<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells"^^ . "Rewired cancer metabolism sprang into the spotlight this century as a crucial aspect of the malignant transformation. Being the century of the DNA, most 20th century\r\ncancer research focused on approaching cancer as a direct result of accumulated mutations while overlooking the metabolic aspects. Albeit very insightful on the origin\r\nof the disease, this approach has fallen short of eradicating cancer. Hence efforts in\r\noncology research embarked on exploring other aspects in a bid for a whole-rounded anti-cancer approach. Consequently, last decade has seen accelerating\r\nbreakthroughs in elucidating the metabolic adaptation of cancer cells to provide the\r\nrequirements of rapid proliferation and the implication thereof as potential drug\r\ntargets.\r\nBasic metabolic networks and enzymes show large degree of evolutionary\r\nconservation between eukaryotes. Moreover, yeast and cancer share the major\r\nmetabolic hallmark of aerobic glycolysis, demonstrate comparable proliferative\r\ntendencies, comparable cell cycle regulation and also undergo apoptosis akin to\r\nhigher eukaryotes. This multiple overlap makes yeast an attractive model for\r\naddressing glucose metabolism as a driver for rapid proliferation.\r\nThis thesis features the results of my investigation into the regulation and effects of\r\nthe key gluconeogenic enzyme fructose 1,6 bis-phosphatase Fbp1 in two distinct\r\neukaryotic systems: the budding yeast Saccharomyces cerevisiae and human breast\r\ncancer cell lines. Based on previous research pointing out links between Fbp1 and\r\nthe particular type of DNA damage elicited by methyl methanesulfonate. When\r\nexposed to MMS, Fbp1 is transcriptionally upregulated as a part of the response to\r\nDNA methylation. Fbp1, on the other hand, bestows an increased MMS-sensitisation\r\nupon yeast. I devised a mutational analysis of evolutionary conserved residues to\r\naddress the mechanism of this additional phenotype, the results of which\r\ndemonstrated that the enzymatic activity could also be decoupled from further MMS\r\nsensitisation, hence suggesting a non-catalytic origin of the additional effect.\r\nii\r\nI then embarked on investigating the effects of Fbp1 in breast cancer cell lines of\r\nboth luminal and basal-like lineages. The findings I present make the case for an anti\r\nproliferative role of Fbp1 as an outcome of diminished glucose sensitivity, uptake and\r\na shift from glycolysis to higher mitochondrial activity. Moreover, Fbp1 exhibited a pro\r\noxidative role in cell lines manifested in increased ROS accumulation and sensitivity\r\nto oxidative agents. My findings also provide transcriptional evidence of a Wide -\r\nscale cell-cycle inhibitory outcome of Fbp1 ectopic expression in Fbp1-deficient\r\nMDA-MB231. Intriguingly, I observed that Fbp1-deficient basal like breast cancer\r\ncells acquired the capability to post-transcriptionally breakdown ectopic Fbp1 upon\r\nlong-term stable over-expression. I also demonstrated that this degradation occurs\r\nthrough the proteasome and exclusively upon the long-term selection of cells with\r\nectopic Fbp1.\r\nAn overview indicates multiple similarities of Fbp1 effects in yeast and cancer cell\r\nsystems. In general, Fbp1 has comparable effects on proliferation, glycolysis, and\r\nRedox balance in both systems. The proteasomal degradation of Fbp1 in cells draws\r\nanother parallel to the regulation of this enzyme in yeast since the so called\r\n“catabolite degradation” of Fbp1 had been long described and well-studied in yeast.\r\nNevertheless, when compared, the two corresponding mutations in yeast and human\r\nFbp1 had distinct consequences for catalytic activity and enzyme stability in each\r\nsystem., therefore hinting at structural differences in the activation mechanisms and\r\nat different interaction partners in the two systems.\r\nAltogether, the results presented in this thesis endorse Fbp1 as a quasi tumour\r\nsuppressor and emphasise the potential therapeutic significance of approaches that\r\ncan de-repress Fbp1 in cancers lacking it and prevent its ablation in cancers that\r\nexpress it."^^ . "2018" . . . . . . . "Ali"^^ . "Ghanem"^^ . "Ali Ghanem"^^ . . . . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (PDF)"^^ . . . "Dissertation A.Ghanem.pdf"^^ . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (Other)"^^ . . . . . . "preview.jpg"^^ . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (Other)"^^ . . . . . . "medium.jpg"^^ . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (Other)"^^ . . . . . . "small.jpg"^^ . . . "On the Regulation and Multiple Functions of the Key\r\nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating\r\nCells: Insights from Yeast and Breast Cancer Cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #25439 \n\nOn the Regulation and Multiple Functions of the Key \nGluconeogenic Enzyme Fbp1 in Rapidly Proliferating \nCells: Insights from Yeast and Breast Cancer Cells\n\n" . "text/html" . . . "000 Allgemeines, Wissenschaft, Informatik"@de . "000 Generalities, Science"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .