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Molecular logic of the Notch ligands in development and disease
Trampotová, Eliška ; Mašek, Jan (advisor) ; Rozbeský, Daniel (referee)
The Notch signalling pathway is one of the key signal transduction pathways in the embryonic development of all metazoa. In mammals, the "canonical" signalling occurs on four Notch receptors, and it is triggered by five ligands varying in both their structures and functions. The importance of the pathway for embryonic development is reflected by the fact that mutations of either receptors or ligands result in various congenital disorders. A prime example is the Alagille syndrome - a rare multisystemic condition caused by mutations of the Notch ligand Jagged1 in 94 % of cases. Much of the research effort so far was concentrated into elucidating how the Notch receptors operate, however one could argue the importance of ligand activity regulation is even higher. This thesis thus aims to provide a comprehensive comparison of the five mammalian Notch ligands' structures and roles in developmental processes. The main focus of the thesis is the variability of ligand-receptor interactions and biophysical mechanisms of signalling, highlighting the importance of the Notch ligands' intracellular domains' interactions.
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Influencing Notch signalling in virus associated tumours
Bujnovská, Ludmila ; Šmahelová, Jana (advisor) ; Grantz Šašková, Klára (referee)
The Notch signalling pathway affects cell differentiation, apoptosis and proliferation. It is an evolutionarily conserved signalling pathway important during embryogenesis and ontogenesis. Its deregulation can lead to carcinogenesis. Cells of various tumour types often contain gene mutations or other abnormalities in the Notch pathway. Its function with regard to oncogenesis has a dual character - in some cases it acts as an oncogenic pathway, in others it has a tumour-suppressive effect. This depends on the cellular context. A large group of tumours with proven abnormalities in the Notch signalling are head and neck squamous cell carcinomas (HNSCC). It is the 7th most common tumour type and the lethality rate is high. Almost 25 % of these tumours are etiologically related to human papillomavirus (HPV) infection. The cell cycle signalling pathways, including the Notch pathway, are the primary target of oncogenic viruses where HPV are no exception. This thesis describes changes in the Notch signalling pathway in HPV-induced HNSCC and the effect of viral oncoproteins E6 and E7 on this signalling pathway.
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A role of Sirt1 in the Notch signalling pathway.
HORVÁTH, Matej
The aim of this thesis was to examine role of Sirt1 in the Notch signalling pathway, using Drosophila as a model organism. Based on in vivo and in vitro studies, we conclude that Sirt1 plays a positive role in Notch signalling. In embryonic S2N cells, Sirt1 is responsible for the protection from metabolic stress-induced down-regulation of subset of E(Spl) genes. During development, Sirt1 is responsible for proper Notch-dependent specification of SOPs and wing development. Sirt1 can regulate the Notch signalling on multiple levels via deacetylation of various substrates involved in the Notch signalling revealed by our proteomic survey.
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