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Function of SWI/SNF chromatin-remodeling complex in tumor initiation and progression of melanoma cells
Ondrušová, Ľubica ; Vachtenheim, Jiří (advisor) ; Goetz, Petr (referee) ; Hejnar, Jiří (referee)
There is an increasing evidence that alterations in chromatin remodeling play an important role in tumorigenesis. The SWI/SNF chromatin remodeling complexes contribute to the regulation of gene expression by altering the local chromatin structure. Depending on the context, they can act as either transcriptional activators or repressors. All SWI/SNF subcomplexes contain one of two ATPase subunits, Brm (Brahma) or Brg1 (Brahma related gene 1), which provide the energy for remodeling. Malignant melanoma is an aggressive cancer and is known for its notorious resistance to conventional anticancer therapies. MITF (microphthalmia-associated transcription factor) plays an essential role in melanoma biology and is placed on the central crossroad in the regulation of melanocyte development, differentation, maintenance of lineage identity, and survival of both normal and malignant melanocytes. Our results show that the active SWI/SNF complex is strictly required for the expression of MITF. This complex is also required for expression of some transcriptional MITF targets. The survival of melanoma cells is absolutely dependent on functional SWI/SNF complex and all subunits of this complex are expressed at high levels in melanoma cell lines. Primarily, Brg1-containing subcomplexes are more important for MITF...
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Molecular mechanisms of tumor pathogenesis of Hedgehog signaling pathway in selected tumor types
Kreisingerová, Kateřina ; Vachtenheim, Jiří (advisor) ; Macůrek, Libor (referee) ; Uldrijan, Stjepan (referee)
The presented doctoral thesis is focused on the role of the Hedgehog (HH) signaling pathway in cancer pathogenesis. HH signaling pathway is an evolutionarily conserved signaling pathway that plays an essential role in embryonic development. Its activity is strictly limited to stem and progenitor cells for example in brain, lung, skin or prostate. HH pathway also plays a key role in tissue homeostasis and regeneration. Aberrantly activated HH pathway is essential in cancer progression. The aim of the presented thesis was to elucidate new details about the HH signaling pathway. We identified a new target gene of the HH pathway - the anti-apoptotic protein survivin. Survivin is considered to be an important tumor marker associated with a poor prognosis of patients. We showed that the inhibitor of HH pathway effectors GLI1 and GLI2 GANT61 reduced the survivin level in cancer cells. Subsequently, we used GANT61 and the inhibitor of the anti-apoptotic BCL2 protein family obatoclax to inhibit melanoma cells growth. We showed that the combination of these inhibitors was very effective in the eradication of melanoma cells in vitro. We also proved that GANT61 triggers the process of apoptosis in melanoma cells. We found out that the HH signaling pathway is canonically activated in many cell lines of various...
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Genetická determinace výskytu skrvnitosti u psů
Košková, Marie
The domestication and subsequent breeding preceded the formation of today's dog breeds and their coloring. The original wild coat color, which is known in ancestors of dogs - wolves, has been preserved in only a few dog breeds. The color of the coat has been and still is one of the most decisive signs in the process of selecting individuals for breeds. The white spotting is caused by the melanogenesis associated transcription factor (MITF), this gene is point of the interest to many experts, and the mechanism of this coat colour is not fully elucidated yet. In presence, several mutations of this gene are currently known, this mutations are associated with the white spotting.
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Function of SWI/SNF chromatin-remodeling complex in tumor initiation and progression of melanoma cells
Ondrušová, Ľubica ; Vachtenheim, Jiří (advisor) ; Goetz, Petr (referee) ; Hejnar, Jiří (referee)
There is an increasing evidence that alterations in chromatin remodeling play an important role in tumorigenesis. The SWI/SNF chromatin remodeling complexes contribute to the regulation of gene expression by altering the local chromatin structure. Depending on the context, they can act as either transcriptional activators or repressors. All SWI/SNF subcomplexes contain one of two ATPase subunits, Brm (Brahma) or Brg1 (Brahma related gene 1), which provide the energy for remodeling. Malignant melanoma is an aggressive cancer and is known for its notorious resistance to conventional anticancer therapies. MITF (microphthalmia-associated transcription factor) plays an essential role in melanoma biology and is placed on the central crossroad in the regulation of melanocyte development, differentation, maintenance of lineage identity, and survival of both normal and malignant melanocytes. Our results show that the active SWI/SNF complex is strictly required for the expression of MITF. This complex is also required for expression of some transcriptional MITF targets. The survival of melanoma cells is absolutely dependent on functional SWI/SNF complex and all subunits of this complex are expressed at high levels in melanoma cell lines. Primarily, Brg1-containing subcomplexes are more important for MITF...
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