Academic literature on the topic 'HIPPO-PATHWAY-YAP'
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Journal articles on the topic "HIPPO-PATHWAY-YAP"
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Matthaios, Dimitrios, Maria Tolia, Davide Mauri, Konstantinos Kamposioras, and Michalis Karamouzis. "YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango." Biomedicines 9, no. 12 (December 20, 2021): 1949. http://dx.doi.org/10.3390/biomedicines9121949.
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Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology.
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Salem and Hansen. "The Hippo Pathway in Prostate Cancer." Cells 8, no. 4 (April 23, 2019): 370. http://dx.doi.org/10.3390/cells8040370.
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Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.
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Agarinis, C., V. Orsini, P. Megel, Y. Abraham, H. Yang, C. Mickanin, V. Myer, T. Bouwmeester, J. S. Tchorz, and C. N. Parker. "Activation of Yap-Directed Transcription by Knockdown of Conserved Cellular Functions." Journal of Biomolecular Screening 21, no. 3 (December 2, 2015): 269–76. http://dx.doi.org/10.1177/1087057115617906.
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The Yap-Hippo pathway has a significant role in regulating cell proliferation and growth, thus controlling organ size and regeneration. The Hippo pathway regulates two highly conserved, transcription coactivators, YAP and TAZ. The upstream regulators of the Yap-Hippo pathway have not been fully characterized. The aim of this study was to use a siRNA screen, in a liver biliary cell line, to identify regulators of the Yap-Hippo pathway that allow activation of the YAP transcription coactivator at high cell density. Activation of the YAP transcription coactivator was monitored using a high-content, image-based assay that measured the intracellular localization of native YAP protein. Active siRNAs were identified and further validated by quantification of CYR61 mRNA levels (a known YAP target gene). The effect of compounds targeting the putative gene targets identified as hits was also used for further validation. A number of validated hits reveal basic aspects of Yap-Hippo biology, such as components of the nuclear pore, by which YAP cytoplasmic–nuclear shuttling occurs, or how proteasomal degradation regulates intracellular YAP concentrations, which then alter YAP localization and transcription. Such results highlight how targeting conserved cellular functions can lead to validated activity in phenotypic assays.
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Grijalva, James L., Megan Huizenga, Kaly Mueller, Steven Rodriguez, Joseph Brazzo, Fernando Camargo, Ghazaleh Sadri-Vakili, and Khashayar Vakili. "Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 2 (July 15, 2014): G196—G204. http://dx.doi.org/10.1152/ajpgi.00077.2014.
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The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.
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Yang, Haitang, Sean R. R. Hall, Beibei Sun, Liang Zhao, Yanyun Gao, Ralph A. Schmid, Swee T. Tan, Ren-Wang Peng, and Feng Yao. "NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma." Cancers 13, no. 7 (March 29, 2021): 1561. http://dx.doi.org/10.3390/cancers13071561.
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(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.
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Huang, Shiyuan, Xiaona Wang, Xinmei Wu, Jiale Yu, JinJing Li, Xiaoyuan Huang, Chunfang Zhu, and Hongshan Ge. "Yap regulates mitochondrial structural remodeling during myoblast differentiation." American Journal of Physiology-Cell Physiology 315, no. 4 (October 1, 2018): C474—C484. http://dx.doi.org/10.1152/ajpcell.00112.2018.
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Yes-associated protein (Yap) is a core transcriptional coactivator in the downstream Hippo pathway that regulates cell proliferation and tissue growth. However, its role in the regulation of myoblast differentiation remains unclear. Regulation of mitochondrial networks by dynamin-related protein 1 (Drp1) and mitofusion 2 (Mfn2) is crucial for the activation of myoblast differentiation. In the present study, we investigated the interplay between the Hippo/Yap pathway and protein contents of Mfn2 and Drp1 during myoblast differentiation. The Hippo/Yap pathway was inactivated at the early stage of myoblast differentiation due to the decreased ratio of phosphorylated mammalian sterile 20 kinases 1/2 (p-Mst1/2) to Mst1/2, phosphorylated large tumor suppressor 1 (p-Lats1) to Lats1, and phosphorylated Yap (serine 112, p-Yap S112) to Yap, which resulted in the translocation of Yap from cytoplasm to nucleus, increased protein content of Drp1, and mitochondrial fission events. Downregulation of Yap inhibited myoblast differentiation and decreased the content of Drp1, which resulted in elongated mitochondria, fused mitochondrial networks, and collapsed mitochondrial membrane potential. Together, our data indicate that inactivation of the Hippo/Yap pathway could induce mitochondrial fission by promoting Drp1 content at the early stage of myoblast differentiation.
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Jagannathan, Radhika, Gregory V. Schimizzi, Kun Zhang, Andrew J. Loza, Norikazu Yabuta, Hitoshi Nojima, and Gregory D. Longmore. "AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol." Molecular and Cellular Biology 36, no. 20 (July 25, 2016): 2526–42. http://dx.doi.org/10.1128/mcb.00136-16.
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The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling duringDrosophilawing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.
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Höffken, Verena, Anke Hermann, Hermann Pavenstädt, and Joachim Kremerskothen. "WWC Proteins: Important Regulators of Hippo Signaling in Cancer." Cancers 13, no. 2 (January 15, 2021): 306. http://dx.doi.org/10.3390/cancers13020306.
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The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms.
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Thaventhiran, James, Anja Hoffmann, and Douglas Fearon. "CTLA-4 activates the hippo pathway to regulate terminal differentiation of the CD8+ T cell. (46.17)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 46.17. http://dx.doi.org/10.4049/jimmunol.186.supp.46.17.
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Abstract Replicating, antigen-specific CD8+ T cells must not commit to terminal differentiation until there has been sufficient clonal expansion. The Hippo pathway of organ size control mediates this requirement by linking expression of the differentiation-inducing transcription factor, Blimp-1, to contact between replicating cells, which would be dependent on their frequency. TCR and IL-2R stimulation assemble the Hippo pathway in the CD8+ T cell by inducing expression of WW45, Mob1, Lats1, and YAP, the transcriptional co-activator that mediates organ growth. Contact between activated CD8+ T cells triggers the Hippo pathway, causing serine phosphorylation and degradation of YAP. This is suppressed by addition of naïve CD8+ T cells, indicating that the ligand-receptor pair triggering the Hippo pathway is expressed only by activated cells. The ligand was identified by suppressing YAP degradation with blocking CD80/86 antibody, and the receptor was defined by inducing YAP degradation by crosslinking CTLA-4. That YAP regulates differentiation was shown by ectopically expressing a non-phosphorylatable, stable form of YAP in activated CD8+ T cells, which suppressed Blimp-1 expression in vitro, and the differentiation/senescence marker, KLRG1, in vivo. This role for CTLA-4 was confirmed by the presence of YAP in T cells from CTLA-4-/-, but not CTLA-4+/-, mice. Therefore, in a process that resembles quorum sensing, the Hippo pathway regulates terminal differentiation of the CD8+ T cell.
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Casati, G., L. Giunti, A. Iorio, A. Marturano, and I. Sardi. "P04.20 The role of YAP in Glioblastoma cell lines." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii22—ii23. http://dx.doi.org/10.1093/neuonc/noab180.074.
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Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.
Dissertations / Theses on the topic "HIPPO-PATHWAY-YAP"
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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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Moleirinho, Susana. "Mammalian upstream Hippo signalling pathway proteins activate core pathway kinases and functionally antagonize oncogenic YAP." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/3662.
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The mechanism of body and organ size control is an unsolved puzzle. Initially characterized in Drosophila melanogaster, the Salvador/Warts/Hippo (Hippo) signalling pathway, highly conserved throughout evolution, defines a novel signalling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis, and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. Previously Willin/FRMD6 has been proposed as the human orthologue of Expanded and, to date, little is known about the functional role of Willin in mammalian cells. My study elucidated the mechanism by which Willin antagonizes the transcriptional co-activator YAP. In MCF10A cells, Willin ectopic expression antagonizes YAP-induced epithelial-mesenchymal phenotypes via YAP Ser127 phosphorylation site. Loss of Willin expression attenuates MST1/2, LATS1, and YAP phosphorylation promoting YAP's oncogenic transformation activity in vitro, as analysed by its ability to display epithelial-to-mesenchymal transition (EMT) features. These biological outputs are YAP dependent. These data support the involvement of Willin in the regulation of the mammalian Hippo signalling activity by activating the core Hippo pathway kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but the functional consequences of these biochemical changes have not been previously addressed. I showed that in MCF10A cells, loss of KIBRA expression displays EMT features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the Ser 127 phosphorylation site and I showed that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Willin/FRMD6 was first identified in rat sciatic nerve, which is composed of Schwann cells and fibroblasts. To elucidate the function of Willin in the mammalian sciatic nerve, I showed that Willin is predominantly expressed in fibroblasts and that its expression activates the Hippo signalling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These evidence show that Willin modulates sciatic nerve fibroblast activity, indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.
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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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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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Astone, Matteo. "A novel Yap/Taz zebrafish reporter reveals a role of Hippo pathway transducers in angiogenesis." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3424650.
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YAP and TAZ, by orchestrating cell proliferation, cell death and cell-fate decisions, are key players of a complex network of signaling pathways acting during development. Deregulation of YAP/TAZ signaling causes robust organ overgrowth during organogenesis, which translates to loss of tissue homeostasis in the adult and consequent cancer development. YAP/TAZ are transcriptional co-activators that interact with TEAD transcription factors to promote cell proliferation and survival. Their transcriptional activity is regulated by nucleocytoplasmic shuttling and nuclear accumulation, which are controlled by the Hippo kinase cascade, but also by mechanical cues sensed by the cell and by other pathways. Among these, Wnt/β-catenin takes on a particular relevance, since it was recently shown to regulate YAP/TAZ activity through AXIN-mediated sequestration of YAP/TAZ in the β-catenin destruction complex.
Here, we describe the generation, validation and characterization of a novel biosensor zebrafish reporting the activity of Yap/Taz. It expresses nuclear mCherry, eGFP or the destabilized green fluorescent protein VenusPEST under the control of a promoter fragment of the human YAP/TAZ target gene CTGF, that contains 3 TEAD DNA-binding sites. Several independent founder fish transmitting the transgene to the germline were identified and used to establish the stable reporter lines. All stable transgenic fish shared a similar expression pattern, which was maintained in subsequent generations. Knockdown and overexpression approaches were used to validate the reporter. Co-injection of two morpholinos targeting Yap and Taz pre-mRNAs reduced the reporter signal, whereas injection of mRNAs coding for a constitutively active form of Yap, Taz and Tead (YAP-5SA, TAZ-4SA, TEAD-VP16) increased it. The CTGF-based transgenic lines represent therefore bona fide Yap/Taz reporters.
During development, strong reporter signal is visible mainly in the lens and otic vesicles, the pharyngeal arches, the heart, the pectoral fin and the vasculature, but the reporter protein expression is also detected in many other tissues and organs. The almost ubiquitous activation of Yap/Taz observed during early embryogenesis, consistent with the general role of YAP/TAZ in promoting cell proliferation and organ growth, is largely silenced in the adult fish, where the reporter signal is restricted to the lens, the ovary, the heart and the whole vasculature. We also showed that the CTGF-based biosensor zebrafish is able to report Yap/Taz activation during larval and adult fin regeneration, as expected from the role that YAP/TAZ signaling plays in the regenerative processes.
The zebrafish CTGF-based reporter permitted to show in a living organism during development the regulation that the Wnt/β-catenin pathway exerts on Yap/Taz activity. Our results in terms of variations of the reporter signal, after both genetic and pharmacological modulation of the Wnt pathway activity, are in accordance with the model recently depicted in vitro.
The general and sustained reporter activity we observed in the endothelium during embryogenesis suggested a functional involvement of Yap/Taz signaling in developmental angiogenesis. Yap/Taz knockdown impaired the intersegmental vessels (ISVs) growth, while the overactivation of Yap/Taz-mediated transcription caused an aberrant sprouting from the ISVs. The vessel sprouting-promoting capacity of Yap/Taz is cell-autonomous, as the same phenomenon was observed by expressing TAZ-4SA under the control of an endothelium-specific promoter.
The CTGF-based zebrafish reporter is a new powerful tool to study in vivo Yap/Taz pathway activation, with possible applications in drug screening, regeneration and cancer biology. It permitted to confirm in vivo during development the crosstalk between Wnt/β-catenin and Yap/Taz pathways and to discover a novel role of Yap/Taz in vessel sprouting, suggesting a pro-angiogenic function of YAP/TAZ transcriptional activity.YAP e TAZ, orchestrando la proliferazione, la morte e il differenziamento cellulari, rappresentano elementi chiave di una complessa rete di vie di segnalazione che agiscono durante lo sviluppo. L’alterazione della segnalazione YAP/TAZ causa una crescita fuori controllo degli organi durante l’organogenesi, che si traduce nella perdita dell’omeostasi tissutale nell’adulto e conseguente sviluppo tumorale. YAP/TAZ sono co-attivatori trascrizionali che interagiscono con i fattori di trascrizione TEAD per promuovere la proliferazione e la sopravvivenza cellulari. La loro attività trascrizionale è regolata dal trasporto nucleo-citoplasmatico e dall’accumulo nucleare, che sono controllati dalla cascata chinasica della via di Hippo, ma anche dagli stimoli meccanici percepiti dalla cellula e da altre vie. Fra queste, la via di Wnt/β-catenina assume una particolare rilevanza, dal momento che è stato recentemente dimostrato che essa regola l’attività di YAP/TAZ attraverso il loro sequestro nel complesso di degradazione della β-catenina mediato da AXIN. In questa tesi vengono descritte la generazione, la validazione e la caratterizzazione di un nuovo zebrafish biosensore che riporta l’attività di Yap/Taz. Esso esprime le proteine mCherry nucleare, eGFP o la proteina verde fluorescente destabilizzata VenusPEST sotto il controllo di un frammento promotoriale del gene umano CTGF target di YAP/TAZ, contenente 3 siti di legame per TEAD. Sono stati identificati diversi pesci fondatori indipendenti in grado di trasmettere il transgene alla linea germinale, i quali sono stati utilizzati per instaurare le linee reporter stabili. Tutti i pesci transgenici condividevano un pattern di espressione similare, mantenuto nelle generazioni successive. Per validare il reporter sono stati usati approcci di downregolazione e overespressione. La co-iniezione di due morfolini diretti contro i pre-mRNA di Yap e Taz ha ridotto il segnale reporter, mentre l’iniezione di mRNA codificanti per una forma costitutivamente attiva di Yap, Taz o Tead (YAP-5SA, TAZ-4SA, TEAD-VP16) lo ha aumentato. Le linee transgeniche basate sul gene CTGF rappresentano perciò bona fide dei reporter dell’attività di Yap/Taz. Durante lo sviluppo, un forte segnale reporter è visibile principalmente nella lente, la vescicola otica, gli archi faringei, il cuore, la pinna pettorale e la rete vascolare, ma l’espressione della proteina reporter è rilevabile in molti altri tessuti e organi. L’attivazione quasi ubiquitaria di Yap/Taz osservata durante l’embriogenesi precoce, consistente con il ruolo generale di YAP/TAZ nel promuovere la proliferazione cellulare e la crescita degli organi, è ampiamente silenziata nel pesce adulto, dove il segnale reporter è ristretto a lente, ovario, cuore e intera rete vascolare. Lo zebrafish biosensore è anche in grado di riportare l’attivazione di Yap/Taz durante la rigenerazione della coda nella larva e nell’adulto, come atteso dal ruolo che riveste la segnalazione YAP/TAZ nei processi rigenerativi. Lo zebrafish reporter basato sul gene CTGF ha permesso di mostrare in un organismo vivente durante lo sviluppo la regolazione che la via di Wnt/β-catenina esercita sull’attività di Yap/Taz. I nostri risultati in termini di variazione del segnale reporter, in seguito alla modulazione genetica e farmacologica dell’attività della via di Wnt, sono in linea con il modello disegnato di recente in vitro. L’attività generale e sostenuta del reporter nell’endotelio durante l’embriogenesi ha suggerito un coinvolgimento funzionale della segnalazione Yap/Taz nell’angiogenesi precoce. La downregolazione di Yap/Taz è risultata in una compromissione della crescita dei vasi intersegmentali (ISVs), mentre l’attivazione spinta della trascrizione mediata da Yap/Taz ha causato un ramificarsi anomalo degli ISVs. La capacità di Yap/Taz di promuovere tale ramificazione vascolare è “cell-autonomous”, dal momento che lo stesso fenomeno è stato osservato esprimendo TAZ-4SA sotto il controllo di un promotore endotelio-specifico. Lo zebrafish reporter sviluppato è un nuovo potente strumento per studiare in vivo l’attivazione della via di Yap/Taz, con possibili applicazioni nello screening farmacologico e nella biologia della rigenerazione e del cancro. Ha permesso di confermare in vivo durante lo sviluppo l’interazione fra le vie di Wnt/β-catenina e Yap/Taz e di scoprire un nuovo ruolo di Yap/Taz nella ramificazione vascolare, suggerendo una funzione pro-angiogenica dell’attività trascrizionale di YAP/TAZ.
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Meléndez, García Rodrigo. "YAP as a Regulator of DNA Replication Timing." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL014.
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Une cellule souche est capable de s’auto-renouveler et de générer des cellules différenciées après division cellulaire. La duplication complète de son génome doit être exempte d'erreurs afin d'éviter la propagation aux cellules filles de mutations délétères. Chez les eucaryotes, il a été montré que des segments d’ADN sur les chromosomes se répliquent de manière coordonnée et à des moments définis pendant la phase de synthèse, un processus appelé programme spatio-temporel de réplication de l'ADN (RT). Des changements majeurs dans le RT sont corrélés avec les changements de détermination des cellules souches et associés à l'organisation et à l’expressivité du génome. Malgré ce rôle central, les mécanismes qui sous-tendent le contrôle du RT restent méconnus. Mon laboratoire a mis en évidence que YAP, l'effecteur en aval de la voie de signalisation Hippo impliquée dans la croissance cellulaire, régule la vitesse et la chorégraphie de la réplication de l’ADN des cellules souches rétiniennes chez l’amphibien xénope. Ces données révèlent YAP comme un nouvel acteur moléculaire dans le contrôle du RT. Pour tester l’implication directe de YAP dans la dynamique de réplication de l’ADN, nous avons tiré profit du système in vitro d’extraits d'œufs de xénope dans lequel toutes les étapes du processus sont reproduites de manière synchrone. Nous montrons que YAP est recruté à la chromatine pendant la réplication et que ce processus se produit seulement après la phase d’initiation des origines de réplication. Des extraits déplétés de la protéine YAP présentent une accélération de la vitesse de réplication et une augmentation du nombre de sites d’activation de la synthèse de l’ADN. Par ailleurs, nous avons identifié RIF1 (Rap1-Interacting Factor 1 ou Replication Timing Regulatory Factor 1), un des rares régulateurs connus du RT, comme un nouveau partenaire de YAP. Comme pour YAP, la perte de fonction de RIF1 dans les embryons de xénope conduit à un phénotype de petit œil et à la dérégulation du RT dans les cellules souches rétiniennes.Dans l'ensemble, nos résultats montrent l’implication de YAP dans le contrôle de la dynamique de réplication de l’ADN et révèlent RIF1 comme un nouveau partenaire dans ce processus. Ce travail ouvre de nouvelles perspectives d’étude quant à l’importance biologique de cette interaction YAP-RIF1 dans le contrôle du RT et sa pertinence comme cible pour influencer le devenir des cellules souchesStemness could be defined as a state in which a cell is able to self-renew and/or to differentiate after cell division. Before this happens, exhaustive duplication of the genome free of errors must occur in order to avoid deleterious mutations, a hallmark of cancer. Thus, DNA replication is particularly important to stem cells because of their continuous division capacities. Regarding DNA replication in eukaryotes, it was discovered that segments of chromosomes close in space, replicate in a coordinated manner during S phase, a process called replication timing. Moreover, major changes in replication timing correlate with cell differentiation, 3D chromatin architecture and transcription. However, the molecules that govern its regulation are poorly understood. Previously, my laboratory found that YAP, the downstream effector of the Hippo pathway, regulates S phase progression of retinal stem cells in Xenopus laevis. To test YAP function in the direct control of replication timing, we took advantage of the powerful in vitro DNA replication system of X. laevis egg extracts. Briefly, we discovered that YAP is recruited to replicating chromatin dependently of origin licensing. In addition, YAP depleted extracts showed increased DNA synthesis and origin activation; revealing that YAP normal function is to slow-down replication by limiting origin firing. Interestingly, we found Rif1, a major regulator of replication timing, as a novel partner of YAP. In vivo, Rif1 expression overlaps that of Yap within the stem cell compartment of the Xenopus retina. Knockdown of Rif1 leaded to a small-eye phenotype and alterations in replication foci of retinal stem cells, resembling the effect observed in YAP deficient cells. Finally, early-embryonic depletion of both molecules resulted in a strikingly acceleration of cell division.Altogether, our findings unveil YAP implication in the regulation of replication dynamis and show Rif1 as a novel partner. Further investigation to analyze this interaction would help us to understand the biological relevance in the control of replication timing and whether it could be used as a target in regenerative medicine
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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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García-García, Diana. "Müller Cells and Retinal Regeneration : The Role of the Hippo/YAP Signaling Pathway Yap Haploinsufficiency Leads to Müller Cell Dysfunction and Late-Onset Cone Dystrophy Linking YAP to Müller Glia Quiescence Exit in the Degenerative Retina." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL068.
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Les maladies dégénératives de la rétine sont une des causes principales de cécité. Parmi les différentes stratégies thérapeutiques actuellement étudiées, notre équipe s’intéresse au potentiel régénératif de la rétine. Une source cellulaire d'intérêt sont les cellules de Müller, principal type de cellules gliales de la rétine capables de se réactiver en cas de dégénérescence, un processus appelé gliose réactive, et dans certaines espèces d’adopter des caractéristiques de cellules souches. Si un tel processus confère la capacité de régénérer la rétine chez les téléostéens, il est cependant largement inefficace chez les mammifères. Avoir une meilleure connaissance des mécanismes moléculaires sous-jacents pourrait aider à transformer leur potentiel de régénération en nouvelles stratégies thérapeutiques en condition pathologique de dégénérescence rétinienne. Dans ce contexte, mon laboratoire s'est focalisé sur l'effecteur terminal de la voie Hippo, le cofacteur de transcription YAP, dont il a été démontré qu'il stimule la régénération de plusieurs organes en cas de lésion. Dans la rétine, YAP est spécifiquement exprimé dans les cellules de Müller et son niveau d’expression augmente en cas de lésion. Cependant, sa fonction dans l'homéostasie rétinienne, et en particulier son rôle dans la régénération rétinienne, sont encore inconnus. La première partie de ma thèse visait donc à décrypter la fonction de YAP dans les cellules de Müller de souris dans des conditions physiologiques et pathologiques. Nous avons révélé que YAP joue un rôle central dans l'homéostasie des cellules de Müller et en tant que tel, est un acteur clé de la survie des cônes au cours du vieillissement. En cas de lésion rétinienne, nous avons montré que YAP est essentiel pour la réactivation des gènes du cycle cellulaire qui accompagne normalement la gliose réactive. Dans ce contexte, nous avons également trouvé une interaction fonctionnelle entre YAP et la voie de signalisation EGFR, suggérant une fonction de YAP en tant qu’intégrateur des réseaux de signalisation mis en jeu dans le contexte régénératif. J'ai également constaté que la suractivation de YAP est suffisante pour induire la reprogrammation des cellules de Müller de souris en cellules hautement prolifératives […]. Dans l'ensemble, ce travail met en évidence le rôle critique de YAP dans la sortie de quiescence des cellules de Müller chez les mammifères et révèle ainsi une cible potentielle pour la médecine régénérative. La deuxième partie de mon projet de doctorat naît des découvertes émergentes mettant en évidence les voies inflammatoires comme régulateurs du processus de régénération. […] De plus, des découvertes récentes sur le rôle de YAP dans la régulation du processus inflammatoire m’ont conduit à faire l'hypothèse qu'il pourrait jouer un rôle dans la relation entre l'inflammation et la régénération rétinienne. J'ai donc cherché à étudier le rôle joué par l'inflammation sur le comportement des cellules de Müller de souris, et à comprendre comment YAP s'inscrit dans cette interaction. J'ai découvert de manière inattendue qu'un contexte pro-inflammatoire établi par les cellules microgliales stimule la prolifération des cellules de Müller de souris dans des explants rétiniens. De plus, mes résultats ont montré que cet effet mitogène se produit de manière dépendante de YAP. Par ailleurs, j'ai découvert que l'effet de la surexpression de YAP sur la prolifération des cellules de Müller peut être potentialisé par un environnement pro-inflammatoire et aboli en cas d’ablation des microglies. Enfin, nous avons constaté que, à son tour, YAP régule des cytokines inflammatoires clés. Dans l'ensemble, cette partie de mon projet permet non seulement d’approfondir nos connaissances concernant l'impact de l'inflammation sur le comportement des cellules de Müller de la souris, mais met également en évidence YAP en tant qu'acteur clé dans la connexion entre l'inflammation et la régénération rétinienneDegenerative diseases of the retina are one of the main causes of blindness. Among the various therapeutic strategies currently being studied, our team is focusing on the regenerative potential of the retina. One cellular source of interest are Müller cells, the main type of glial cells in the retina capable of reactivating in case of degeneration, a process called reactive gliosis, and in some species adopting certain characteristics of stem cells. If such a process sustains powerful regeneration abilities in teleosts, it is however largely inefficient in mammals. Hence, increasing our knowledge of the molecular mechanisms underlying the behaviour of these cells under pathological conditions may help turning their regenerative properties into new therapeutic strategies. In this context, my laboratory focused on the terminal effector of the Hippo pathway, the co-transcriptional factor YAP, which has been shown to stimulate regeneration of several injured organs. In the retina, YAP is specifically expressed in Müller cells and upregulated in case of damage. However, its function in retinal homeostasis, and its role in retinal regeneration remained unknown.The first part of my PhD aimed at deciphering YAP function in mouse Müller cells in both physiological and pathological conditions. In essence, we revealed a central role of YAP in Müller cell-dependent retinal homeostasis and as such, as a key player for cone survival during aging. In case of retinal damage, we showed that YAP upregulation is critical for cell-cycle gene reactivation that normally accompanies reactive gliosis. In this context, we also found a functional interaction between YAP and the EGFR signaling pathway, supporting a function of YAP as a hub within the complex signaling network of key regenerative signaling pathways. I also found that YAP overactivation is sufficient to induce mouse Müller cell reprogramming into highly proliferative cells, mimicking a fish or amphibian condition, when Müller cells spontaneously proliferate upon injury. As a whole, this work highlights the critical role of YAP in driving mammalian Müller cells to exit quiescence and thus reveals a potential target for regenerative medicine.The second part of my PhD project stemmed from the emerging discoveries highlighting inflammatory pathways as regulators of the regenerative process. Although inflammation is considered to hamper retinal regeneration in mammals, there are no studies regarding the influence of inflammation on mouse Müller cell-dependent regenerative process. In addition, recent discoveries on the role of YAP in the regulation of the inflammatory process lead to the hypothesis that it could play a role in the relationship between inflammation and retinal regeneration. I thus aimed at investigating the role played by the injury-induced inflammation on mouse Müller cell behavior and how YAP fits in this interplay. I unexpectedly discovered that a microglial-dependent pro-inflammatory context stimulates mouse Müller cell proliferation in retinal explants. Importantly, my results showed that this mitogenic effect occurs in a YAP-dependent manner. Moreover, I uncovered that the effect of YAP overexpression on Müller cell proliferation can be potentiated by a pro-inflammatory environment, and abolished upon microglia depletion. Finally, we found that, in turn, YAP regulates key inflammatory cytokines. Altogether, this part of my project not only deepen our knowledge regarding the impact of inflammation on mouse Müller cell behavior, it also highlights YAP as a key player in the crosstalk between inflammation and retinal regeneration
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Kimura, Masahiro. "Homeobox A4 Suppresses Vascular Remodeling as a Novel Regulator of YAP/TEAD Transcriptional Activity." Kyoto University, 2020. http://hdl.handle.net/2433/253486.
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Ruggeri, Naomi. "REGULATION OF YAP BY GLUCOCORTICOIDS." Doctoral thesis, Università degli studi di Trieste, 2015. http://hdl.handle.net/10077/11122.
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2013/2014The Hippo signalling pathway is tumour suppressor cascade with a central role in the regulation of fundamental cellular biological processes, such as cell proliferation, apoptosis, organ size control and stem cell functions. The Hippo pathway transduces external signals that come to the cell into the nucleus, where it can control the expression of specific target genes, mainly involved in cell proliferation and differentiation. The Hippo pathway is an inhibitory pathway that control by phosphorylation and inhibition Yes-associated protein (YAP) coactivator, one of the two nuclear effectors of this signalling, involved in the regulation of proliferation and organ size. As consequence, deregulation of Hippo tumor suppressor pathway or hyperactivation of its downstream effectors is often associated with formation, development and tumour dissemination. Consistently, YAP is often over-expressed in a broad range of different tumours and it has aberrant activity in breast cancer as well as in several other human carcinomas. Up-regulation of YAP activity increases stem cell self-renewal in normal and cancer stem cells. In this work we describe the identification of a new hormonal-dependent layer for YAP regulation in breast cancer by the glucocorticoids and we analyze the mechanisms through which this regulation occurs. We found that Glucocorticoid Receptor (GR) binds directly the YAP promoter and induces the transcription of YAP mRNA after GC stimulation in cancer cells. Moreover, GC lead to efficient YAP de-phosphorylation and transcriptional activation, in a transcription-independent manner, by inducing actin cytoskeleton reorganization. Importantly, inhibition of the GR by means of RU486 (GR competitive antagonist) strongly blunted the expansion of the cancer stem cell pool in breast cancer cells by blunting the GR/YAP axis.
XXVII Ciclo
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Book chapters on the topic "HIPPO-PATHWAY-YAP"
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Reuven, Nina, and Yosef Shaul. "The c-Abl/YAP/p73 Apoptotic Module and the HIPPO Pathway." In The Hippo Signaling Pathway and Cancer, 173–95. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-6220-0_9.
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Yi, Chunling, and Joseph Kissil. "Merlin and Angiomotin in Hippo-Yap Signaling." In The Hippo Signaling Pathway and Cancer, 11–25. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-6220-0_2.
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Yu, Fa-Xing, Bin Zhao, and Kun-Liang Guan. "Regulation of YAP and TAZ Transcription Co-activators." In The Hippo Signaling Pathway and Cancer, 71–87. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-6220-0_5.
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Piccolo, Stefano, and Michelangelo Cordenonsi. "Regulation of YAP and TAZ by Epithelial Plasticity." In The Hippo Signaling Pathway and Cancer, 89–113. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-6220-0_6.
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Donzelli, Sara, Sabrina Strano, and Giovanni Blandino. "YAP and p73: A Matter of Mutual Specificity in Tumor Suppression." In The Hippo Signaling Pathway and Cancer, 147–72. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-6220-0_8.
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Nazir, Aqsa, Muhammad Aqib, and Muhammad Usman. "Liver Cancer-Genesis, Progression and Metastasis." In Liver Cancer - Genesis, Progression and Metastasis [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106020.
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Liver cancer or hepatocellular carcinoma (HCC) is a malignant tumor in liver tissue and worldwide it is fourth leading death cause among all cancers. The most common causes of liver cancer are hepatitis B or C virus infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), smoking and obesity. The development and metastasis of liver cancer is a multistage and branched process of morphological and genetic traits. Various corresponding signaling pathways such as Yes-Associated Protein-Hippo Pathway (YAP-HIPPO), Wnt/β-catenin and inflammation by interleukin-6 (IL-6), tumor necrosis factor (TNF), nuclear factor-Κb (NF-κB), biological pathways including epithelial–mesenchymal transition (EMT), tumor microenvironment, tumor-stromal interactions and cancer stem cells and gut microbial dysbiosis are allied to both origination, progression and metastasis of liver cancer. Numerous therapeutic approaches are classified into different categories such as pharmacological therapy including sorafenib, lenvatinib and ramuciruma, surgery of HCC patients includes surgical resection, adjuvant therapy after surgical resection and liver transplantation. Loco-regional ablative therapy includes cryotherapy, ethanol injection and radiofrequency ablation, cytotoxic chemotherapy, natural compounds such as piperine, as curcumin and oleocanthal, oncolytic virus therapy, immunotherapies and nanotechnology.
Conference papers on the topic "HIPPO-PATHWAY-YAP"
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Schönbeck, K., A. Winkler, MJ Witthauer, A. Szymansky, J. Toedling, A. Schramm, F. Hertwig, A. Eggert, and JH Schulte. "Hippo-YAP pathway activation favors neuroblastoma progression." In 31. Jahrestagung der Kind-Philipp-Stiftung für pädiatrisch onkologische Forschung. Georg Thieme Verlag KG, 2018. http://dx.doi.org/10.1055/s-0038-1645011.
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Tang, Tracy T., Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, and Leonard Post. "Abstract PR07: Targeting the Hippo-YAP pathway with small-molecule compounds." In Abstracts: AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; May 8-11, 2019; San Diego, CA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1557-3125.hippo19-pr07.
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Kulkarni, A., J. Vissers, and K. Harvey. "PO-100 Targeting YAP and TAZ to treat hippo pathway mutant malignant mesotheliomas." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.141.
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Isago, Hideaki, Akihisa Mitani, Shiho Kohno, Hiroyuki Nagoshi, Taro Ishimori, Minako Saito, Hiroyuki Tamiya, et al. "The Hippo pathway effectors TAZ and YAP are sequentially required in lung development." In ERS International Congress 2019 abstracts. European Respiratory Society, 2019. http://dx.doi.org/10.1183/13993003.congress-2019.oa3604.
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Tang, Tracy T., Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, and Leonard Post. "Abstract 2693: Targeting the Hippo-YAP pathway with novel small-molecule inhibitors of the YAP-TEAD transcription activity." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2693.
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Tang, Tracy T., Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, and Leonard Post. "Abstract 2693: Targeting the Hippo-YAP pathway with novel small-molecule inhibitors of the YAP-TEAD transcription activity." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2693.
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Liu, K., M. Tóth, T. Guo, F. Rose, SME Weiler, S. Wan, M. Heikenwälder, P. Schirmacher, T. Longerich, and K. Breuhahn. "Hippo pathway effectors YAP and TAZ are opponents in the regulation of hepatic fibrosis." In 36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0039-3402120.
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Isfort, Ilka, Sandra Elges, Magdalene Cyra, Danielle Brandes, Ruth Berthold, Marcus Renner, Gunhild Mechtersheimer, et al. "Abstract 2139: Hippo pathway transcriptional coactivators YAP/TAZ in soft tissue and bone tumors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2139.
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Isfort, Ilka, Sandra Elges, Magdalene Cyra, Danielle Brandes, Ruth Berthold, Marcus Renner, Gunhild Mechtersheimer, et al. "Abstract 2139: Hippo pathway transcriptional coactivators YAP/TAZ in soft tissue and bone tumors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2139.
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Kim, Ji Su, Ei Yong Ahn, and Young Nyun Park. "Abstract C87: Regulation of stemness by Hippo-YAP pathway under hypoxia in hepatocellular carcinoma." In Abstracts: AACR Special Conference on Tumor Invasion and Metastasis - January 20-23, 2013; San Diego, CA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.tim2013-c87.
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