Добірка наукової літератури з теми "Mesothelioma, primary cilium, hedgehog pathway"

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Статті в журналах з теми "Mesothelioma, primary cilium, hedgehog pathway"

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Barbarino, Marcella, Maria Bottaro, Laura Spagnoletti, Maria Margherita de de Santi, Raffaella Guazzo, Chiara Defraia, Cosimo Custoza, et al. "Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology." Cancers 14, no. 21 (October 25, 2022): 5216. http://dx.doi.org/10.3390/cancers14215216.

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Анотація:
The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.
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Ma, Ming, Emilie Legué, Xin Tian, Stefan Somlo, and Karel F. Liem. "Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease." Journal of the American Society of Nephrology 30, no. 11 (August 26, 2019): 2103–11. http://dx.doi.org/10.1681/asn.2018121274.

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BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.
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Gómez, Arianna Ericka, Angela K. Christman, Julie Craft Van De Weghe, Malaney Finn, and Dan Doherty. "Systematic analysis of cilia characteristics and Hedgehog signaling in five immortal cell lines." PLOS ONE 17, no. 12 (December 29, 2022): e0266433. http://dx.doi.org/10.1371/journal.pone.0266433.

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Анотація:
Dysfunction of the primary cilium, a microtubule-based signaling organelle, leads to genetic conditions called ciliopathies. Hedgehog (Hh) signaling is mediated by the primary cilium in vertebrates and is therefore implicated in ciliopathies; however, it is not clear which immortal cell lines are the most appropriate for modeling pathway response in human disease; therefore, we systematically evaluated Hh in five commercially available, immortal mammalian cell lines: ARPE-19, HEK293T, hTERT RPE-1, NIH/3T3, and SH-SY5Y. Under proper conditions, all of the cell lines ciliated adequately for our subsequent experiments, except for SH-SY5Y which were excluded from further analysis. hTERT RPE-1 and NIH/3T3 cells relocalized Hh pathway components Smoothened (SMO) and GPR161 and upregulated Hh target genes in response to pathway stimulation. In contrast, pathway stimulation did not induce target gene expression in ARPE-19 and HEK293T cells, despite SMO and GPR161 relocalization. These data indicate that human hTERT RPE-1 cells and murine NIH/3T3 cells, but not ARPE-19 and HEK293T cells, are suitable for modeling the role of Hh signaling in ciliopathies.
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Jung, Bomi, Daniela Padula, Ingo Burtscher, Cedric Landerer, Dominik Lutter, Fabian Theis, Ana C. Messias, et al. "Pitchfork and Gprasp2 Target Smoothened to the Primary Cilium for Hedgehog Pathway Activation." PLOS ONE 11, no. 2 (February 22, 2016): e0149477. http://dx.doi.org/10.1371/journal.pone.0149477.

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Zhang, Boyan, Tenghan Zhuang, Qiaoyu Lin, Biying Yang, Xiaowei Xu, Guangwei Xin, Shicong Zhu, et al. "Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 874–79. http://dx.doi.org/10.1073/pnas.1804042116.

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Анотація:
The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.
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Yuan, Gongjie, Gurpreet Singh, Serafine Chen, Kristy Carrington Perez, Yan Wu, Bo Liu, and Jill Ann Helms. "Cleft Palate and Aglossia Result from Perturbations in Wnt and Hedgehog Signaling." Cleft Palate-Craniofacial Journal 54, no. 3 (May 2017): 269–80. http://dx.doi.org/10.1597/15-178.

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Objective The objective of this study was to explore the molecular basis for cleft secondary palate and arrested tongue development caused by the loss of the intraflagellar transport protein, Kif3a. Design Kif3a mutant embryos and their littermate controls were analyzed for defects in facial development at multiple stages of embryonic development. Histology was employed to understand the effects of Kif3a deletion on palate and tongue development. Various transgenic reporter strains were used to understand how deletion of Kif3a affected Hedgehog and Wnt signaling. Immunostaining for structural elements of the tongue and for components of the Wnt pathway were performed. BrdU activity analyses were carried out to examine how the loss of Kif3a affected cell proliferation and led to palate and tongue malformations. Results Kif3a deletion causes cranial neural crest cells to become unresponsive to Hedgehog signals and hyper-responsive to Wnt signals. This aberrant molecular signaling causes abnormally high cell proliferation, but paradoxically outgrowths of the tongue and the palatal processes are reduced. The basis for this enigmatic effect can be traced back to a disruption in epithelial/mesenchymal signaling that governs facial development. Conclusion The primary cilium is a cell surface organelle that integrates Hh and Wnt signaling, and disruptions in the function of the primary cilium cause one of the most common—of the rarest—craniofacial birth defects observed in humans. The shared molecular basis for these dysmorphologies is an abnormally high Wnt signal simultaneous with an abnormally low Hedgehog signal. These pathways are integrated in the primary cilium.
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Hoogendoorn, Sascha. "Small Molecules Targeting the Hedgehog Pathway: From Phenotype to Mechanistic Understanding." CHIMIA International Journal for Chemistry 74, no. 9 (September 30, 2020): 652–58. http://dx.doi.org/10.2533/chimia.2020.652.

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Анотація:
Since the beginning of 2019, the Hoogendoorn lab is active at the University of Geneva. We are a Chemical Biology lab and our research focuses on the Hedgehog (Hh) signalling pathway and the primary cilium, a small cellular organelle which corrects structure and function, is required to conduct the Hh signal. Ciliary Hh signalling plays an important role in embryonic development, and its dysregulation consequently results in developmental disorders as well as a variety of cancers. We use an interdisciplinary approach, ranging from organic chemistry to cell biology and genetics, to develop chemical tools to study and perturb ciliary signalling. In this account, I will highlight existing small molecules that target the Hh pathway, our efforts to discover new compounds, and the methodologies that we employ for target deconvolution and mechanism of action studies.
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Kiprilov, Enko N., Aashir Awan, Romain Desprat, Michelle Velho, Christian A. Clement, Anne Grete Byskov, Claus Y. Andersen, et al. "Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery." Journal of Cell Biology 180, no. 5 (March 10, 2008): 897–904. http://dx.doi.org/10.1083/jcb.200706028.

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Анотація:
Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC differentiation, demonstrating the existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation. Using electron microscopy (EM), immunofluorescence, and confocal microscopies, we show that primary cilia are present in three undifferentiated hESC lines. EM reveals the characteristic 9 + 0 axoneme. The number and length of cilia increase after serum starvation. Important components of the hedgehog (Hh) pathway, including smoothened, patched 1 (Ptc1), and Gli1 and 2, are present in the cilia. Stimulation of the pathway results in the concerted movement of Ptc1 out of, and smoothened into, the primary cilium as well as up-regulation of GLI1 and PTC1. These findings show that hESCs contain primary cilia associated with working Hh machinery.
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Ku, Pei-I., Jamuna S. Sreeja, Benjamin R. Myers, and Radhika Subramanian. "Real time imaging of the trafficking of a Hedgehog pathway kinesin in the primary cilium." Biophysical Journal 121, no. 3 (February 2022): 85a. http://dx.doi.org/10.1016/j.bpj.2021.11.2286.

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Girardet, Laura, Agathe Bernet, Ezéquiel Calvo, Denis Soulet, Charles Joly-Beauparlant, Arnaud Droit, Daniel G. Cyr, and Clémence Belleannée. "Hedgehog signaling pathway regulates gene expression profile of epididymal principal cells through the primary cilium." FASEB Journal 34, no. 6 (April 13, 2020): 7593–609. http://dx.doi.org/10.1096/fj.202000328r.

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Дисертації з теми "Mesothelioma, primary cilium, hedgehog pathway"

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Marcella, Barbarino. "PRIMARY CILIUM LOSS IN ADVANCED MESOTHELIOMA CORRELATES WITH CONSTITUTIVE GLI1 OVEREXPRESSION." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1161108.

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Анотація:
Malignant mesothelioma is an aggressive cancer of the membranes covering the lung and chest cavity (pleura), or the abdomen (peritoneum), mainly linked to asbestos exposure. It is characterized by high intrinsic heterogeneity, diagnosis in the late stages and a high immunosuppressive microenvironment. In the past years many agents have been evaluated for use in mesothelioma but with modest results so that the prognosis remains poor. Recently, in light of the promising results achieved in other cancers, the targeting of the Hedgehog-GLI (HH-GLI) pathway has been investigated as possible new therapy for MPM cure. The HH-GLI pathway starts at Primary Cilium (PC), an organelle protruding from the extracellular membrane of the cells that expresses specific receptors for the Hedgehog ligands. In cells lacking PC, the HH-GLI pathway can also be activated by intracellular signaling that make cells resistant to HH-GLI ligand-dependent pathway inhibitors. In MPM the HH-GLI signaling is active but response to targeting agents is poor. Activating mutations in the core components of the pathway that in other cancers lead to drug resistance in MPM are rare. Here we studied the presence of PC in mesothelioma and its correlation with HH-GLI pathway activation. We found an heterogeneous presence of PC in MPM and, in the cells loosing PC, GLI1 was overexpressed. Our preliminary results suggested that PI3K/AKT pathway can be, at least in some cells, responsible for the activation of HH-GLI1 pathway. In summary, we have documented for the first time the loss of PC in mesothelioma and the activation of a non-canonical HH-GLI pathways in this cancer.
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Тези доповідей конференцій з теми "Mesothelioma, primary cilium, hedgehog pathway"

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Senicourt, Blanche. "Abstract 4430: Implication of the primary cilium in the Hedgehog pathway in colorectal cancer cells." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4430.

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2

Moran, Emma C., Pedro M. Baptista, Kenichiro Nishii, David Wasnick, Shay Soker, and Jessica L. Sparks. "Expression of Primary Cilia on Liver Stem and Progenitor Cells: Potential Role for Mechanosensing in Liver Development." In ASME 2013 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/sbc2013-14122.

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Анотація:
The primary cilium is a non-motile organelle that projects out from the plasma membrane of many cell types in the body. It consists of an axoneme with microtubules arranged in a 9+0 arrangement that extends from the mother centriole contained within the basal body. Once thought to be a non-essential organelle, it is now known that primary cilia have an important role in embryonic and post-natal development, as well as maintenance of adult tissues. Mutations affecting primary ciliary development result in a class of serious diseases known as ciliopathies [1, 2]. Recent research suggests that the primary cilia/ centrosomes might play a role in embryonic stem cell differentiation through cell cycle regulation and their association with the Hedgehog signaling pathway [3, 4].
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