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The role of JAK-STAT signalling pathway in cellular senescence
Černohorská, Markéta ; Hodný, Zdeněk (advisor) ; Schierová, Michaela (referee)
Proliferating human cells cultivated in vitro after certain number of population doublings withdraw from the cell cycle and enter a specific state termed replicative cellular senescence. Lately, several other forms of senescence independent of the proliferative history and telomere shortening were described. This is called premature senescence, and can be elicited by exposure of cells to aberrant mitogenic or oncogenic signals, to oxidative stress or to variety of chemically and functionally unrelated DNA damaging agents. Senescent cells alter their morphology and expression pattern. This complex phenotype is characterized by enlarged cytoplasm, activation of cell cycle inhibitors, expression of tumor supressors and profound changes in cell secretory phenotype. These cytokines/chemokines induce many different cascades, for example Jak/STAT signaling pathway, that are activated in response to viral infection or inflammation. Senescent cells were found also in vivo in the tumor tissue that produces altered cytokines itself. This diploma thesis inquires into the role of interferon-Jak/STAT signaling pathway in premature cellular senescence induced by genotoxic agents that are often used in chemotherapy. Obtained results might help to understand the complexity of tumorogenesis and senescence. Powered by TCPDF...
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New regulatory mechanisms of microtubule nucleation
Černohorská, Markéta ; Dráber, Pavel (advisor) ; Binarová, Pavla (referee) ; Hašek, Jiří (referee)
MT nucleation from γ-tubulin complexes, located at centrosome, is an essential step in the formation of MT cytoskeleton. In mammalian cells, -tubulin is encoded by two genes. We functionally characterized two γ-tubulin proteins and have found that both are functionally equivalent. γ-Tubulin 2 is able to substitute for γ-tubulin 1 in MT nucleation. However, we revealed that unlike TUBG1, TUBG2 expression is downregulated in mouse preimplantation development. Mast cells represent effectors of the allergy reaction. Their activation by antigen induces number of cellular processes such as degranulation, proliferation and cytoskeleton rearrangements. The regulatory mechanisms of MT reorganization during mast cell activation are unknown. We identified new signaling proteins, GIT1 and PIX that interact with - tubulin. Depletion of GIT1 or PIX leads to changes in MT nucleation. GIT1 is phosphorylated on tyrosine and associates with γ-tubulin in a Ca2+ -dependent manner. Our data suggested a novel signaling pathway for MT rearrangement in mast cells where tyrosine kinase-activated GIT1 and βPIX work in concert with Ca2+ signaling to regulate MT nucleation. We tested the capability of GIT1 and PIX to influence -tubulin function in more cell types. We found out that GIT1/βPIX signaling proteins together...
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The role of JAK-STAT signalling pathway in cellular senescence
Černohorská, Markéta ; Schierová, Michaela (referee) ; Hodný, Zdeněk (advisor)
Proliferating human cells cultivated in vitro after certain number of population doublings withdraw from the cell cycle and enter a specific state termed replicative cellular senescence. Lately, several other forms of senescence independent of the proliferative history and telomere shortening were described. This is called premature senescence, and can be elicited by exposure of cells to aberrant mitogenic or oncogenic signals, to oxidative stress or to variety of chemically and functionally unrelated DNA damaging agents. Senescent cells alter their morphology and expression pattern. This complex phenotype is characterized by enlarged cytoplasm, activation of cell cycle inhibitors, expression of tumor supressors and profound changes in cell secretory phenotype. These cytokines/chemokines induce many different cascades, for example Jak/STAT signaling pathway, that are activated in response to viral infection or inflammation. Senescent cells were found also in vivo in the tumor tissue that produces altered cytokines itself. This diploma thesis inquires into the role of interferon-Jak/STAT signaling pathway in premature cellular senescence induced by genotoxic agents that are often used in chemotherapy. Obtained results might help to understand the complexity of tumorogenesis and senescence. Powered by TCPDF...
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