In contrast, blocking the expression of r150 by an antisense approach enhanced the above responses. Importantly, immunohistochemical analysis showed that r150 expression is markedly decreased in psoriatic lesions when compared to adjacent normal skin.<br>In summary, our results demonstrated that r150 is a negative modulator of TGF-beta responses in keratinocytes, and that it might be a potential marker or molecular target for therapeutic intervention in modulating TGF-beta action in human diseases where TGF-beta plays a pathophysiological role.
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Chojnowska-Monga, Monika. "Involvement of deubiquitinating enzymes in TGF[beta] receptor trafficking and signalling." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569178.
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The transforming growth factor-β (TGF β) superfamily of ligands controls a wide range of biological processes, including cellular differentiation, proliferation, motility, adhesion and apoptosis. It exerts its biological processes mainly through the TGF β receptor and downstream Smad proteins. Deregulation of TGF β signalling is associated with a variety of human diseases, including cancer. Ubiquitination is a reversible post-translational modification implicated In a variety of cellular processes, including proteasome-mediated protein degradation, DNA repair, regulation of transcription, endocytosis and receptor trafficking. Reversible ubiquitination tightly regulates the TGF β signaling pathway by controlling the basal expression level of TGF β pathway components, terminating signals after prolonged activation of signalling cascade or regulating activity of transcription factors involved in regulation of TGF β target gene expression. In this study, I assessed the involvement of two deubiquitinating enzymes (DUBs) AMSH (~ssociated molecule with the SH3 domain of STAM) and AMSH-LP (AMSH like protein) in the signalling of the TGF~ superfamily of ligands. I compared cellular localisation of both DUBs in HeLa cells as well as their relative protein levels in HEK293T cells. I performed a comparative analysis of the interactions of both AMSH and AMSH-LP with the components of the Smad family of signal transducers using a yeast two- hybrid approach. I also demonstrated evidence for the role of AMSH and AMSH-LP in the regulation of signalling by the TGF~ superfamily ligands, using a luciferase reporter driven by the TGF β or BMP-responsive promoters. Importantly, I showed differential dependence of AMSH and AMSH-LP effect on TGF~ signalling on their DUB activity. I then tested the importance of endosomal localisation for the role of AMSH and AMSH-LP in TGF β signalling and presented evidence for AMSH regulation of TGF β type I receptor levels. Finally, I report on a comprehensive siRNA screen testing the involvement of other DUBs in these signalling pathways.
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Horbelt, Daniel Walter [Verfasser]. "Context specific signaling of TGF-beta receptor II / Daniel Walter Horbelt." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1026694299/34.
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Henning, Kirsten. "TGF-beta induzierte Expression extrazellulärer Matrixproteine durch Herzmuskelzellen der adulten Ratte." Giessen VVB Laufersweiler, 2009. http://geb.uni-giessen.de/geb/volltexte/2009/7319/index.html.
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Hachoumi, Mounia el. "Die Funktion von Bx42/Skip im TGF-beta/Dpp Signal Transduktionsweg." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15635.
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Die Notwendigkeit von Bx42 für Drosophila Entwicklung und seine Beteiligung an unterschiedlichen zellulären Prozessen wurde mit Hilfe von RNA Interference (RNAi) demonstriert. Das ubiquitäre Ausschalten oder die Reduktion der Bx42 Expression mittels RNAi führte dabei zu embryonaler Letalität. Weiterhin führte eine gewebespezifische Induktion von Bx42 in Abhängigkeit der verwendeten Treiberlinien bei unterschiedlichen Temperaturen zu mehreren verschiedenen adulten Phänotypen. Diese Phänotypen waren die Grundlage für die Annahme, dass Bx42 eine Rolle in der Regulation mehrerer verschiedener Zellsignalwege spielt. In der Tat interagiert Bx42 mit den Proteinen des Notch-Signalweges Suppressor of hairless [Su(H)] und Notch intracellular domain (N-IC). Zusätzlich werden bei einer Verminderung von Bx42 die Notch Zielgene cut (ct) und enhancer of split m8 [e(Spl)m8] reprimiert (Negeri et al., 2002). In dieser Arbeit wurde die Beteiligung von Bx42 am TGF-ß/Dpp Signalweg untersucht. Es wurde gezeigt, dass Bx42 mit den TGF-ß/Dpp-Signalweg Proteinen Mad und Medea sowohl in vitro als auch in vivo interagiert. Die dabei verwendeten Methoden waren das Hefe-Zwei Hybrid-Sytem und Ni-NTA-Pulldown-Assays. Domänen der Smad Proteine (Mad und Medea), die für die Interaktion mit Bx42 notwendig sind, wurden mit Hilfe von Deletionskonstrukten untersucht. Es konnte gezeigt werden, dass die stark konservierte MH2-Domäne dieser Proteine für die Interaktion notwendig ist. Zudem belegten Versuche die genetische Interaktion zwischen Bx42 und Medea, in denen ein Bx42-RNAi-Phänotyp durch die gleichzeitige Überexpression von Medea gerettet werden konnte. Es ist bekannt, dass das humane Bx42-Homolog Skip sowohl mit den Proteinen Smad2 und 3 des TGF-ß/Activin Signalweg, als auch mit den Onkogenen Sno und Ski interagiert. Skip wirkt hier als Antagonist der Ski/Sno-Wirkung auf den TGF-ß/Activin-Signalweg und fungiert als Koaktivator (Leong et al., 2001). Die Interaktion zwischen Bx42 und der TGF-ß/Activin-Signalweg Komponente dSmad2, sowie mit dem Onkogen dSno konnte in dieser Arbeit auch für Drosophila bewiesen werden. Die Bedeutung dieser Wechselwirkung muss noch in weiteren Arbeiten analysiert werden. Der Einfluss der Bx42-RNAi-Induktion auf die TGF-ß/Dpp Zielgene distal-less (dll), optomotor blind (omb) und spalt (sal) wurde anhand von Reportergen Untersuchungen mit enhancer-trap-Linien und RNA in situ Hybridisierung untersucht. Es konnte gezeigt werden, dass das Ausschalten von Bx42 die Expression dieser Gene in ähnlicher Weise reprimiert, wie eine Elimination des TGF-ß/Dpp-Signals. Diese Ergebnisse unterstützen die Annahme, dass Bx42 in der Lage ist, TGF-ß/Dpp Zielgene durch eine Wechselwirkung mit Mad und Medea zu aktivieren.<br>The importance of Bx42 in Drosophila development was demonstrated using Bx42-RNA interference. The ubiquitous downregulation of Bx42 generated embryonic lethality, indicating the importance of this protein in early development. The tissue specific induction of Bx42-RNAi resulted in several different phenotypes depending on the driver line and the temperature at which animals were raised. The phenotypes obtained were the key point for the assumption that Bx42 may play a role in the regulation of a number of different cellular signalling pathways. Indeed, within the Notch signalling pathway Bx42 interacts genetically with Suppressor of hairless [Su(H)] and Notch intracellular domain (N-IC). Additionally, the reduction of Bx42 negatively affected the expression of the Notch target Genes cut (ct) and enhancer of split m8 [e(Spl)m8] (Negeri et al., 2002). In this work, the involvement of Bx42 in the Dpp signalling pathway was investigated. It was shown that Bx42 interacts both in vitro and in vivo, as demonstrated by yeast two hybrid protein-protein studies and Ni-NTA pull-down assays, with the TGF-ß/ Dpp components Mad and Medea. Domains of Smads (Mad and Medea) required for Bx42 interaction were examined using deletion constructs of Smads and the importance of the well conserved MH2 domains of Mad and Medea for this interaction was revealed. Moreover, the rescue of the Bx42-RNAi phenotype by the simultaneous overexpression of Medea demonstrated the genetic interaction between Bx42 and Medea. Furthermore, evidences for the interaction of Bx42 with the TGF-ß/Activin pathway component dSmad2 and with the oncogene protein dSno were obtained from interaction assays. The human homologue of Bx42, Skip, also interacts with Smad2/3 or Sno. The meaning of this interaction in Drosophila has yet to be analysed. The influence of Bx42-RNAi induction on the expression of Dpp target genes distal less (dll), optomotor blind (omb) and spalt (sal) was also investigated using enhancer trap lines and RNA in situ hybridisation. In this way it was proven that these genes are suppressed as they are by elimination of Dpp signalling. These results suggest that Bx42 may be able to modulate positively TGF-ß/Dpp signalling through an interaction with the signalling transducer Mad and Medea.
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Handra-Luca, Adriana Alina. "Rôle de la signalisation par la voie du TGF-beta et des protéines de réparation des mésappariements de l'ADN dans la prolifération cellulaire et dans la progression tumorale au cours de la cancérogenèse colorectale et de certains modèles de cancérogenèse pancréatique." Paris 6, 2004. http://www.theses.fr/2004PA066543.
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