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HSP90 as a target for antitumor therapy
Drápalová, Kateřina ; Zatloukalová, Pavlína (advisor) ; Dibus, Nikol (referee)
Stability and correct tertiary structure of proteins are necessary for maintaining cellular homeostasis. The cell uses molecular chaperones, including Hsp90, to achieve this balance. Hsp90 is an essential protein for healthy and cancer cells. Overexpression of this chaperone is noticeable in many cancers. This thesis summarizes current understandings of the Hsp90 protein and its role in carcinogenesis. Hsp90 became a target of anticancer therapy in the 90s. Inhibition of this chaperone, though successful in many studies, has not yet reached the wanted results in clinical practice. Current failures are mostly caused by high hepatotoxicity and other side effects accompanying the therapy, or the inhibition having insufficient antitumor effects. Nevertheless, the inhibition of the Hsp90 protein represents an interesting approach in antitumor therapy. New inhibitors are constantly being developed and tested in monotherapy or in combination therapy, which demonstrates significantly higher efficacy and, thanks to the synergistic effect, enables the application of a lower concentration of therapeutics.
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Functional Characterization of SCFFBXO38 Ubiquitin Ligase-dependent Protein Degradation
Dibus, Nikol ; Čermák, Lukáš (advisor) ; Konvalinka, Jan (referee) ; D´Angiolella, Vincenzo (referee)
Ubiquitin ligases are responsible for the specific recognition of proteins targeted for proteasome-dependent degradation. This project focused on the molecular and functional characterization of the SCFFBXO38 ubiquitin ligase. As with many others, its biological function has not yet been elucidated in detail, although it is the only ubiquitin ligase whose mutations lead to the onset of a distal form of muscle atrophy. In the first part of our project, we identified new substrates for this ubiquitin ligase, the nuclear proteins ZXDA and ZXDB, with insufficiently characterized functions. Using genetic and biochemical methods, we have shown that ZXDA/B proteins act as positive regulators of centromeric chromatin integrity and that experimental inactivation of the SCFFBXO38 ubiquitin ligase resulted in a ZXDA/B-dependent stabilization of CENP-A and CENP-B proteins in the centromeric regions. In the second part of the project, we focused on analyzing the mouse model deficient in the Fbxo38 gene. We demonstrated that loss of Fbxo38 leads to growth retardation affecting various organs, including the male reproductive system. A detailed histological examination revealed pathological alterations in the seminiferous tubules, accompanied by a lower number of spermatozoa and decreased fertility. We have shown...
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