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1
Newton, Paul K. "HIPPO : an adaptive open hypertext system." Thesis, University of Nottingham, 1998. http://eprints.nottingham.ac.uk/11477/.
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The hypertext paradigm offers a powerful way of modelling complex knowledge structures. Information can be arranged into networks, and connected using hypertext links. This has led to the development of more open hypertext design, which allow hypertext services to be integrated seamlessly into the user's environment. Recent research has also seen the emergence of adaptive hypertext, which uses feedback from the user to modify objects in the hypertext. The research presented in this thesis describes the HIPPO hypertext model which combines many of the ideas in open hypertext research, with existing work on adaptive hypertext systems. The idea of fuzzy anchors are introduced which allow authors to express the uncertainty and vagueness which is inherent in a hypertext anchor. Fuzzy anchors use partial truth values which allow authors to define a "degree of membership" for anchors. Anchors no longer have fixed, discrete boundaries, but have more in common with contour lines used in map design. These fuzzy anchors are used as the basis for an adaptive model, so that anchors can be modified in response to user actions. The HIPPO linking model introduces linkbase trees which combine link collections into inheritance hierarchies. These are used to construct reusable inheritance trees, which allow authors to reuse and build on existing link collections. An adaptive model is also presented to modify these linkbase hierarchies. Finally, the HIPPO system is re-implemented using a widely distributed architecture. This distributed model implements a hypertext system as a collection of lightweight, distributed services. The benefits of this distributed hypertext model are discussed, and an adaptive model is then suggested.
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Mohamed, Abdalla Ahmed Diaai. "The Hippo effector TAZ in rhabdomyosarcoma." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=228577.
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Persistent hyperactivity of the Hippo effector YAP in activated but not quiescent satellite cells (muscle stem cells) can give rise to embryonal rhabdomyosarcoma (ERMS). Taz is a paralogue of Yap and both have similar functions in most cell types. However, one report has suggested that Taz can, unlike Yap, promote the differentiation of myoblasts into myotubes. To further characterise the role of Taz in the muscle lineage and rhabdomyosarcoma TAZ abundance and localisation in rhabdomyosarcoma tissue arrays were assessed to test for association with clinical outcome. Additionally, wildtype TAZ and constitutively active TAZ S89A pMSCV retroviral vectors were created to stably transduce C2C12 myoblasts testing for Taz function. In addition, anchorage independent soft agarose assay has been performed in order to assess the tumourigenic property of Taz in C2C12 myoblasts. The presence of TAZ staining in ERMS was significantly associated with poorer survival. TAZ S89A expression in comparison to empty vector (negative control) significantly increased the proliferation of C2C12 myoblasts in reduced foetal calf serum (FCS). TAZ S89A- expressing myoblasts were able to grow and to form more colonies than empty vector myoblasts. In marked contradiction to the pro-tumourigenic role of TAZ in C2C12 myoblasts, ectopic TAZ expression enhanced the differentiation of C2C12 myoblasts. These findings point out the complex and obscure role of TAZ in the muscle lineage. Collectively, these results suggest that TAZ staining is associated with poorer survival in ERMS and that TAZ can transform C2C12 myoblasts indicating a contextual role for TAZ in the muscle lineage.
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Sousa, Nidia de. "Role of the Hippo pathway in planarians." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/406086.
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A successful cell renewal, which occurs throughout the life of an organism, relies on multiple events, including proliferation and differentiation of progenitor cell populations, and death of unnecessary cells. Out of the multiple molecular mechanisms involved in the control of cellular renewal, the Hippo signaling pathway currently appears as a hub. Although it was first identified as a key regulator of organ size through the control of cell death and proliferation, growing evidence suggests that it also plays pivotal roles in coordinating stem cell maintenance, cell differentiation, cell-fate decisions and cell survival.
To further understand the role of the Hippo pathway in driving adult cellular renewal and, specifically, in promoting cellular sternness, we studied its function in planarians. Due to the presence of a population of pluripotent adult stem cells (neoblasts), planarians have the ability to constantly grow and degrow depending on food availability, and to regenerate any missing body part within a few days. This active and continuous regulation of the stem cell and post-mitotic cell compartments makes planarians an ideal ' in vivo' context to gain an integrated view of the different events underlying homeostatic cell renewal and tissue regeneration.
Here, we address whether downregulation of Hippo signaling exerts its sternness promoting function by increasing the proliferation of resident stem cells or promoting cell dedifferentiation. We show that inhibition of Smed-hippo (to simplify, hippo) in planarians reduces apoptotic activity and increases mitotic rates. However, this imbalance between cell death and mitotic activity does not lead to an increase in planarian body size or cell number, since hippo (RNAi) does not increase the number of cycling cells but blocks mitotic exit. hippo (RNAi) animals develop overgrowths and extensive regions composed of undifferentiated cells, accompanied by a general decrease in the number of differentiated cells throughout their body. A detailed study of the epidermal lineage reveals that hippo is required to determine the hierarchical transitions required for proper epidermal differentiation, from epidermal-restricted
stem cells to differentiated epidermal cells. We also demonstrate that hippo is required to maintain the differentiated state in planarian cells, since hippo inhibition promotes dedifferentiation of post-mitotic cells. Overall, these results in di cate that thE overgrowths and undifferentiated regions observed after hippo inhibition in planarians are not caused by the unbalance between cell death and proliferation but to the inability of cells to reach and maintain the appropriate fate.
Furthermore, during this study we demonstrate that the Hippo-Yki signaling cascade is conserved in planarians and plays a role in cell differentiation during planarian regeneration. We further show the conservation of the up-stream regulators of the Hippo pathway in planarians since the inhibition of Hippo up-stream regulators, as lg/- 2, phenocopies the hippo (RNAi) phenotype. Transcriptomic analysis of hippo (RNAi) animals allowed the identification of several putative Hippo pathway targets in planarians, which silencing reproduces the formation of overgrowths.
Overall, we propose an essential role for Hippo signaling in restricting cell plasticity and thus in preventing tumoral transformation.La renovación celular, que tiene lugar durante toda la vida en los organismos adultos, depende de multiples eventos, incluyendo el control de la proliferación, la diferenciación de las celulas progenitoras y la muerte de células innecesarias. La vía de señalización de Hippo ejerce un papel central en el control de todos estos procesos. A pesar de haber sido primeramente identificada como una vía reguladora clave en el control del tamaño de los órganos a través de la regulación de la proliferación y la muerte, evidencias recientes sugieren que esta vía puede estar también involucrada en el mantenimiento de las células madre, en la diferenciación celular, en el mantenimiento del estado diferenciado y en la supervivencia de las células. Para profundizar en el conocimiento del papel de la vía de Hippo durante la renovación celular en tejidos adultos, específicamente en su función reguladora del estado pluripotente de las células, abordamos su estudio en planarias. Debido a la presencia de una población de células pluripotentes adultas, los neoblastos, las planarias poseen la capacidad de crecer y decrecer dependiendo de la disponibilidad de alimento, así como de regenerar cualquier parte de su cuerpo en apenas algunos días. Esta activa y continua regulación de las células madre y de los compartimentos postmitóticos convierte a las planarias en un contexto "in vivo" ideal para obtener una vision integrada de los diferentes mecanismos que controlan la renovación celular durante la homeostasis y la regeneración de los tejidos. En esta tesis hemos abordado la cuestión de si el silenciamiento de la vía de señalización de Hippo afecta a la promoción del estado indiferenciado, concretamente a través del control de la proliferación de células madre o bien promoviendo la desdiferenciación celular. Los resultados obtenidos demuestran que la inhibición de Smed-hippo (para simplificar, hippo) en planarias reduce la actividad apoptótica y aumenta los índices mitóticos. Sin embargo, este desequilibrio entre muerte celular y actividad mitótica no conduce al aumento del tamaño de las planarias ni al aumento del número de células. Uno de los motivos es que la inhibición de hippo no aumenta el numero de células que ciclan si no que bloquea la salida de mitosis. Sin embargo, aunque no hay un incremento en el numero de células, el silenciamiento de hippo produce la aparición de sobrecrecimientos, precedidos por la aparición de amplias regiones compuestas por células no diferen ciadas, yla reducción del numero de células diferenciadas en todo el animal. El estudio detallado del linaje epidermico, demuestra que hippo es necesario para determinar las transiciones jerarquicas requeridas para una correcta diferenciación de las células epidermicas. Ademas, demostramos que hippo es necesario para mantener el estado diferenciado de las células, ya que su inhibición promueve la desdiferen ciación de células postmitóticas. En conjunto, estos resultados indican que los sobrecrecimientos y regiones indiferenciadas observadas despues de la inhibición de hippo no son causados por el desequilibrio entre la muerte celular y la proliferac ión sino por la incapacidad de las células adquirir y mantener su estado diferenciado. Ademas, durante este estudio hemos demostrado que la cascada de sena lización Hippo-Yki esta conservada en planarias y desempeña un papel fundamental durante la regeneración. También hemos visto que los mecanismos reguladores "up-stream " de la via Hippo parecen estar conservados en planarias, ya que la inhibición de algunos elementos, como lg/2, fenocopia el fenotipo de los animales hippo (RNAi). A su vez, el analisis transcriptómico de los animales hippo (RNAi) ha permitido identificar genes diana de la vía Hippo en planarias. El silenciamiento de algunos de estos genes candidatos también promueve la aparición de sobrecrecimientos. Para finalizar, nuestros estudios nos permiten proponer que el papel principal de Hippo en las planarias es restringir la plasticidad celular y así prevenir la transformación tumoral.
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Bui, Duyen Amy. "The Hippo Pathway Effector YAP Regulates Cytokinesis." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467231.
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Yes-associated protein (YAP) is a co-transcription factor that acts downstream of the evolutionarily conserved Hippo pathway. Canonically, this pathway regulates tissue growth in flies and mammals, by controlling the nuclear localization of YAP. Interestingly, in addition to the conserved functions of this pathway, some of the mammalian orthologs of pathway components (e.g. MST, RASSF1, WW45, and LATS) have been shown to localize to the nucleus and alterations in their expression induces alterations in mitotic processes, suggesting additional roles for these proteins in mitosis.
In this thesis, I have uncovered a role for the Hippo pathway effector protein, YAP, in cytokinesis. YAP was found to localize to the central spindle and cytokinetic midbody and biochemical analysis demonstrated that YAP is phosphorylated by the mitotic regulatory kinase CDK1 during mitosis. Time-lapse microscopy of cells in which YAP was downregulated by shRNA revealed that reduction in YAP expression causes a delay in abscission and induces a cytokinesis phenotype associated with increased contractile force, membrane blebbing and bulges, and abnormal spindle orientation; consequently, this leads to an increased frequency of multinucleation, micronuclei, and aneuploidy. Expression of or expression of a variant of YAP that could not be phosphorylated at the mitotic phosphoacceptor sites induced a phenotype similar to that of YAP knockdown, suggesting that mitotic YAP phosphorylation is critical for YAP’s function in cytokinesis. Reduction in YAP expression also disrupted the localization of ECT2, MgcRacGap, Anillin, and RHOA, proteins important for cleavage furrow function during cytokinesis, Reduction of YAP also increased levels of phosphorylated myosin light chain, which activates myosin II contractile activity. These findings suggest that YAP is required for proper coordination of these contractile processes involved in cytokinesis. In addition, the YAP mitotic phosphorylation sites are required for interaction with the scaffold polarity protein PATJ, and PATJ co-localizes with YAP at the cytokinesis midbody. PATJ knockdown induces cytokinesis defects and spindle orientation alterations similar to those detected in YAP- depleted cells or cells expressing a non-phosphorylatable mutant of YAP.
This study reveals an unanticipated role for YAP during mitosis and implicates YAP in processes that control the proper organization of cytokinesis machinery through interaction with the polarity protein PATJ. Thus, these studies demonstrate a previously unanticipated role for YAP that is independent of its activity as a transcriptional coactivator. In addition, although YAP is known to function as a potent oncogene, our findings indicate that YAP may also act as a tumor suppressor in certain contexts since loss of YAP could lead to genetic alterations associated with defective cytokinesis. These studies add to the complexity of YAP regulation in cancer as well as in normal development and provide a framework for future studies in a new area of Hippo pathway biology.Medical Sciences
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Toloczko, Aleksandra. "Deubiquitination and control of the Hippo pathway." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/deubiquitination-and-control-of-the-hippo-pathway(8afdf3df-8635-4116-99c8-57fbe423501e).html.
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The Hippo signalling pathway is an evolutionarily conserved kinase cascade responsible for the cell proliferation, tissue growth and apoptosis during development and its dysregulation contributes to tumourigenesis. This signalling pathway was initially discovered in Drosophila and soon after that, it was shown to be highly conserved in mammals. The core Lats kinases of this tumour suppressive pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Latest reports revealed various E3 ubiquitin ligases to negatively regulate the Hippo pathway through ubiquitination, yet few deubiquitinating enzymes have been described. In the present study, we report USP9X deubiquitinating enzyme as an essential regulator of the central components of this pathway. USP9X interacted strongly with Lats2 kinase and to a lesser extent with WW45, Kibra and Angiomotin family proteins. The knockdown of USP9X resulted in notable downregulation and destabilisation of Lats kinase and to lesser extents WW45, Kibra and Amot. This resulted in enhanced nuclear localisation of YAP and TAZ accompanied with activation of their target genes, CTGF and CYR61. USP9X was shown to stabilise Hippo components through its deubiquitinating activity. USP9X enzyme defective mutant lost the activity to stabilise Lats2, WW45, Kibra and Angiomotins through deubiquitination, leading to their ubiquitination. In the absence of USP9X, cells exhibited epithelial to mesenchymal transition phenotype and additionally gained anchorage-independent growth in soft agar. Moreover, USP9X knockdown disrupted acinar organisation of breast cells in three-dimensional acini cultures. In addition, YAP/TAZ target gene activation in USP9X knockdown cells could be rescued by knockdown of YAP, TAZ and TEAD2. Lastly, USP9X protein expression showed a positive correlation with Lats kinases, but negative correlation with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. The results strongly indicate that USP9X cooperates with Lats2 and other important Hippo components to suppress tumour growth.
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Srivastava, Diwas. "Modulation of hippo pathway by alternative splicing." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT015/document.
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La voie Hippo est une voie conservée impliquée dans la croissance des tissus et la suppression de tumeurs. Des études ont démontré son implication dans le développement des cancers chez l'homme. Cette cascade contrôle l'activité du co-activateur transcriptionnel Yorkie (Yki) chez la drosophile et de la protéine YAP (Yes Associated Protein) chez les mammifères. En raison de l'épissage alternatif de leur transcrits, les protéines Yki et YAP existent sous deux isoformes contenant un domaine WW (Yki1/YAP1) ou deux (Yki2/YAP2). Puisque les domaines WW sont essentiels pour l’interaction avec des partenaires spécifiques, l’inclusion alternative de ce domaine dans la protéine Yki/YAP peut remodeler leur réseau d’interaction et donc leur activité. La régulation et les conséquences fonctionnelles de l’épissage alternatif de yki / YAP in vivo sont inconnues.Dans le cadre de ce doctorat, nous avons constaté que la déplétion du facteur d’épissage B52 chez la drosophile réduit l’inclusion de l’exon alternatif dans l’ARNm de yki et favorise l’expression de l’isoforme Yki1 aux dépens de l’isoforme Yki2. La déplétion en B52 dans l'aile réduit la croissance et l'activité de Yki. Nous montrons que l'isoforme Yki1 est une version atténuée de la protéine Yki qui peut entrer en concurrence avec l'isoforme Yki2 dans le noyau. Pour déterminer le rôle de l’épissage alternatif de yki in vivo et l'importance de l'isoforme courte Yki1, nous avons abrogé cet épissage en utilisant la technologie CRISPR/Cas9 et avons créé des mouches capables d'exprimer uniquement l'isoforme Yki2. Ces mouches yki2only sont viables mais présentent un phénotype aléatoire d’ailes asymétriques. Cette augmentation de l'«asymétrie fluctuante», qui traduit une déviation par rapport au développement normal, suggère que l’épissage alternatif de yki est crucial pour la stabilité développementale. Ces résultats mettent en évidence un nouveau niveau de modulation de la voie Hippo via l’épissage alternatif de yki.L'inclusion alternative du deuxième domaine WW est une caractéristique conservée entre Yki et YAP. Cela conforte l'idée que les isoformes Yki1 et YAP1 ont une fonction importante in vivo et que l'épissage alternatif de yki/YAP est un mécanisme conservé de contrôle de la voie Hippo. Cette étude ouvre de nouvelles perspectives pour la modulation de la voie Hippo dans les cellules cancéreuses en modifiant l’épissage alternatif de YAPThe Hippo pathway is a conserved pathway involved in tissue growth and tumor suppression. Studies have demonstrated its significance in the development of human cancers. This cascade controls the activity of the transcription co-activator Yorkie (Yki) in flies and Yes-associated protein (YAP) in mammals. Due to Alternative Splicing (AS), both Yki and YAP proteins exist as two isoforms containing one (Yki1/YAP1) or two (Yki2/YAP2) WW domains. Since WW domains are essential for interaction with specific partners, the alternative inclusion of this domain in Yki/YAP protein may remodel their interaction network and therefore their activity. The regulation and functional consequences of AS of yki/YAP in vivo are unknown.In this Ph.D. project, we identified that depletion of splicing factor B52 in Drosophila lowers inclusion of the alternative exon in yki mRNAs and favors the expression of Yki1 isoform at the expense of the Yki2 isoform. B52 depletion in the wing reduces growth and Yki activity. We demonstrate that Yki1 isoform is an attenuated version of Yki protein that can compete with Yki2 isoform in the nucleus. To ascertain the role of yki AS in vivo and the importance of short isoform Yki1, we abrogated this splicing by using CRISPR/Cas9 technology and created flies that can express Yki2 isoform only. yki2only flies are viable but display a random phenotype of asymmetric wing size. This rise in “fluctuating asymmetry” that is the consequence of subtle deviation from normal development, suggests that AS of yki is crucial for the development robustness. Taking together, these results highlight a new layer of modulation of Hippo pathway via AS of yki.Alternative inclusion of the second WW domain is a conserved feature between Yki and YAP. This further supports the idea that Yki1 and YAP1 isoforms have an important function in vivo and that AS of yki/YAP is a conserved mechanism of control of the Hippo pathway. This study opens up new perspectives for modulation of the Hippo pathway in cancer cells by altering YAP AS
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Morgan, David Edward Charles. "The theology of language of Augustine of Hippo." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613105.
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Kilby, Maria Lucy. "Augustine of Hippo on episcopal authority and honour." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610473.
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Griffith, Susan Blackburn. "Medical imagery in the sermons of Augustine of Hippo." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523099.
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Dunwell, Thomas Lawson. "Epigenetic analysis of childhood leukaemia and the Hippo pathway." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/991/.
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Hypermethylation of CpG islands is one of the many processes that a developing cancer cell may use for the inactivation of tumour suppressor genes. The Sav/Hippo/Warts pathway was originally identified in Drosophila and shown to be responsible for controlling both growth and apoptosis, implying this is a tumour suppressor pathway. This pathway is both evolutionarily and functionally conserved in mammals. Work presented here shows that apart from FAT1 and YAP other pathway members are not epigenetically silenced in common epithelial or haematological cancers. FAT1 and YAP were frequently methylated in childhood acute lymphoblastic leukaemia (ALL) but unmethylated in epithelial cancers. Childhood ALL is a blood cancer with peak prevalence between the ages of 3-5 years. The epigenetics of this cancer were examined with three separate approaches; the first, a candidate gene approach, second a NotI restriction enzyme based array examining the methylation of genes residing on chromosome 3, and thirdly the methylated-CpG island recovery assay (MIRA) combined with CpG island arrays examining methylation on a genome-wide scale. These approaches identified a large number of novel genes which were frequently methylated in ALL. Many of the identified genes were new methylation targets and were shown to be likely targets for methylation in both common epithelial and haematological cancers. A series of these genes was seen to be specifically methylated in different leukaemia sub types, and to cluster T-ALL and B-ALL samples into high and low methylation clusters. When examined in chronic lymphoblastic leukaemia (CLL) methylation of two of the above genes was associated with disease progression and methylation of another gene was associated with response to clinical treatment.
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Shaw, R. L. "Regulation of Drosophila intestinal regeneration by the Hippo pathway." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1366711/.
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Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate in order to self-renew and produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid SC proliferation and faster tissue turnover. I have investigated the role of the Hippo (Hpo) pathway in the Drosophila midgut. The Hpo pathway regulates tissue size via the control of both apoptosis and proliferation during Drosophila development. In the midgut, Hpo pathway inactivation in either the SCs or their differentiated daughter cells, the enterocytes (ECs), induces a phenotype similar to that observed under stress situations, including increased proliferation and expression of Upd cytokines. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the pathway functions as a sensor of cellular stress in the ECs. In addition, Yki, the pro-growth transcription factor target of the pathway, is required in ISCs to drive the proliferative response to stress. Yki inactivation has no obvious effect on baseline homeostasis, while survival upon infection is affected by loss of Yki in either the ISCs or ECs. My findings suggest that the Hpo pathway is a mediator of the regenerative response in the midgut. In the final part of the project, I have addressed possible mechanisms of Yki activation, with a view to gaining further insight into Yki function in the ECs. The data suggest a possible link between the generation of reactive oxygen species, JNK signalling and Yki activation. Several explanations could account for the requirement of Yki expression in the ECs. Yki expression itself might induce stress in the ECs, leading to upd expression and the regenerative response. Alternatively, the Hpo pathway might function as a stress sensor, triggering Upd release in response to noxious stimuli.
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Hall, Sarah Lynne. "Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis." Thesis, University of Iowa, 2017. https://ir.uiowa.edu/etd/5769.
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Sarcomas are cancers of mesenchymal origin. Though they comprise 15-20% of childhood cancers, and have a 5-year survival rate of 16% for metastatic disease, few targeted therapies exist, and the underlying mechanisms of their development are poorly understood. Transcriptional coactivators TAZ and YAP promote cell growth and proliferation, and are constitutively activated in a number of carcinomas. Accompanying TAZ/YAP activation in these cancers is decreased expression of Hippo pathway kinases MST1/2 and LATS1/2. As the Hippo pathway is the primary negative regulator of TAZ/YAP, this provides a potential mechanistic explanation for constitutive TAZ/YAP activation. TAZ and YAP are also thought to play a prominent role in sarcomagenesis, as TAZ-CAMTA1 and YAP-TFE3 gene fusions are the specific initiating events leading to formation of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. However, the mechanisms causing constitutive activation of wild-type TAZ/YAP in sarcomas have not been well-characterized.
The purpose of this study was to determine if Hippo pathway dysregulation occurs in sarcomas with constitutively active, wild-type TAZ/YAP, as well as the mechanisms by which this regulation is lost. We also investigated whether TAZ/YAP could be therapeutically targeted in sarcomas using verteporfin, a small-molecule inhibitor of the TAZ/YAP-TEAD interaction. To address these questions, sarcoma cell lines and patient clinical samples were utilized. Using 159 patient tumor sections, we constructed a tissue microarray, stained for activated (nuclear localized) TAZ/YAP, and Hippo kinases MST1/2 and LATS1/2. A majority of sarcomas contained activation of both TAZ and YAP, while significant decreases in MST1/2 and LATS1/2 expression were observed. Results indicated a majority of tumors which stained positively for nuclear-localized TAZ/YAP also contained loss of expression of at least one of the four kinases evaluated.
All cell lines evaluated via immunofluorescence also had constitutively active (nuclear) TAZ/YAP when grown to confluence, which suggested they were no longer being negatively regulated by the Hippo pathway. In ~50% of lines, protein loss of MST1/2 and LATS2 occurred and mRNA expression of MST1 and MST2 was notably decreased in ~50%, although loss of LATS1 and LATS2 was minimal. Potential mechanisms which could account for Hippo kinase loss were next investigated. It was found that protein degradation diminished MST2 in 25% of cell lines. Regulation by epigenetic modifications was also investigated; hypermethylation accounted for slightly reduced MST1/2, while 67% of lines had histone deacetylation in both kinases. Whether TAZ/YAP can be therapeutically targeted using verteporfin was tested; treatment significantly inhibited anchorage-independent growth, proliferation, and TAZ/YAP transcriptional activity in sarcoma cell lines.
Our results collectively demonstrate TAZ/YAP activity can be targeted in sarcomas with verteporfin, and their constitutive activation is due to loss of MST1/2 and LATS2 kinase expression through protein degradation, histone deacetylation, and promoter hypermethylation. Such findings enhance our current comprehension of the molecular events which promote sarcomagenesis; this knowledge also opens up the possibility of creating targeted pharmacological interventions.
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Wang, Evan Yifan. "Transcriptional regulation by the Hippo signaling pathway in the liver." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63403.
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Development and maintenance of the hepatic phenotype is a tightly controlled process regulated by both master regulatory transcription factors and signaling pathways. Perturbations in these transcriptional networks are frequently seen in diseases such as liver cancer. The Hippo signaling pathway has been implicated in regulation of liver size and dysregulation of this pathway contributes to tumorigenesis. The primary mechanism of action of the Hippo pathway is to inhibit nuclear localization of the transcriptional co-regulator YAP, and thereby preventing YAP from binding to the TEAD family of transcription factors. Although it has been established that YAP plays a role in promoting cell proliferation, how it regulates its transcriptional targets in the liver have yet to be well-characterized. In this study, I show that YAP-overexpression in the adult mouse liver results in a shift from a mature hepatocyte to a hepatic progenitor-like gene expression pattern. Comparison of differentially expressed genes by RNA-seq revealed downregulation of hepatocyte metabolism genes and re-expression of hepatoblast genes, including Glypican-3 (Gpc3). Analysis of ChIP-seq data from both mouse liver and the human hepatoma cell line, HepG2, identified putative Gpc3 enhancers regulated by TEAD and HNF4a. I interrogated these regions using luciferase assays and identified important TEAD and HNF4a binding motifs necessary for transcriptional regulation. In addition, pathway analysis identified enrichment of the ERBB signaling pathway in the YAP-overexpressing liver. Examination of individual ERBB receptors identified upregulation of Her2 (Erbb2), which is normally enriched in hepatoblasts compared to hepatocytes. Analysis of HepG2 ChIP-seq data revealed a TEAD peak at the HER2 promoter. Using luciferase assays, I identified an important TEAD binding site contributing to transcriptional activity. Functionally, I found YAP to regulate EGF-induced HepG2 cell proliferation and PI3K-AKT signaling. This work explored novel mechanisms of gene regulation by YAP in the liver., I found that YAP activation results in re-expression of hepatic progenitor genes such as Gpc3 and Her2. Furthermore, I found the ERBB signaling pathway to be an important growth mediator downstream of YAP.Medicine, Faculty of
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Keech, Dominic. "The anti-pelagian Christology of Augustine of Hippo, 396-430." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527334.
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Coruche, Gaspar P. M. "Investigating the role of the actin cytoskeleton in hippo signalling." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1414999/.
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The Hippo pathway is composed of a phosphorylation cascade involving the kinases Hippo/MST and Warts/LATS, which inactivate the pro-growth transcriptional co-activator Yorkie/YAP. By sensing the status of the actin cytoskeleton, Yorkie/YAP is believed to respond to cell crowding and the rigidity of the environment, but the molecular details and in vivo relevance of this remain unclear. I have investigated the role of mechanical cues and the actin cytoskeleton, in the regulation of Yorkie/YAP. I have applied several forms of mechanical stresses to cell cultures and present evidence to suggest that cell-substrate adhesion and compliance plays role in regulating the localization of YAP. The transduction of mechanical signals is often mediated by the force-displacement of cytoskeletal elements within the cell. Therefore, I took a genetic approach to analyse the contribution of the actin cytoskeleton to Yorkie regulation in Drosophila. Surprisingly, I showed that the Hippo pathway restricts apical F-actin levels in some epihtelia. My work also revealed a novel function of actin-polymerization-factors, such as Capping Proteins, Zyxin and Enabled in regulating Yorkie activity. I have recovered the genes zyxin and ajuba in a modifier screen for actin-associated molecules that modulate hippo-dependent growth. I established that Zyxin is a positive regulator of Yorkie activity, being sufficient to drive epithelial growth and activation of the Yorkie target gene expanded. Interestingly, Expanded was shown to bind Yki directly and is believed to act as a Yki cytoplasmic tether. I have shown that Zyxin can interact with Expanded and prevent its association with Yki, leading me to hypothesize that Zyxin might antagonise Expanded function. Finally, I show that Drosophila Zyxin interacts with the actin-polymerisation-factor Enabled and this is essential to promote tissue growth and Yorkie activity. Furthermore, I establish that Capping Proteins can antagonize the function of Zyxin to restrict tissue growth.
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Norris, Gregory. "Targeting the Hippo Signaling Pathway in Atypical Teratoid Rhabdoid Tumor." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/623631.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.
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Boone, Émilie. "Étude de dilp8, une hormone de couplage de la croissance tissulaire." Thesis, Nice, 2016. http://www.theses.fr/2016NICE4026/document.
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Au cours du développement, les organismes croissent de façon harmonieuse suivant un programme génétique intrinsèque et en adaptation avec les conditions environnementales. Chaque tissu atteint une taille cible qui est proportionnelle à la taille finale des autres organes et à celle de l’organisme. Des expériences de régénération effectuées sur différents modèles animaux ont révélé que chaque organe possède un programme autonome de croissance. Ainsi, des mécanismes de coordination entre la croissance tissulaire et le programme de développement sont nécessaires afin d’assurer une régulation fine de l’allométrie avant le passage du stade juvénile au stade adulte fixant la taille finale du corps. Dilp8 (Drosophila Insulin Like Peptide 8) est une hormone analogue aux peptides de la famille des insulines/relaxines. Elle est produite par les tissus dont la croissance est lésée, en régénération ou néoplasique. dilp8 inhibe la production d’hormone stéroïde et retarde ainsi le passage à la forme adulte. Les mutants dilp8 présentent une augmentation du bruit développemental qui se traduit par une perte de la symétrie bilatérale des organes (asymétrie fluctuante FA). Ceci suggère un rôle de dilp8 dans la coordination de la croissance entre les organes. Au cours de ma thèse, j’ai pu montrer que la voie de signalisation Hippo, son activateur transcriptionnel Yorkie et son co-partenaire Scalloped régulent directement les niveaux transcriptionnels de dilp8 via un Hippo Responsive Element (HRE) présent dans le promoteur de dilp8. La voie Hippo joue un rôle clé dans le contrôle de la taille des organes en couplant les paramètres biomécaniques des tissus avec la prolifération cellulaireGrowth of different body parts needs to be coordinated and scaled with the overall body size to give rise to adults of correct proportions. Since different organs follow autonomous growth programs, mechanisms must operate to ensure that each organ has reached an appropriate size before proceeding through developmental transitions. We recently identified Dilp8 (Drosophila insulin-like peptide 8) as a key hormone in coupling organ growth with animal maturation. Dilp8 is secreted from abnormally growing tissues and acts on the brain complex to delay pupariation. In addition, dilp8 mutant flies exhibit elevated fluctuating asymmetry (FA) demonstrating a function for Dilp8 in coordinating organ growth and ensuring developmental stability. Identifying signals that control dilp8 expression is therefore likely to provide a better understanding of organ size assessment mechanisms. The Hippo tumour suppressor pathway plays a major function in restricting organ growth by promoting cell cycle exit and apoptosis. Hippo signalling is responsive to the mechanical forces operating in growing organs making it an ideal candidate for assessing organ size. Activation of the Hippo pathway restricts nuclear translocation of the transcriptional co-activator Yorkie (Yki), which together with its DNA-binding partner Scalloped (Sd), regulates downstream growth-promoting target genes. Using a molecular biology approach, we show that Yki/Sd directly regulate dilp8 expression through a Hpo Responsive Element (HRE) in the dilp8 promoter
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Schlegelmilch, Karin [Verfasser]. "YAP1 and the Hippo Signaling Pathway Regulate Progenitor Proliferation / Karin Schlegelmilch." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1042186170/34.
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Thomas, Anthony J. IV. "BEAUTY SPEAKING: BEAUTY AND LANGUAGE IN PLOTINUS AND AUGUSTINE OF HIPPO." UKnowledge, 2015. http://uknowledge.uky.edu/mcllc_etds/3.
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Much has been said about the influence of Plotinus, the Platonist philosopher, on the ideas of Augustine of Hippo, the Western Church Father whose writings had the largest impact on Western Europe in the Middle Ages. This thesis considers both writers’ ideas concerning matter, evil, and language. It then considers the way in which these writers’ ideas influenced their style of writing in the Enneads and the Confessions. Plotinus’ more straightforward negative attitude towards the material word and its relationship to the One ultimately makes his writing more academic and less emotionally powerful. Augustine’s more complicated understanding of the material world and its relationship to God results in a more mystical and more emotionally powerful style, which derives its effectiveness especially from its use of antithesis and the first and second person.
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Cherrett, Claire. "Structural and functional studies of proteins from the Hippo signalling pathway." Thesis, University of Bath, 2011. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548103.
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The paralogous multi-functional adaptor proteins YAP and TAZ are nuclear effectors of the Hippo pathway, a central regulator of developmental organ size control, tissue homeostasis and tumour suppression. YAP/TAZ target the TEAD transcription factor family to promote cell survival and inhibit apoptosis. TEAD proteins contain a DNAbinding domain and a YAP/TAZ interaction domain. PCR analysis of medaka fish TEAD cDNA revealed the presence of alternative TEAD splice-forms with variations at the C-terminus of the DNA-binding domain. Structural analysis indicated the YAPbinding domain of TEAD proteins is folded and globular. NMR spectroscopy showed that the TEAD binding domain of YAP does not contain secondary structure. YAP and TAZ both contain WW domains, which are small protein-protein interaction modules. Two YAP isoforms are known, YAP1 and YAP2 that contain one and two WW domains, respectively. To date, only a single WW isoform of TAZ has been described. PCR analysis of medaka TAZ cDNA identified both single WW and tandem WW isoforms of TAZ. NMR spectroscopy was used to characterise structural, conformational, and peptide binding features of the tandem WW domains from YAP and TAZ. The YAP WW2 solution structure confirms that the domain has the canonical anti-parallel β-sheet WW fold. WW1 of YAP and both WW domains of TAZ undergo conformational exchange. The region linking the two WW domains is flexible and allows interaction of both WW domains with peptides containing single and dual PPxY binding motifs. In addition to YAP and TAZ, tandem WW domains are also present in the core and upstream Hippo pathway proteins Salvador and Kibra. Both proteins contain one atypical WW domain; the tandem WW domains of these two proteins are unstable. Understanding structure and function of Hippo pathway components could contribute to drug development and will also contribute to knowledge of protein folding and interactions.
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Kulaberoglu, Y. "The functional characterisation of MOB1-regulated Hippo core cassette kinase signalling." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1537606/.
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The Hippo tumour suppressor pathway regulates tissue growth by co-ordinating cell death, proliferation and differentiation. The central Hippo core cassette consists of MST1/2, LATS1/2, NDR1/2 and MOB1, with recent studies of MOB1 knockout mice indicating MOB1 functions as the central hub of Hippo signalling. However, it has remained unknown which interactions of MOB1 with the Hippo core cassette kinases MST1/2, LATS1/2 and NDR1/2 are required for normal life and tumour suppression. Therefore, my PhD project focused on deciphering the complex protein-protein interactions of MOB1 with MST1/2, LATS1/2 and NDR1/2. To do so, we generated a series of MOB1 variants that are selectively impaired in their binding to NDR1/2 (Trc), MST1/2 (Hippo), or LATS1/2 (Warts) in human (fly) cells. Using these selective lossof-interaction (SLOI) variants we studied the effects of MOB1 overexpression on the proliferation and anchorage-independent growth of human cancer cell lines, thereby establishing which MOB1 interactions are required for the tumour suppressive role of MOB1. Equally importantly, we found that human MOB1 can restore the survival of mats loss-of-function (LOF) in Drosophila. By generating and studying transgenic flies expressing our SLOI MOB1 variants combined with Mats LOF, we discovered that the Hippo/MOB1A interaction is dispensable for fly development and reproduction, while the Trc/MOB1A and Wts/MOB1A interactions are essential. Taken together, my PhD thesis defined a completely novel panel of MOB1 SLOI variants to study the importance of MOB1 interactions. By studying transgenic human cells lines and flies expressing these SLOI variants we delineated which MOB1 interactions are essential for life of a complex multicellular organisms and for tumour suppression in human cancer cells. Collectively, our findings suggest that the Hippo/MOB1 interaction is neither required for life nor for tumour suppression, while the other interactions of MOB1 with Hippo core cassette kinases are essential in a context-dependent manner.
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Arbon, Jed. "Phenotype-genotype correlation between the Hippo pathway and 3D craniofacial phenotypes." Thesis, University of Iowa, 2016. https://ir.uiowa.edu/etd/3042.
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Introduction: The purpose of this study was to examine phenotypic expression of craniofacial form, shape, and size as it relates to the genotype of an individual. Shape analyses were completed on 3-D images of each subject's craniofacial structure by landmarking 45 points of interest on the cranial base, facial bones, and upper and lower jaws. A candidate gene analysis was undertaken focusing on specific genes in the Hippo Signaling Pathway to examine genotype-phenotype correlations that play a role in craniofacial development. This study is a continuation of a larger project aimed at the identification of candidate genes associated with human dento-skeletal bite problems led by Dr. Lina Moreno-Uribe.
Methods: The sample size for our study included 166 individuals who had never been treated orthodontically at the time of records. Each individual was genotyped and a CBCT of the craniofacial complex was captured. Each CBCT image was landmarked by a single observer using 45 points to mark points on the cranial base and facial bones including the maxilla and mandible. General Procrustes superimposition was used to find correlations with phenotype and genotype. Size analysis was completed with average Euclidean Distances and ANOVA analysis.
Results: 2 SNP's from the FOX03 gene had significant associations with size. The AA genotyped individuals appeared larger in overall size than AB genotyped individuals. 3 SNP's had statistically significant associations with facial form. The FOX06 SNPs had significant associations with increased anterior-posterior growth of the maxilla. The AJUBA SNP had significant associations with increased overall craniofacial breadth.
Conclusion: Genes in the Hippo signaling pathway have specific roles in the development of facial form and size.
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Strocchi, Silvia <1988>. "Studies on the Hippo Pathway: new insights about a multifaceted signalling." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9409/1/Silvia%20Strocchi%20PhD%20Thesis.pdf.
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The Hippo pathway is a well-known master regulator of cell growth and proliferation. Many studies have shed light on the centrality of Hippo functions, as this signalling is able to respond to different stimuli and translate them into distinct transcriptional outputs. Therefore, it is clearly implicated in a number of important processes, which alteration has consequences on the correct specification of the single cell, as well as the whole tissue. Even if the core of the signalling has been extensively characterized, it remains unclear which are the “co-workers” that permit the Hippo pathway to answer to so many different stimuli and act as a coordinator of the growth/differentiation balance.
Taking advantage of the Drosophila model, which has witnessed most of the discoveries on this signalling pathway, this thesis aims to add some new knowledge about the Hippo pathway molecular mechanisms in different contexts, from development to disease.
In the first part I studied the dynamics of the Hippo core kinase protein Warts in the development of the pupal eye. I have found out a critical time point in which the expression and the localization of Warts change suddenly, suggesting the intervention of upstream regulators modulating its activity in an extremely narrow time window.
The second goal was investigating the role of the Hippo pathway in the neurodegenerative Gaucher disease. Indeed, I have produced some preliminary results which demonstrate a growth deficit associated with a massive reduction of some Yki targets, supporting a Hyper-Hippo condition underlying this neuropathic syndrome.
Finally, I have evaluated the transcription factor Orthodenticle as a co-factor of Yorkie in driving tissue overgrowth, and my findings support a model of interaction of these two molecules based on Yki conformational changes.
Altogether, my results lay the foundation for new important studies on the molecular mechanisms ruling Hippo pathway activity.
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Fulford, Alexander. "Investigating the role of phosphorylation and ubiquitylation dependent regulation of Hippo signalling." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/31794.
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The Hippo Pathway is a highly conserved regulator of tissue growth and size determination, limiting the activity of the transcriptional co-activator Yorkie (Yki), which promotes proliferation and inhibits apoptosis. Hippo signalling integrates and transduces cell polarity and cell-cell adhesion inputs thereby responding to the state of tissue architecture. The transmembrane apical polarity protein Crumbs (Crb) controls the activity of Yki by regulating Expanded (Ex), a protein that promotes Hippo signalling through kinase-dependent and -independent mechanisms to robustly inhibit Yki activity. Crb plays a dual role in the regulation of Ex by controlling its apical localisation, facilitating Yki inhibition, and by promoting Ex degradation, thus activating Yki. Crb regulates the stability of Ex by stimulating a phosphorylation-dependent ubiquitylation and proteasomal degradation. Characterisation of the precise mechanisms by which Crb regulates Ex has been the focus of this thesis. Based on candidates identified by mass spectrometry and from literature, the Casein Kinase 1 (CK1) family of kinases, and the deubiquitylating enzyme (DUB) Usp2 have both been identified as novel regulators of Ex stability. CK1s promote Ex phosphorylation and degradation, acting as Ex inhibitors, while Usp2 promotes Ex function by promoting its stabilisation. Furthermore, in a screen to identify DUBs that regulate Drosophila adult wing size, CG10889 has been established as a novel regulator of growth that interacts with members of the Hippo pathway.
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Bauerschmidt, John Crawford. "Sexual difference and the relation of the sexes in the theology of Saint Augustine." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260122.
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Philippe, Chloe. "Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0454/document.
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L’AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) est un intermédiaire de la voie de biosynthèse des purines. A des concentrations importantes, ce métabolite a un effet cytotoxique sur les cellules cancéreuses aneuploïdes, c’est-à-dire contenant un nombre anormal de chromosome. Or,90% des tumeurs solides sont aneuploïdes. Les mécanismes responsables de cette cytotoxicité doivent donc être mieux étudiés pour une utilisation éventuelle en thérapie anti-cancéreuse.Dans la littérature, l’effet de l’AICAR est expliqué par son rôle mimétique de l’AMP sur l’AMPK.Cependant, certaines données de la littérature et du laboratoire laissent penser que l’inhibition de la croissance par l’AICAR peut impliquer plusieurs types de mécanismes dont certains sont dépendantsde l’AMPK et d’autres indépendants. L’identification des cibles de l’AICAR alternatives à l’AMPK estdonc nécessaire pour une meilleure compréhension de ses effets.Dans ce projet, j’ai pu confirmer la présence d’autres cibles de l’AICAR indépendantes de l’AMPKet responsables de son effet cytotoxique. Grâce à une approche transcriptomique, j’ai montré un effetde l’AICAR sur l’expression et l’activation de LATS1 et LATS2 (large tumor suppressor 1 and 2). Ces protéines kinases fond partie du core enzymatique de la voie HIPPO, dont le rôle en cancérologie est fondamental. Les effecteurs finaux de cette voie sont YAP et TAZ, deux cofacteurs de transcription,aussi régulés par l’AICAR. J’ai pu montrer que la cytotoxicité de l’AICAR est due en partie à l’activation de cette voie. Depuis la découverte récente de la voie HIPPO, de nombreuses études visent à identifier des molécules permettant l’inhibition directe de cette voie. L’AICAR s’avère être une molécule puissante dans le cadre d’une thérapie anticancéreuse ciblant la voie HIPPOAICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) is an intermediate of the purine biosynthesis pathway. At high concentrations, this metabolite has a cytotoxic effect on aneuploid cancer cells that is cells containing an abnormal chromosome number. However, 90% of solid tumorsare aneuploid. The mechanisms responsible for this cytotoxicity should be better studied for possible use in anti-cancer therapy.In the literature, the effect of AICAR is explained by its AMP mimetic role on the AMPK. However,some literature and laboratory data suggest that AICAR growth inhibition may involve several types of mechanisms, some of which are dependent and other independent of AMPK. Therefore, the identification of AMPK alternative targets is necessary for a better understanding the AICAR effects. In this project, I was able to confirm the presence of other AICAR targets independent of AMPK and responsible for its cytotoxic effect. Using a transcriptomic approach, I showed an effect of AICAR on the expression and activation of LATS1 and LATS2 (large tumor suppressor 1 and 2). These proteinkinases form part of the enzymatic nucleus of the HIPPO pathway, whose role in oncology is fundamental. The effectors of this pathway are YAP and TAZ, two transcription cofactors, also regulated by the AICAR. I have been able to show that the cytotoxicity of AICAR is due to the activation of this pathway. Since the recent discovery of the HIPPO pathway, numerous studies aim to identify molecules allowing direct inhibition of this pathway. AICAR has proven to be a potent molecule in anticancer therapy which goal is targeting the HIPPO pathway
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Occhi, Simona. "The fat gene cooperates with the Hippo pathway to prevent neuronal degeneration." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.525845.
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Genevet, A. "Control of cell polarity and growth by the Hippo pathway in Drosophila." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20453/.
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The Hippo (Hpo) signalling pathway comprises the kinases Hpo and Warts (Wts), the adaptors Salvador and Mats, the cytoskeletal proteins Expanded (Ex) and Merlin (Mer), the atypical cadherin Fat and the transcriptional co-factor Yorkie (Yki). This pathway has been shown to restrict tissue size through the control of cell division and apoptosis during development in Drosophila. In addition to their well-characterised overproliferation phenotype, adult epithelial cells mutant for the kinases Hpo and Wts present a hypertrophy of the apical domain. I examined the molecular basis of this apical hypertrophy and its impact on cell proliferation. In the wing imaginal disc epithelium, I observe increased staining for members of the apical polarity complexes aPKC and Crumbs as well as adherens junction components when Hpo activity is compromised, while baso-lateral markers are not affected. This increase in apical proteins is correlated with a hypertrophy of the apical domain and adherens junctions. Interestingly however, while the polarity determinant Crumbs is required for the accumulation of apical proteins, this does not appear to significantly contribute to the overproliferation defect elicited by loss of Hpo signalling. Therefore, the Hpo pathway controls growth and apical domain size via distinct mechanisms. In collaboration with the Thompson lab (CRUK LRI) we identified the WWdomain- containing protein Kibra (Kib) as a new member of the Hpo pathway. Kib, which colocalises and physically interacts with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kib/Mer interaction is conserved in human cells. Loss of kib induces a hpo-like phenotype and genetic experiments place it upstream of the core kinase cassette. Finally, Kib binds to Wts and kib depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. My work therefore suggests that Kib is part of an apical scaffold that promotes Hpo pathway activity.
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Morice, Sarah. "Rôle de la voie de signalisation Hippo dans le développement des ostéosarcomes." Thesis, Nantes, 2019. http://www.theses.fr/2019NANT1037.
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L'ostéosarcome (OS) est la tumeur osseuse primitive maligne la plus fréquente chez les enfants et les adolescents dont le pronostic reste mauvais, surtout lorsque des métastases sont présentes au diagnostic. Des analyses transcriptomique de biopsies de patients atteint d’OS révèlent la présence d’une signature génique de la voie de signalisation Hippo dans l’OS. Son principal effecteur, YAP, est connu pour son rôle oncogène dans un certain nombre de cancer. Afin d’étudier son rôle dans le développement de l’OS, nous avons développé une approche moléculaire en surexprimant une protéine YAP capable ou non d’interagir avec son facteur de transcription TEAD. Des expériences in vitro et in vivo révèlent le rôle crucial de TEAD dans la prolifération cellulaire et la croissance tumorale médiée par YAP. De plus nous avons montré que la surexpression de YAP augmente la migration cellulaire in vitro et la dissémination métastatique in vivo, indépendamment de son interaction avec TEAD. Des analyses transcriptomique ont montré un enrichissement de gènes liés à la transition épithéliaux-mésenchymateuse, à la migration cellulaire et au TGF-β dans les cellules surexprimant YAP, quel que soit sa capacité à interagir avec TEAD. Des expériences de PLA et d’immunoprécipitation montrent une interaction YAP/Smad3, le principal effecteur de la voie du TGF-β. A l’aide d’un inhibiteur spécifique du TGF-β, le SD-208, nous montrons le rôle essentiel de la signalisation TGF-β/Smads dans la dissémination métastatique médiée par YAP. Ces résultats ont défini le rôle spécifique de TEAD et Smad3 dans la progression tumorale de l’OS, et identifié YAP comme un acteur central du développement de l’OS. Ainsi, YAP pourrait être une cible thérapeutique prometteuse dans l’OSOsteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Transcriptomic analyses of biopsies from OS patients reveal the presence of an Hippo signalling pathway gene signature in the OS. Its main effector, YAP, is known for its oncogenic role in a number of cancers. In order to study its role in the development of OS, we developed a molecular approach by overexpressing YAP that could or not interact with its transcription factor TEAD. In vitro and in vivo experiments revealed the crucial role of TEAD in cell proliferation and tumor growth mediated by YAP. In addition, we showed that overexpression of YAP increases cell migration in vitro and metastatic dissemination in vivo, regardless of its interaction with TEAD. Transcriptomic analysis showed a genes enrichment related to epithelial-mesenchymal transition, cell migration and TGF-β in cells overexpressing YAP, regardless of its ability to interact with TEAD. PLA and immunoprecipitation experiments showed YAP/Smad3 interaction, the main effector of the TGF-β pathway. Using a specific inhibitor of TGF-β, SD-208, we demonstrated the essential role of TGF- β/Smads signalling in YAP-mediated metastatic dissemination. These results defined the specific role of TEAD and Smad3 in the tumor progression of OS, and identified YAP as a central actor in the development of OS. Thus, YAP could be a promising therapeutic target in OS
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Hwang, Katie Lee. "The Metabolic Role of the Hippo Pathway in Liver Development and Cancer." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467350.
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Hepatocellular carcinoma (HCC) is a global health problem with poor prognosis and limited therapeutic options. While the clinical risk factors for HCC are well described, the precise molecular and metabolic mechanisms contributing to malignant transformation remain largely unknown. Recently, the Hippo signaling pathway has been identified as a key regulator of cellular proliferation, organ size, and tumorigenesis in numerous tissues, including the liver. However, the metabolic impact of the pathway in supporting liver growth and tumorigenesis has not been studied. The zebrafish, Danio rerio, has successfully been applied as a model to investigate signaling pathways important in organ development to model liver development and cancer. Here, we utilize the zebrafish to investigate the functional and metabolic roles of the Hippo pathway in liver development and cancer in vivo.
Using a transgenic zebrafish model with liver-specific activation of the transcriptional co-activator Yap, the downstream target of the Hippo pathway, we show Yap is functionally conserved in its ability to promote embryonic and adult hepatomegaly. These livers demonstrate signs of dysplasia and increased tumor susceptibility upon chemical carcinogen exposure. Using transcriptomic and metabolomic analysis, we discover that nitrogen metabolism is significantly altered in Yap-transgenic livers. Yap upregulates glutamine synthetase (Glul) expression leading to elevated steady-state levels of glutamine, which significantly contributes to its ability to enhance liver growth and de novo purine biosynthesis.
To further probe the functional and metabolic role of Yap prior to liver outgrowth, we utilize yap knockout zebrafish and heat-shock inducible transgenic zebrafish that modulate
Yap activity to examine early liver development. We show Yap is important for hepatoblast formation and expansion. Further, Yap modulates glucose uptake and glycolytic flux into de novo nucleotide synthesis. Overall, this dissertation reveals novel roles of Yap in cellular metabolism to support proliferation and growth by directing glucose into the building blocks of DNA in the context of development and cancer.Medical Sciences
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Schuler, Stephen J. Russell Richard Rankin. "Augustinian Auden the influence of Augustine of Hippo on W. H. Auden /." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5248.
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Lössl, Josef. "Intellectus gratiae : die erkenntnistheoretische und hermeneutische Dimension der Gnadenlehre Augustins von Hippo /." Leiden : Brill, 1997. http://catalogue.bnf.fr/ark:/12148/cb38854816f.
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Sabra, Hiba. "Etude des mécanismes moléculaires régulant la voie Hippo via les intégrines ß1." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV026/document.
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L'adhérence cellulaire à la matrice extracellulaire joue un rôle clé dans leur prolifération,leur différenciation ou l'apoptose. Par conséquent ce processus est critique pour undéveloppement normal et pour l'homéostasie tissulaire. La dérégulation de ce mécanismecontribue souvent à des situations pathologiques. Ainsi, la dérégulation de nombreux gènesimpliqués dans les adhérences cellule-cellule ou cellule-matrice extracellulaire sont liés à despathologies conduisant à un défaut de développement, la progression tumorale, oul'inflammation.Les intégrines sont des récepteurs transmembranaires hétéro dimériques jouant un rôlemajeur dans les interactions cellule-matrice extracellulaire. Ce rôle n'est pas limité à unesimple interaction mécanique puisqu'elles permettent également la transduction dessignaux de la matrice extracellulaire à la cellule afin de permettre à cette dernière des'adapter à son micro environnement. Dans le but d’étudier le rôle des intégrines à chaîneβ1 dans le développement osseux, le laboratoire a mis en place un modèle murind'inactivation conditionnelle du gène Itgb1 basée sur l'expression de la recombinase Cre austade pré-ostéoblastique. Les souris mutées présentent un défaut de développementosseux, dû à une faible prolifération des ostéoblastes.Contrairement à ce qui était généralement admis, cette faible prolifération desostéoblastes est indépendante de la voie classique mettant en jeu la voie classique des MAPkinases. En revanche, elle est contrôlée par la voie Hippo: cette signalisation a étérécemment identifiée chez la Drosophile et les Mammifères comme un mécanismeinhibiteur majeur de la prolifération cellulaire. Le cofacteur de transcription YAP, effecteurfinal de cette voie, est une navette nucléo-cytoplasmique. Son expression est amplifiée dansdivers cancers dont l'ostéosarcome où cette surexpression associée à celle de l’Itgb1 est unfacteur de mauvais pronostique.Mes travaux consistent à comprendre comment les intégrines à chaîne β1 contrôlent lavoie Hippo, et donc la prolifération. Nous avons confirmé que la délétion des intégrines β16active la phosphorylation de YAP et sa séquestration dans le cytoplasme. En utilisant destechniques de Biologie Cellulaire et de Biochimie, nous avons montré que suite à la délétionde l’Itgb1, les cellules présentent un défaut de trafic vésiculaire réduisant la translocationmembranaire de Rac1. La séquestration cytoplasmique de Rac1 diminue l’activation de soneffecteur majeur la kinase PAK responsable de la dissociation d'un complexe membranaired'inactivation composé de la protéine adaptatrice NF2, la kinase LATS et de son effecteurprincipal YAP. Les intégrines en provocant la perte de ce complexe induisent ladéphosphorylation de YAP, sa translocation nucléaire et donc stimulent la proliférationcellulaireCell adhesion to the extracellular matrix plays a key role in their proliferation,differentiation or apoptosis. Therefore, this process is critical for normal development andtissue homeostasis. The deregulation of this mechanism often contributes to pathologicalsituations. Thus, the deregulation of many genes involved in cell-cell or cell-extracellularmatrix adhesions are linked to pathologies leading to developmental defects, tumorprogression, or inflammation.Integrins are heterodimeric transmembrane receptors that play a major role in cellextracellularmatrix interactions. This role is not limited to a simple mechanical interactionsince integrins also allow the transduction of the signals from the extracellular matrix to thecell in order to permit the latter to adapt to its microenvironment. In order to study the roleof β1 integrins in bone development, the laboratory has implemented a mouse model withconditional inactivation of the Itgb1 gene based on the expression of recombinase Cre at thepre-osteoblastic stage. The mutated mice show a defect in bone development due to a lowproliferation rate of osteoblasts.Contrary to what was generally accepted, this reduced proliferation is independent of theclassical pathway involving the classical pathway of MAP kinases. On the other hand, it iscontrolled by Hippo: this signaling pathway has recently been identified in Drosophila andMammals as a major inhibitory mechanism of cell proliferation. The transcription cofactorYAP, the end effector of this pathway, is a nucleo-cytoplasmic shuttle. Its expression isamplified in various cancers including osteosarcoma where this overexpression associatedwith that of Itgb1 is a factor of poor prognosis.My work involves understanding how β1 integrins control the Hippo pathway, and thusproliferation. We confirmed that deletion of β1 integrins activates the phosphorylation ofYAP and its sequestration in the cytoplasm. Using Cell Biology and Biochemistry techniques,we showed that following the deletion of Itgb1, the cells exhibit a defect in vesicular trafficthat reduces the membrane translocation of Rac1. The cytoplasmic sequestration of Rac18decreases the activation of its major effector, the PAK kinase. PAK is responsible for thedissociation of an inactivating membrane complex composed of the adaptor protein NF2,the LATS kinase, and its main effector YAP. The integrins by provoking the loss of thiscomplex induce the dephosphorylation of YAP, its nuclear translocation, and thus stimulatecell proliferation
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Martin, Alexandre. "La kinase STK38 contrôle la distribution subcellulaire de partenaires en phosphorylant le domaine d'auto-inhibition de XPO1." Thesis, Paris Sciences et Lettres (ComUE), 2019. https://tel.archives-ouvertes.fr/tel-02631780.
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STK38 est une sérine/thréonine kinase appartenant à la voie de signalisation Hippo et possédant de multiples fonctions dans des cellules tant normales que cancéreuses. De précédents travaux, réalisés par notre équipe et par des collaborateurs, ont permis d’identifier le rôle central de STK38 dans la progression du cycle cellulaire, la duplication centrosomale, l’apoptose, ainsi que l’activité transcriptionnelle. De façon importante, STK38 a été caractérisée comme agissant en aval des protéines Ral (des effecteurs de la famille de protéine Ras) dans deux processus cellulaires nécessaires au maintien de l’homéostasie cellulaire se trouvant souvent dérégulés dans les cellules cancéreuses. D’un côté, STK38 établis un pont à la croisée des voies de signalisation Ral-Ral et Hippo en régulant positivement l’autophagie. D’un autre côté, STK38 est indispensable à la résistance des cellules cancéreuses à l’anoïkis lors du détachement de la matrice extracellulaire. Ces observations montrent l’implication de STK38 dans des processus cellulaires, semblant n’avoir aucun lien entre eux, régulas par diverses cascades de signalisation.Dans ce travail, nous avons découvert que STK38 interagit avec différents partenaires protéiques, pour un total de plus 250 protéines identifiées, en fonction du contexte cellulaire. Dans le détail, nous avons trouvé que STK38 augmente son association avec des protéines cytoplasmiques lors de l’autophagie induite par carence nutritive, alors que STK38 augmente son association avec des partenaires nucléaires, au détriment de partenaires cytoplasmiques, lors du détachement à la matrice extracellulaire. Nous avons découvert que STK38 navigue entre le noyau et le cytoplasme, en fonction du contexte cellulaire, sous la dépendance de XPO1. Nous avons caractérisé STK38 comme le tout premier activateur de XPO1 via la phosphorylation du domaine auto-inhibiteur de XPO1, phosphorylation nécessaire à la présentation de sa région de liaison du cargo. En plus de décider de sa propre disponibilité subcellulaire, STK38 régule également l’export nucléaire d’effecteurs protéiques, telles que Beclin1, YAP1 et Centrin, effecteurs ayant été caractérisé comme impliqués dans certaines fonctions liées à STK38.Ces résultats révèlent que de multiples fonctions cellulaires, semblant régulées par une unique protéine, une kinase dans notre cas, STK38, peuvent en fait être expliquées par un mécanisme moléculaire unique : réguler la distribution subcellulaire d’effecteurs clés en modulant l’activité exportatrice de XPO1 via la phosphorylation de sa région auto-inhibitriceThe Hippo pathway STK38 serine/threonine protein kinase is implicated in multifarious biological processes in both normal and cancer cells. Previous work performed by our team and collaborators have identified the central role of STK38 in cell cycle progression, centrosome duplication, apoptosis, and transcriptional activity. Importantly, STK38 has been characterized to act downstream of the Ral proteins (effectors of Ras proteins family) in two cellular processes required for proper cellular homeostasis and deregulated in cancer cells. On one hand, STK38 establish a bridge between the Ras-Ral and Hippo transduction pathways by positively regulating autophagy. On the other hand, STK38 is required for anoïkis resistance in Ras-driven cancer cells. All these observations reveal the implication of STK38 in unrelated cellular functions regulated by diverse transduction pathways.In this work, we discovered that STK38 associates with more than 250 identified interactors, depending on the cellular context. In details, we found that STK38 increases its association with cytoplasmic proteins upon nutrient starvation-induced autophagy, while STK38 increases its interaction with nuclear proteins to the detriment of cytoplasmic ones upon ECM detachment. Furthermore, we discovered that STK38 shuttles between the nucleus and the cytoplasm depending on the context in a XPO1-dependent manner. We characterized STK38 as the first activator of XPO1 by phosphorylating XPO1’s auto-inhibitory domain: this phosphorylation being required for the presentation of XPO1’s cargo docking site. In addition of being its own gatekeeper, STK38 regulates the subcellular distribution of several effectors, such as Beclin1, YAP1, and Centrin, effectors that play a crucial role in STK38-related well characterized functions.Taken together, these results presented in this work reveal that multifarious functions harboured by a single protein, a kinase in our case, STK38, can be explained by a unique molecular mechanism: regulating the subcellular distribution of key effectors by modulating XPO1 export activity through phosphorylation of its auto-inhibitory domain. STK38 is in charge of controlling the supply chain of components of these machineries assembled in the cytoplasm
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Arngården, Linda. "Analysis of signaling pathway activity in single cells using the in situ Proximity Ligation Assay." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-281716.
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A cell that senses signals from its environment uses proteins for signal transduction via post translational modifications (PTMs) and protein- protein interactions (PPIs) from cell membrane into the nucleus where genes controlling cell proliferation, differentiation and apoptosis can be turned on or off, i.e. changing the phenotype or fate of the cell. Aberrations within such proteins are prone to cause diseases, such as cancer. Therefore, it is important so study aberrant signaling to be able to understand and treat diseases. In this thesis, signaling aberrations of PTMs and PPIs were analyzed with the use of the in situ proximity ligation assay (in situ PLA), and the thesis also contain method development of rolling circle amplification (RCA), which is the method used for signal amplification of in situ PLA reaction products. Paper I considers the integrity of RCA products. Here, the aim was to generate a smaller and more compact RCA product, for more accurate either visual or automated analysis. This was achieved with the use of an additional so called compaction oligonucleotide that during RCA was able to bind and pull segments of RCA products closer together. The compaction oligonucleotide served to increase the signal to noise ratio and decrease the number of false positive signals. The crosstalk between the Hippo and TGFβ signaling pathways were studied in paper II. Activity of the Hippo signaling pathway is regulated by cell density sensing and tissue control. We found differences in amounts and localization of interactions between the effector proteins of the two pathways depending on cell density and TGFβ stimulation. In paper III the NF-кB signaling pathway constitutively activated in chronic lymphocytic leukemia (CLL) was studied. A 4 base-pair frameshift deletion within the NFKBIE gene, which encodes the negative regulator IкBε, was found among 13 of a total 315 cases by the use of targeted deep sequencing. We found reduced levels of IкBε protein, decreased p65 inhibition, and increased phosphorylation, along with increased nuclear localization of p65 in NFKBIE deleted cases compared to healthy cases. Crosstalk between the Hippo and Wnt signaling pathway are studied within paper IV. Here, we found differences in cellular localization of TAZ/β-catenin interactions depending on colon cancer tumor stage and by further investigate Hippo/WNT crosstalk in cell line model systems we found an increase of complex formations involved in the crosstalk in sparse growing HEK293 cells compared to dense growing cells. Also, active WNT3a signaling was affected by cell density. Since cell density showed to have a big effect on Hippo/WNT crosstalk we continued to investigated the effect of E-cadherin, which has a function in cell junctions and maintenance of epithelial integrity on Hippo/WNT crosstalk. Interestingly, we found that E-cadherin is likely to regulate Hippo/WNT crosstalk.
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Harrison, Simon James. "De libero arbitrio : Augustine's way in to the will." Thesis, University of Cambridge, 1996. https://www.repository.cam.ac.uk/handle/1810/273059.
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Dutta, Shubham. "Role of TRIP6 and Angiomotins in the Regulation of the Hippo Signaling Pathway." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/964.
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Mechanical tension is an important regulator of cell proliferation, differentiation, migration and cell death. It is involved in the control of tissue architecture and wound repair and its improper sensing can contribute to cancer. The Hippo tumor suppressor pathway was recently shown to be involved in regulating cell proliferation in response to mechanical tension. The core of the pathway consists of the kinases MST1/2 and LATS1/2, which regulate the target of the pathway, the transcription co-activator YAP/ TAZ (hereafter referred to as YAP). When the Hippo pathway is inactive, YAP remains in the nucleus and promotes cell proliferation and stem cell maintenance. When the Hippo signaling pathway is turned on, MST1/2 phosphorylate and activates LATS1/2. LATS1/2 phosphorylates and inactivates YAP in the cytoplasm which is sequestered and degraded, stopping cell proliferation and promoting differentiation of stem cells. Mechanical forces are transmitted across cells and tissues through the cell-cell junctions and the actin cytoskeleton. However, the factors that connect cell-cell junctions to the Hippo signaling pathway were not clearly known. We identified a LIM domain protein called TRIP6 that functions at the adherens junctions to regulate the Hippo signaling pathway in a tension-dependent manner. TRIP6 responds to mechanical tension at adherens junctions and regulates LATS1/2 activity. Under high mechanical tension, TRIP6 sequesters and inhibits LATS1/2 at adherens junctions to promote YAP activity. Conditions that reduce tension at adherens junctions by inhibition of actin stress fibers or disruption of cell-cell junctions reduce TRIP6-LATS1/2 binding, which activates LATS1/2 to inhibit YAP. Vinculin has been shown to act as part of a mechanosensory complex at adherens junctions. We show that vinculin promotes TRIP6 inhibition of LATS1/2 in response to mechanical tension. Furthermore, we show that TRIP6 competitively inhibits MOB1 (a known LATS1/2 activator) from binding and activating LATS1/2. Together these findings reveal TRIP6 responds to mechanical signals at adherens junctions to regulate the Hippo signaling pathway in mammalian cells.
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Sidor, C. M. "Mask proteins are co-factors of Yorkie/YAP in the Hippo signaling pathway." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1352451/.
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One of the key questions in developmental biology is how tissue growth is controlled to give rise to organs of specific sizes and shapes. Although some genes and pathways involved in the genetic and environmental control of tissue growth have been uncovered, the understanding of this process remains incomplete. In order to find new regulators of growth we carried out an in vivo RNAi screen in the Drosophila wing. I participated in the validation of candidate genes from the screen and identified the mask gene as an essential regulator of tissue growth acting in the Hippo signaling pathway. This pathway acts via the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional co-activator to control tissue growth in both Drosophila and mammals. Yki/YAP translocates from the cytoplasm to the nucleus to activate target genes, a process that is negatively regulated by the Warts kinase, one of the core components of the Hippo pathway. I found that Mask is an essential positive regulator of Yki acting downstream of Warts. Mask is required for normal tissue growth, for the expression of Yki target genes and for the overgrowth phenotype caused by Yki overexpression. Mask binds to Yki and the two proteins translocate from the cytoplasm to the nucleus together in response to various stimuli. My results show that Mask acts in the nucleus to promote Yki target gene activation. Finally, Mask’s function appears to be conserved in humans, as two human homologues of Mask (hMask1 and hMask2) translocate with YAP to the cytoplasm upon cell contact inhibition, and we demonstrate that one of these homologues promotes YAP’s transactivation function.
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Smither, Edward. "Principles of mentoring spiritual leaders in the pastoral ministry of Augustine of Hippo." Thesis, University of Wales Trinity Saint David, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683370.
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Vermöhlen, Vanessa, Petra Schiller, Sabine Schickendantz, Marion Drache, Sabine Hussack, Andreas Gerber-Grote, and Dieter Pöhlau. "Hippotherapy for patients with multiple sclerosis: A multicenter randomized controlled trial (MS-HIPPO)." Sage, 2018. https://tud.qucosa.de/id/qucosa%3A35527.
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Background: Evidence-based complementary treatment options for multiple sclerosis (MS) are limited.
Objective: To investigate the effect of hippotherapy plus standard care versus standard care alone in MS patients.
Methods: A total of 70 adults with MS were recruited in five German centers and randomly allocated to the intervention group (12 weeks of hippotherapy) or the control group. Primary outcome was the change in the Berg Balance Scale (BBS) after 12 weeks, and further outcome measures included fatigue, pain, quality of life, and spasticity.
Results: Covariance analysis of the primary endpoint resulted in a mean difference in BBS change of 2.33 (95% confidence interval (CI): 0.03–4.63, p = 0.047) between intervention (n = 32) and control (n = 38) groups. Benefit on BBS was largest for the subgroup with an Expanded Disability Status Scale (EDSS) ⩾ 5 (5.1, p = 0.001). Fatigue (−6.8, p = 0.02) and spasticity (−0.9, p = 0.03) improved in the intervention group. The mean difference in change between groups was 12.0 (p < 0.001) in physical health score and 14.4 (p < 0.001) in mental health score of Multiple Sclerosis Quality of Life-54 (MSQoL-54).
Conclusion: Hippotherapy plus standard care, while below the threshold of a minimal clinically important difference, significantly improved balance and also fatigue, spasticity, and quality of life in MS patients.
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Verghese, Shilpi. "Interaction of Hippo Pathway and Dronc to Regulate Organ Size in Drosophila melanogaster." University of Dayton / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1417813436.
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Mösch, Sophia Cornelia. "Augustine of Hippo and the art of ruling in the Carolingian imperial period." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/augustine-of-hippo-and-the-art-of-ruling-in-the-carolingian-imperial-period(e0cb2f90-b0ac-43b6-a3fe-bf4bb298c74a).html.
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This thesis investigates how the political thought of Augustine of Hippo was understood and modified by Carolingian-era writers to serve their own distinctive purposes. The research concentrates on Alcuin of York and Hincmar of Reims, advisers to Charlemagne and Charles the Bald, respectively. The analysis focuses on Alcuin's and Hincmar's discussions of empire, rulership and the moral conduct of political agents, in the course of which both made extensive use of Augustine's De civitate Dei, though each came away with a substantially different understanding of its message. By applying a philological-historical approach, this thesis offers a deeper reading that views their texts as political discourses defined by content and language; it also explains why Augustine, despite being understood in such different ways, remained an author that Carolingian writers found useful to think with. Methodological problems are outlined in the Introduction. Chapter One contains an analysis of selected concepts of Augustinian thought, chosen both for their prominence in the De civitate Dei and relevance to the Carolingian material. Chapter Two explores the range of Augustinian influences in Alcuin's Epistolae, with emphasis on political thought. Chapter Three studies the impact of Augustine on Hincmar's Epistolae, Expositiones ad Carolum Regem and De regis persona, with a focus on political ethics. The Conclusion contextualises the findings on Augustinian influence from the previous chapters and attempts to show more clearly why Alcuin's and Hincmar's versions of Augustinian thought are so different. In particular, it considers the differences between Augustine's, Alcuin's and Hincmar's understandings of 'church' and 'state' and the distinctive ways in which each of them interpreted the relationship between religion and political power. A comparison of Alcuin's and Hincmar's uses of Augustine sheds light on the differences between Charlemagne's reign and that of his grandson.
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Cabochette, Pauline. "CARACTERISATION DU RESEAU DE SIGNALISATION IMPLIQUE DANS LA MAINTENANCE ET LA PROLIFERATION DES CELLULES SOUCHES DE LA RETINE DU XENOPE." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T089/document.
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Contrairement aux mammifères adultes, la rétine des amphibiens possède la particularité de croître durant toute la vie de l'animal grâce à l'activité continue d'une population de cellules souches localisée au sein d'une niche bien délimitée, la zone marginale ciliaire (ZMC). Ce modèle offre ainsi la possibilité d'étudier in vivo les mécanismes moléculaires à l'origine du maintien et de la prolifération des cellules souches neurales à des stades post-embryonnaires. Dans ce but, l'identification et la caractérisation des différentes voies de signalisation présentes au sein de la niche biologique des cellules souches rétiniennes est une première étape indispensable. Mon projet de thèse a été divisé en deux objectifs principaux: l'étude des interactions entre les voies Wnt et Hedgehog au sein de la ZMC chez le xénope et la réalisation de l'étude fonctionnelle de Yap, l'effecteur principal de la voie de signalisation Hippo dans ce modèle. Par des approches génétiques et pharmacologiques, la première partie de ce projet a permis de mettre en évidence un antagonisme inattendu entre les signaux Wnt et Hedgehog au sein de la ZMC qui régule l'activité proliférative des cellules souches et des progéniteurs rétiniens. Ce travail nous a conduit à proposer un modèle dans lequel ces deux voies réguleraient la balance prolifération/différenciation dans la rétine post-embryonnaire. Dans un deuxième temps, les expériences de gain et de perte de fonction du gène Yap ont montré que ce dernier joue un rôle essentiel dans la régulation du programme temporel de la phase de réplication de l'ADN des cellules souches rétiniennes. En effet, l'inhibition de Yap entraîne une importante réduction de la durée de la phase S du cycle cellulaire associée à une instabilité génomique. Une surexpression de c-Myc et de la voie p53-p21 semble impliquée dans ce phénotype. Nos travaux nous ont également permis d'identifier un nouveau partenaire de YAP, le facteur de transcription PKNOX1. L'ensemble de ces données nous a ainsi conduit à proposer un modèle selon lequel le complexe YAP/PKNOX1 pourrait être nécessaire au bon déroulement de la phase de réplication des cellules souches, indispensable à la maintenance de l'intégrité du génome de ces cellules et de leur descendanceIn contrast to the adult mammals, the retina of amphibians shows continuous growth during adulthood through active neural stem cells localized in the defined niche called ciliary marginal zone (CMZ). This model offers an exceptional tool to study in vivo the molecular mechanisms involved in the maintenance and proliferation of neural stem cells during post-embryonic stages. In this order, the identification and the characterization of the signaling pathways acting in biological retinal stem cell niche is an essential step.My PhD research was divided in two main parts: the study of the interaction between the Wnt and Hedgehog pathways within the CMZ and the functional study of Yap, the downstream effector of the Hippo pathway in this model. By using genetic and pharmacological tools, the first part of this project demonstrated an unexpected antagonism between the Wnt and the Hedgehog signaling in the CMZ that regulates proliferative activity of retinal stem and progenitor cells. In this article, we propose a model in which an antagonistic interplay of Wnt and Hedgehog pathways may regulate the balance proliferation/differentiation in the post-embryonic retina. Second, gain and loss of function experiments of Yap have shown that this factor plays a key role in the regulation of temporal replication of DNA retinal stem cells. Indeed, inhibition of Yap leads to strong reduction of the S-phase length during the cell cycle associated with genomic instability. c-Myc and p53-p21 overactivation seems to be involved in this phenotype. This work also allowed us to identify a novel YAP partner, the transcriptional factor PKNOX1. We indeed propose a model in which the YAP/PKNOX1 complex may be required for the successful convening of the replication phase on stem cells, essential for the maintenance of genome integrity on the cells and their progeny
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Tholen, Ivonne. "Die Donatisten in den Predigten Augustins Kommunikationslinien des Bischofs von Hippo mit seinen Predigthörern." Berlin Münster Lit, 2007. http://d-nb.info/1000783332/04.
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Cotton, Jennifer L. "Requirement and Function of Hippo Pathway Signaling in the Mammalian Gastrointestinal Tract: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/867.
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In cancer, aberrant activation of developmental signaling pathways such as the Hippo Pathway has been shown to drive proliferation and invasion of cancer cells. Therefore, understanding the normal function of the Hippo Pathway during embryonic development can provide critical insight into how aberrant activity contributes to tumorigenesis. This dissertation explores the role of the Hippo Pathway members YAP and TAZ in gastrointestinal (GI) development and tumorigenesis. I use mouse genetics to systematically dissect the roles of YAP/TAZ in the endoderm-derived gastrointestinal epithelia and mesoderm-derived gastrointestinal mesenchyme during mammalian development. In the GI epithelium, I demonstrate that YAP/TAZ are dispensable for development and homeostasis. However, YAP/TAZ are required for Wnt pathway-driven tumorigenesis. I find that YAP/TAZ are direct transcriptional targets of Wnt/TCF4 signaling. In the GI mesenchyme, I describe a previously unknown requirement for YAP/TAZ activity during mammalian GI development. YAP/TAZ are involved in normal GI mesenchymal differentiation and function as transcriptional co-repressors in a progenitor cell population. In this way, YAP/TAZ act as molecular gatekeepers prior to Hedgehog-mediated differentiation into smooth muscle cells. This work unveils a previously unknown requirement for Hippo pathway signaling in the mammalian GI tract and a novel mechanism wherein YAP/TAZ function as transcriptional co-repressors to maintain a mesenchymal progenitor cell population.
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Morris, Zachary James. "Actin Binding Proteins Regulate the Localization of the Fission Yeast Hippo Pathway Protein Mob1p." University of Toledo / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1533229650651521.
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Molina-Castro, Silvia. "Study of the Hippo/YAP1 signaling pathway in gastric carcinogenesis induced by Helicobacter pylori." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0623/document.
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Le cancer gastrique (CG) est une maladie multifactorielle, fréquemment associée à l’infection chronique par des souches CagA+ d’Helicobacter pylori. La transition épithélio-mésenchymateuse (EMT) est un processus réversible dans lequel une cellule épithéliale polarisée acquiert un phénotype mésenchymateux. L’EMT est à l’émergence de cellules souches cancéreuses (CSC) qui expriment CD44 et présentent une activité ALDH élevée. L’infection des cellules épithéliales gastriques humaines (CEGs) par CagA+ H. pylori induit des cellules CD44+ avec des propriétés des CSCs via une EMT. La voie Hippo est composée par les kinases MST et LATS, et leurs cibles, les YAP1 et TAZ. Suite à la phosphorylation, YAP1 et TAZ sont inhibés. YAP1 et TAZ activés lient les facteurs TEAD pour promouvoir la croissance cellulaire et l’inhibition de l’apoptose.Notre premier objectif était de rechercher si H. pylori change l’état d’activation de la voie Hippo et l'effet sur l’EMT et les CSC in vitro et in vivo. Le deuxième but est la caractérisation du rôle de YAP1/TEAD dans les propriétés de CSCs gastriques in vitro et les conséquences de son inhibition dans la croissance tumorale in vivo.Pour étudier la régulation de la voie Hippo pendant l’infection par H. pylori, LATS2, YAP1 et CD44 ont été évalués dans la muqueuse gastrique de sujets non-infectés et infectés par H. pylori, qui ont été augmentés avec l’infection et leur surexpression a été associée avec la gastrite et la métaplasie intestinale. Dans les CEGs l’expression de gènes de la voie Hippo a été altérée par l’infection. La régulation de la voie Hippo par H. pylori a une cinétique diphasique et dépendante de CagA. Dans l’infection précoce, H. pylori déclenche l’activité transcriptionelle de YAP1. Cette période d’inactivité de la voie Hippo est suivi de son activation progressive, soutenue par l’accumulation de LATS2 et la phosphorylation inhibitrice de YAP1. La répression de LATS2 avec siRNAs a accéléré l’acquisition du phénotype mésenchymateux après l’infection, l’augmentation de marqueurs de l’EMT (Zeb1 et Snail1), et la diminution des miR-200 épithéliaux. Les CSC induites par H. pylori ont été potentialisées par l’inhibition de LATS2, ce qui suggère que LATS2 limite l’EMT et le phénotype de CSC acquis pendant l’infection. L’inhibition de LATS2 ou YAP1 diminue l’expression de ces deux protéines, révélant ainsi une boucle de régulation positive. Dans des coupes de tissu de CG, l’expression de LATS2 et YAP1 est hétérogène et positivement corrélée, fait qui a été confirmé dans 38 CEGs de la CCLE. L’expression LATS2 est fortement corrélée à celle de CTGF et CYR61, ce qui suggère que LATS2 peut aussi être un gène cible de YAP1/TEAD.La verteporfine (VP) est capable d’interrompre l’interaction YAP1/TEAD, et donc d’inhiber son activité transcriptionelle. In vitro, utilisant CEGs et des cellules de tumeurs de patients amplifiées chez la souris (patient-derived xenograft PDX), le traitement à la VP a diminué la croissance cellulaire, l’expression de gènes cible de YAP1/TAZ/TEAD, l’activité du rapporteur TEAD-luciférase et la capacité de formation de sphères. L’activité de la VP a été testée in vivo par injection péri-tumorale dans un modèle de greffe sous-cutanés des CEGs MKN45 et MKN74 et le PDX GC10 chez la souris NSG. La croissance tumorale a été diminuée. Le poids des tumeurs, l’analyse par IHC (CD44, ALDH, Ki67) et la capacité de formation de sphères des CSCs résiduelles ont été diminuées. Ces résultats montrent une activité inhibitrice de la VP sur les CSCs gastriques in vitro et in vivo.Ce travail montre pour la première fois que l’axe LATS2/YAP1/TEAD est précocement activé pendant l’infection chronique avec H. pylori et que celui-ci contrôle l’EMT et les propriétés de CSC. Le ciblage de la voie Hippo a été montré comme étant efficace dans la prévention de la croissance tumorale, mettant en évidence le potentiel de son inhibition dans le traitement du cancer gastriqueGastric cancer (GC) is a multifactorial disease, most frequently associated to chronic infection with CagA-positive Helicobacter pylori strains. Epithelial-to-mesenchymal transition (EMT) is reversible process in which polarized epithelial cells acquire a mesenchymal phenotype. EMT is at the origin of cancer stem cells (CSC). In GC, CSCs express CD44 and high aldehyde-dehydrogenase (ALDH) activity. Infection with H. pylori of human gastric cancer cell lines (hGECs) in vitro induces the emergence of a population of CD44+ cells with CSC-properties through an EMT process in a CagA-dependent manner. The Hippo pathway is composed by the kinases MST and LATS, and their phosphorylation targets,YAP1 and TAZ. Upon phosphorylation by LATS, YAP1 and TAZ are inhibited. Active YAP1 and TAZ bind to TEAD transcription factors to promote the expression of genes that regulate cell growth and apoptosis.The first aim of this work was to investigate whether H. pylori affects the activation state of the Hippo pathway, and its effect on the EMT process and the CSCs. Second, we intended to characterize the role of YAP1/TEAD in gastric CSC properties in vitro and the consequences of its pharmacological inhibition on tumor growth in vivo.To study the Hippo pathway regulation during infection, LATS2, YAP1 and CD44 were evaluated in gastric mucosae of non-infected or H. pylori-infected patients. They were upregulated in infected mucosae and were associated to pathology. Hippo pathway regulation by H. pylori infection has biphasic kinetics and is CagA-dependent. Early in infection, H. pylori transiently triggered YAP1 expression and co-transcriptional activity, along with LATS2. This period of Hippo pathway inactivity is followed by a progressive activation, sustained by LATS2 accumulation and inhibitory YAP1Ser127-phosphorylation. LATS2 siRNA-mediated repression accelerated the acquisition of the EMT-phenotype upon infection, the up-regulation of EMT-markers ZEB1 and Snail1, and the decrease of the epithelial miR-200. H. pylori-induced CD44 upregulation, invasion and sphere-forming capacity were further enhanced upon LATS2 knockdown, suggesting that LATS2 restricts the EMT and CSC-like phenotype in hGECs upon H. pylori infection. Inhibition of either LATS2 or YAP1 reduced the expression of both proteins, revealing a positive feedback loop. In tissue sections of GC, LATS2 and YAP1 were heterogeneous and co-expressed. The positive correlation between LATS2 and YAP1 was confirmed in the 38 hGECs of the CCLE. The expression of CTGF and CYR61 was also strongly correlated to LATS2, suggesting that LATS2 could also be a YAP1/TEAD target gene.hGECs of the CCLE. The expression of CTGF and CYR61 was also strongly correlated to LATS2, suggesting that LATS2 could also be a YAP1/TEAD target gene.Verteporfin (VP) disrupts the YAP1/TEAD interaction inhibiting its transcriptional activity. In vitro, using hGECs and cells from patient derived primary tumor xenogratfs (PDXs), we showed that treatment with VP decreased cell growth, expression of YAP1/TAZ/TEAD target genes, TEAD-luciferase reporter activity and sphere-forming capacity. The activity of VP was tested in vivo, by peritumoral injection in a model of subcutaneous graft of hGECs (MKN45 and MKN74) and PDX (GC10) in NGS mice. Tumor growth was followed and a decrease was observed. Tumor weight measurement, IHC analysis (CD44, ALDH and Ki67), and CSCs were decreased in treated tumors. These results show the CSC-inhibitory activity of VP both in vitro and in vivo.We showed for the first time that the LATS2/YAP1/TEAD axis is early activated during the carcinogenesis process induced by chronic H. pylori infection and controls the subsequent EMT and CSC-like features. Targeting the Hippo pathway efficiently prevented tumor growth in a PDX model, highlighting the potential of its inhibition to be implemented in gastric cancer therapy
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Weldrick, Jonathan. "Gene Expression Analysis of the Perinatal Heart and the Identification of MiR-205 as a Regulator of Cardiomyocyte Maturation." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39809.
Full textAbstract:
Background:
Extensive research has characterized the embryonic development of a four-chambered heart in mammals. After birth, mammalian cardiomyocytes undergo a transition characterized by a final cell cycle with nuclear division (karyokinesis) in the absence of cytoplasmic division (cytokinesis), generating mature binucleated cardiomyocytes. Downregulation of pro-proliferative signaling and epigenetic changes permanently ‘lock’ cardiomyocytes out of the cell cycle, and nearly all subsequent growth is accomplished via cellular hypertrophy. Before this transition, cardiomyocytes exhibit robust proliferative potential, but afterward are unable to divide.
Rationale & Hypothesis:
Recent evidence suggests that non-coding RNAs influence early neonatal cardiac development and hypertrophy. We hypothesize that transient expression of regulatory miRNAs may impact the neonatal heart’s transition from proliferation to hypertrophy.
Results:
Cardiac mRNA and miRNA were systematically analyzed using microarrays to identify targets that were transiently and significantly changing after birth. Through our analysis we identified three primary ontogenies significantly changing: metabolism, extracellular matrix remodeling, and cell cycle regulation.
Global analysis of micro-RNA expression patterns during perinatal heart development identified miR-205 as a novel candidate for modulating cardiomyocyte maturation. We observed miR-205 expression undergoing a 20-fold increase from 1-day postpartum (1D) to 5D, returning to prenatal levels by 10D. It is expressed in cardiomyocytes of the epicardium, the primary location of fetal cardiomyocyte proliferation. MiR-205 targets two important cell cycle regulators: Pten phosphatase of the PI3K/AKT pathway, and Yap1 in the Hippo pathway. Both pathways have proven to be essential for proper heart development. Previous research showed that germline deletion of miR-205 results in death at 5D.
To define its role in the heart, we generated an αMHC-Cre postnatal miR-205 cardiac-specific deletion mouse model. Systematic characterization of miR-205-/- hearts confirmed miR-205’s interaction with Pten and Yap1 by western blot and immunohistochemistry. Postnatal miR-205-/- hearts exhibit Hippo pathway dysregulation, increased cardiomyocyte number, more actively cycling cardiomyocytes beyond 7D, and no difference in binucleation.
We also generated a DOX-inducible cardiac-specific miR-205 over-expression mouse model. Perinatal miR-205OE hearts expedited the transitional period, with more cardiomyocytes present at 5D and no difference at 14D. These hearts show increased Hippo signaling immediately after birth, suggesting compensatory mechanisms to ensure sufficient cardiomyocyte number.
Conclusions:
Our data strongly supports miR-205 as a regulator of cardiomyocyte maturation in the neonatal heart, by promoting the neonatal cardiomyocyte transition from hyperplastic to hypertrophic growth. In turn, miR-205’s antiproliferative properties originate in part from suppressing the expression of Pten and Yap1.
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Willecke, Maria. "Regulation of organ size by the atypical cadherins fat and dachsous through the hippo pathway /." Tübingen, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253071.
Full text
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Vahid, Sepideh. "Heat shock protein 27 inhibits the Hippo tumor suppressor pathway by facilitating MST1 proteasomal degradation." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/56740.
Full textAbstract:
Heat shock protein 27 (Hsp27) is a molecular chaperone highly and ubiquitously expressed in aggressive cancers where it controls a variety of pro-tumorigenic signaling pathways. Using gene expression profiling in prostate cancer cells with loss of Hsp27 function, we identified for the first time that Hsp27 regulates target genes in signaling pathways dependent on YAP and TAZ. Suppression of these transcriptional co-activators occurs via their phosphorylation and cytoplasmic retention by the Hippo tumor suppressor pathway. Mechanistic studies revealed that Hsp27 expression is associated with reduced YAP phosphorylation and enhanced transcription of YAP/TAZ target genes. Examination of the core components of the Hippo kinase cascade revealed that Hsp27 facilitates the proteasomal degradation of the core Hippo kinase, MST1, leading to reduced phosphorylation/activity of other main kinases responsible for YAP phosphorylation/inactivation, LATS1 and MOB1. Importantly, our data from cell lines was supported by data from human tumors; clinically, high expression of Hsp27 correlates with increased expression of YAP target genes in prostate cancer as well as reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. Together, our data reveal a novel mechanism by which Hsp27 regulates the Hippo tumor suppressor pathway, providing further rationale to target Hsp27 in multiple cancers.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate