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Cell response to genotoxic stress-based anti-cancer therapies
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rossmeislová, Lenka (referee) ; Rotrekl, Vladimír (referee)
The dissertation deals with a cell response to genotoxic stress, specifically to anti-cancer treatments with a genotoxic mechanism of action. In principle, cells can respond to these perturbing stimuli in several ways: in case of severe DNA damage, they usually undergo apoptosis or enter senescence. In case of minor DNA damage, or upon defective checkpoint mechanisms, they may continue the cell cycle, either with successfully repaired DNA or with mutations of various kind. Thanks to selection pressure, the mutations that provide cells with a certain growth advantage under conditions of continuing genotoxic stress, gradually accumulate and render the tumor treatment-resistant. In my thesis, I focus on several aspects of this whole process. First, I participated in a characterization of a radioresistant and anoikis-resistant population of prostate cancer cells. This population was generated by irradiating cells 35 times by 2 Gy, a regime used in clinics. After this treatment, a population of low-adherent cells emerged that demonstrated increased expression of EMT- and stem cell markers. The low-adherent state of these cells was maintained by Snail signaling and their anoikis resistance by ERK1/2 signaling. Interestingly, after a protracted period of time, these cells were able to re-adhere and...
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The role of promyelocytic leukemia protein in genome maintenance
Kindlová, Martina ; Vašicová, Pavla (advisor) ; Kadlečková, Dominika (referee)
Promyelocytic leukemia protein (PML) is a key component for the formation of the PML nuclear bodies (PML−NBs), nonmembrane organelles, in which PML forms a shell surrounding an inner core of this dynamic multiprotein complex. PML is a multifunctional protein that is able to interact with sumoylated proteins and sequestrate them to PML NBs which can work as storage for these proteins or as a platform for biochemical reactions. PML is known for its tumor- suppressive character. However, it can have oncogenic potential under certain conditions which suggests its contradictory role in cancer. PML NBs are highly dynamic structures that undergo structural changes due to the phase of the cell cycle which can physically interact with chromatin. PML NBs maintain genome stability by playing a role during important cellular processes which are regulation of the cell cycle, DNA repair mechanisms, alternative telomere lengthening in cancer cells, or protection of the genome against viral DNA. PML itself can participate in genome maintenance. Concretely, its cytosolic isoform can have a role in inducing apoptosis. The purpose of this section is to provide information about how PML participates in genome stability maintenance and about the possible consequences of the failure of these mechanisms.
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The role of promyelocytic leukemia protein in genome maintenance
Kindlová, Martina ; Vašicová, Pavla (advisor) ; Moudrý, Pavel (referee)
Promyelocytic leukemia protein (PML) is a key component for a formation of the PML nuclear bodies (PML−NBs) in which PML forms a shell surrounding an inner core of this dynamic multiprotein komplex. PML may act as a tumor supressor or a regulator of transcription factors. PML-NBs plays a role in the genome stability maintenance by participating in DNA repair including the alternative lenghtening of telomer, regulation of the cell cycle and antivirus protection. The purpose of this section is to provide information about how PML participate in the genome stability maintenance and about possible consequences of failure of these mechanisms.
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Cell response to genotoxic stress-based anti-cancer therapies
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rossmeislová, Lenka (referee) ; Rotrekl, Vladimír (referee)
The dissertation deals with a cell response to genotoxic stress, specifically to anti-cancer treatments with a genotoxic mechanism of action. In principle, cells can respond to these perturbing stimuli in several ways: in case of severe DNA damage, they usually undergo apoptosis or enter senescence. In case of minor DNA damage, or upon defective checkpoint mechanisms, they may continue the cell cycle, either with successfully repaired DNA or with mutations of various kind. Thanks to selection pressure, the mutations that provide cells with a certain growth advantage under conditions of continuing genotoxic stress, gradually accumulate and render the tumor treatment-resistant. In my thesis, I focus on several aspects of this whole process. First, I participated in a characterization of a radioresistant and anoikis-resistant population of prostate cancer cells. This population was generated by irradiating cells 35 times by 2 Gy, a regime used in clinics. After this treatment, a population of low-adherent cells emerged that demonstrated increased expression of EMT- and stem cell markers. The low-adherent state of these cells was maintained by Snail signaling and their anoikis resistance by ERK1/2 signaling. Interestingly, after a protracted period of time, these cells were able to re-adhere and...
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