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Glial cells in central nervous system pathology: the role of Wnt signaling
Bronišová, Denisa ; Kriška, Ján (advisor) ; Heleš, Mário (referee)
Wnt signaling plays an important role in regulating cell growth, differentiation, or movement. This represents a potential in the treatment of pathologies in which the proliferation or differentiation of new cells could be key to the regeneration and mitigation of the consequences of the disease. Glial cells are more than just a glue for neurons, and they have important roles in pathologies in maintaining cell metabolism and survival, and brain functioning in general. The aim of this bachelor thesis is to provide a literature review of the roles of Wnt signaling in glial cells in the healthy brain, but especially in central nervous system (CNS) pathologies. The work provides an overview of the main types of glial cells in the CNS, a description of three Wnt signaling pathways, and focuses in detail on selected CNS pathologies and the role and changes of Wnt signaling that occur in these pathologies. Further research utilizing the potential of Wnt signaling in glial cells might lead to the development of novel therapies that could change the fate of patients with CNS diseases.
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Molecular mechanisms and components controlling the Wnt signaling pathway output
Krausová, Michaela ; Kořínek, Vladimír (advisor) ; Drbal, Karel (referee) ; Bryja, Vítězslav (referee)
Beyond its essential roles in embryonic development, the Wnt-mediated signal transduction cascade is critically implicated in homeostasis of adult tissues. In the gastrointestinal epithelium, the threshold of active Wnt signaling is kept in a physiological range by a spectrum of regulatory networks and loops, thereby balancing the opposing processes of cell fate determination, proliferation and stem cell self-renewal. Furthermore, compelling evidence undoubtedly link an aberrant Wnt activity to the onset of bowel cancer. Understanding the principle causes and effects secondary to excessive Wnt signaling can provide valuable insights into the pathology of the malignant transformation of the colorectum. The proposed thesis attempts to focus on novel modes of the Wnt pathway modulation; both general and context-specific nuances of the Wnt level adjustment are thereby delineated. The results are presented in three distinct research publications and one review article. The first study examines the contribution of the distinct post-translational modifications, which the Wnt proteins undergo, to their proper processing, secretion and signaling activity. First, we investigated the sequential order and mutual interdependence of cysteine and serine-linked fatty acylation and N-linked glycosylation of murine...
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Characterization of the Caenorhabditis elegans pop-1 gene
Jakšová, Soňa ; Vacík, Tomáš (advisor) ; Macůrková, Marie (referee)
The TCF/LEF transcriptional factors regulate the target genes of the Wnt signalling pathway - one of the key signalling mechanisms involved in development of multicellular organisms. The TCF/LEF genes produce a number of various protein isoforms, which consequently leads to a great functional diversity of the TCF/LEF proteins. In this diploma project we focused on the Caenorhabditis elegans gene pop-1, the ortholog of the TCF/LEF genes, whose isoforms have not been studied yet. Using the Northern blot analysis we tried to identify alternative isoforms of the pop-1 mRNA in C. elegans. Using quantitative RT-PCR we also analyzed the pop-1 mRNA levels during seven developmental stages of C. elegans. Further, we also determined the expression profile of two important partners of pop-1, the bar-1 and sys-1 genes, whose protein products function as transcriptional co-activators. Key words: canonical Wnt signaling pathway, TCF/LEF transcription factors, Caenorhabditis elegans, pop-1
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The role of Wnt signaling in interaction between circadian clock and cell cycle
Herrmannová, Terezie ; Sumová, Alena (advisor) ; Macůrková, Marie (referee)
The Wnt signaling represents a highly conserved signal transduction cascade that regulates stem cell proliferation and differentiation. It plays an irreplaceable role not only during embryonic development, but also in maintaining homeostasis of adult tissues. The cell division is also influenced by the circadian clock. The clock can interact with the cell cycle either directly within a single cell or regulate it intercellularly. In order to impact surrounding cells, it uses the Wnt signaling pathway that mediates signal transduction through the extracellular space. Both Wnt signaling and the circadian clock are essential for the physiological functioning of the mammalian organism, and their disruption can lead to the development of cancer. Keywords: circadian clock, clock genes, cell cycle, Wnt signaling, cell proliferation, cancer
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Characterization of the Caenorhabditis elegans pop-1 gene
Jakšová, Soňa ; Vacík, Tomáš (advisor) ; Macůrková, Marie (referee)
The TCF/LEF transcriptional factors regulate the target genes of the Wnt signalling pathway - one of the key signalling mechanisms involved in development of multicellular organisms. The TCF/LEF genes produce a number of various protein isoforms, which consequently leads to a great functional diversity of the TCF/LEF proteins. In this diploma project we focused on the Caenorhabditis elegans gene pop-1, the ortholog of the TCF/LEF genes, whose isoforms have not been studied yet. Using the Northern blot analysis we tried to identify alternative isoforms of the pop-1 mRNA in C. elegans. Using quantitative RT-PCR we also analyzed the pop-1 mRNA levels during seven developmental stages of C. elegans. Further, we also determined the expression profile of two important partners of pop-1, the bar-1 and sys-1 genes, whose protein products function as transcriptional co-activators. Key words: canonical Wnt signaling pathway, TCF/LEF transcription factors, Caenorhabditis elegans, pop-1
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The role of the Msx1 transcription factor in the intestinal epithelia and colorectal cancer
Šťastná, Monika ; Kořínek, Vladimír (advisor) ; Pergner, Jiří (referee) ; Doubravská, Lenka (referee)
The Wnt signaling pathway represents the principal evolutionarily conserved signaling cascade found in all multicellular organisms. It plays a key role not only in many processes during embryogenesis, but also in maintaining tissue homeostasis and regeneration. By contrast, mutations in genes encoding components of the pathway often result in increased activation of Wnt signaling and underlie onset of many human diseases, particularly cancer. The canonical Wnt signaling pathway is essential for proliferation and maintenance of the pluripotent state of intestinal stem cells and thus for homeostatic renewal of the intestinal epithelium. However, aberrant (hyper)activation of the Wnt signaling pathway is the initial step in development of intestinal neoplasia. Understanding the causes and identifying the consequences of the Wnt signaling hyperactivation is crucial for deciphering mechanisms leading to malignant transformation. Although the canonical Wnt signaling pathway has been the subject of scientific studies for several decades, all regulatory mechanisms and consequences of its hyperactivation have not been completely elucidated yet. During my PhD studies, I focused on understanding function(s) of some components and target genes of this signaling cascade. In this theses, results of my first...
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Characterization of the Caenorhabditis elegans pop-1 gene
Jakšová, Soňa ; Vacík, Tomáš (advisor) ; Cmarko, Dušan (referee)
The human proteom diversity is caused by the ability of a single gene locus to encode more protein isoforms. The TCF/LEF genes produce a broad spectrum of protein variants, which consequently leads to a great functional diversity of the TCF/LEF proteins. The TCF/LEF transcriptional factors regulate the canonical Wnt signaling target genes. In this diploma project we focused on the Caenorhabditis elegans gene pop-1, the ortholog of the TCF/LEF genes. Using the Northern blot analysis we tried to identify alternative isoforms of the pop-1 mRNA in C. elegans. Using quantitative RT-PCR we also analyzed the pop-1 mRNA levels. Key words: canonical Wnt signaling pathway, TCF/LEF transcription factors, Caenorhabditis elegans, pop-1
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Molecular mechanisms of physiological renewal and cancer transformation of mammalian gastrointestinal tissues
Stančíková, Jitka ; Kořínek, Vladimír (advisor) ; Macůrková, Marie (referee) ; Machoň, Ondřej (referee)
The plot of this PhD thesis is dedicated to investigation of the molecular pathways and events and their disruptions in the gastrointestinal tract (further abbreviated as GIT). The major role in this part plays the Wnt signaling pathway. This marvelous multipurpose machinery is responsible for epithelia renewal from stem cells (SCs) in the stomach and intestine, and for correct zonation and function of hepatic units. Of note, the Wnt pathway directs also development of embryo as well as homeostasis of many tissues apart from GIT in all metazoans, thus its flawless function is indispensable from one's origin to death. The main part of the thesis follows canonical Wnt signaling in its physiological condition and, in contrast, with pathological disturbances. This issue can be taken by variety of means as it is described in attached publications. The first publication deals with searching for new participants of Wnt signaling and their functions and describing unique markers of SCs in the intestine. Troy, the member of tumor necrosis factor receptor (TNFR) superfamily, was identified as a novel marker of intestinal SCs by probing microarray data from chromatin immunoprecipitation obtained in cultured colorectal cancer cell lines. Moreover, we found that Troy is a Wnt target gene inhibiting the...
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Wnt signaling in intestinal homeostasis and tumorigenesis
Janečková, Lucie ; Kořínek, Vladimír (advisor) ; Macůrek, Libor (referee) ; Truksa, Jaroslav (referee)
The canonical Wnt signaling pathway is one of the most important pathways involved in cell proliferation and differentiation. It is highly conserved in evolution and participates not only in embryonic development but also in adult tissue homeostasis. In the intestine, Wnt signaling is closely connected to maintenance of intestinal stem cells and renewal of the epithelia. Conversely, aberrant activation of the Wnt signaling pathway underlies different types of human diseases. Its constitutive activation results in neoplasia and specifically in development of colorectal cancer, which is the third most common malignancy in western world. The aim of this thesis was to uncover various aspects of the regulatory mechanisms of the Wnt/β-catenin signaling cascade. Furthermore, I headed to find novel Wnt pathway modulators and confirm their function in vivo. The results are presented in four publications. The first study examines murine Wnt proteins processing and the sequential order of Wnt post-translational modifications which are required for the secretion and signaling activity of the ligands. Next publication focuses on the gene Troy, which we identified as negative regulator of Wnt signaling. TROY was discovered as a Wnt target gene during DNA microarray profiling of human colorectal cancer cells....
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Phosphoinositides and their effectors in regulation of the Wnt signalling pathway
Knop, Filip ; Macůrková, Marie (advisor) ; Krausová, Michaela (referee)
Phosphoinositides (PIs) make up only a small proportion of overall amount of lipids in cell membranes. However, their function mediated through protein effectors is indispensable for cell signaling, vesicular trafficking, cell movement and other important aspects of cellular life. In this bachelor thesis function of PIs is described in relation to Wnt signaling pathway. Proper execution of several steps of the Wnt signaling pathway requires the presence of PIs. Retrograde transport of Wntless (Wls) from the plasma membrane (PM) back to the Golgi apparatus (GA) in Wnt producing cells or internalization of Wnt receptors in Wnt receiving cells are only two examples. All processes are tightly regulated and malfunction of enzymes processing PIs can cause their deregulation resulting in disruption of the Wnt signaling pathway. As deregulated Wnt signaling is a known cause of serious diseases including cancer, understanding the crosstalk between PIs and Wnt signaling could help in designing novel strategies for therapeutic intervention.
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