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Vlastnosti DNA vazebných mutant proteinů CSL
Teska, Mikoláš ; Folk, Petr (advisor) ; Šťovíček, Vratislav (referee)
Notch pathway plays a critical role during the development and life of metazoan organisms. CSL proteins are the component of the Notch pathway that mediates the regulation of target genes. The discovery of CSL-like proteins in yeast raised the question of their function in unicellular organisms which did not utilize the canonical Notch pathway. CSL-homologues in yeast are conserved in parts that are important for DNA binding and for fission yeast proteins it was shown that they bind to CSL recognition elements in vitro. In fission yeast, CSL paralogues Cbf11 and Cbf12 play antagonistic roles in cell adhesion and the coordination of cell and nuclear division. Yeast CSL proteins have long and intrinsically unstructured N- terminal domains compared to metazoan CSL proteins. In this study, we investigated the functional significance of these extended N-termini of CSL proteins by their complete removal. For newly constructed truncated variants of proteins Cbf11 and Cbf12 in Schizosaccharomyces pombe we observed the lack of ability to bind CSL recognition RBP probe. The removal of N-terminal parts of CSL proteins in fission yeast led to the change in their cellular localization. Once strongly preferred nuclear localization changed by the removal of N-terminal domains to cytoplasmic localization with a...
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The effects of a molecular change caused by new taxanes in experimental models and patients with solid tumors
Koucká, Kamila ; Stiborová, Marie (advisor) ; Dračínská, Helena (referee)
Ovarian cancer is the most common cause of death from gynecological malignancy. Taxanes and platinum derivatives are most used therapeutics for its treatment. Development of multi drug resistance to chemotherapy represents a serious complication of the treatment. Therefore, new chemotherapeutic and therapeutic targets are investigated, which could help to overcome tumor cell resistance. The main objectives of the thesis were to study: i) the efficiency of new derivatives of conventional taxanes in vitro with the aim to determine the potentially most effective taxane derivatives in resistant tumor ovarian cells and, ii) the gene expression profile of the Notch signaling pathway, as a possible therapeutic target for the treatment of ovarian cancer. Specifically, the thesis focused on the relationship between levels of Notch signaling gene expression in patients with ovarian carcinoma and their prognosis, progression and survival. This thesis revealed that Stony Brook Taxanes - "SB-T"; SB-T-121402, SB-T-121605, and SB-T-121606 derivatives are very effective in NCI/ADR-RES tumor carcinoma cells resistant to conventional taxane - paclitaxel, and should be further studied in more advanced models, e.g. in vivo patient derived xenografts. In a study of the importance of the Notch signaling pathway in...
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Vlastnosti DNA vazebných mutant proteinů CSL
Teska, Mikoláš ; Folk, Petr (advisor) ; Šťovíček, Vratislav (referee)
Notch pathway plays a critical role during the development and life of metazoan organisms. CSL proteins are the component of the Notch pathway that mediates the regulation of target genes. The discovery of CSL-like proteins in yeast raised the question of their function in unicellular organisms which did not utilize the canonical Notch pathway. CSL-homologues in yeast are conserved in parts that are important for DNA binding and for fission yeast proteins it was shown that they bind to CSL recognition elements in vitro. In fission yeast, CSL paralogues Cbf11 and Cbf12 play antagonistic roles in cell adhesion and the coordination of cell and nuclear division. Yeast CSL proteins have long and intrinsically unstructured N- terminal domains compared to metazoan CSL proteins. In this study, we investigated the functional significance of these extended N-termini of CSL proteins by their complete removal. For newly constructed truncated variants of proteins Cbf11 and Cbf12 in Schizosaccharomyces pombe we observed the lack of ability to bind CSL recognition RBP probe. The removal of N-terminal parts of CSL proteins in fission yeast led to the change in their cellular localization. Once strongly preferred nuclear localization changed by the removal of N-terminal domains to cytoplasmic localization with a...
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