<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB"^^ . "Hypoxia is a hallmark of solid tumors, including HPV-positive cervical cancers, and it poses a\r\nsignificant challenge to cancer treatment, as hypoxic tumor regions are often associated with\r\nincreased therapy resistance and poor patient prognosis. One possible contributing factor to\r\nthis resistance is the ability of hypoxic cancer cells to evade cellular senescence – a process\r\nleading to an irreversible growth arrest. While the repression of the HPV E6/E7 oncogenes in\r\nnormoxic HPV-positive cells efficiently induces senescence, hypoxic HPV-positive cells,\r\ndespite efficiently shutting off E6/E7 expression, evade senescence and induce a reversible\r\ngrowth arrest that can be overcome by reoxygenation.\r\nThe overall aim of this thesis was to uncover mechanisms that enable hypoxic HPV-positive\r\ncancer cells to evade senescence. Through comparative gene and protein expression\r\nanalyses following E6/E7 repression under normoxic and hypoxic conditions, I identified\r\ndistinct regulatory patterns of key cell cycle regulatory factors. Notably, B-MYB emerged as a\r\ncritical factor differentially regulated under these conditions. Its strong downregulation in\r\nnormoxic cells following E6/E7 knockdown was associated with the onset of senescence, while\r\nits sustained expression under hypoxia correlated with senescence evasion, suggesting a role\r\nfor B-MYB in controlling this process. To further investigate the functional role of B-MYB, I\r\nperformed knockdown experiments and assessed the phenotypic consequences using various\r\ncellular assays. Interestingly, B-MYB depletion led to a partial senescence induction under\r\nnormoxia. I further showed that this limited senescence response was due to the compensatory\r\ninduction of a B-MYB paralog, A-MYB, which could counteract the pro-senescent effects of\r\nB-MYB loss. Consequently, the combined repression of both B-MYB and A-MYB was needed\r\nfor efficient senescence induction under normoxia. Strikingly, I found that this compensatory\r\nmechanism is disrupted under hypoxia, rendering hypoxic cancer cells particularly susceptible\r\nto the pro-senescent effects of B-MYB loss. This increased vulnerability of hypoxic cells could\r\nbe reversed by ectopic A-MYB overexpression. Further, my studies revealed that the\r\nB-MYB/A-MYB axis also plays a key role for the senescence response of normoxic and hypoxic\r\nHPV-negative cancer cells of various histological backgrounds, indicating that this newly\r\ndiscovered mechanism could be broadly conserved across different tumor types.\r\nCollectively, my findings provide novel insights into the regulation of senescence in normoxic\r\nand hypoxic cancer cells and identify B-MYB and A-MYB as central factors in these processes.\r\nFurther, they reveal a particular vulnerability of hypoxic cancer cells to B-MYB inhibition that\r\ncould be exploited to develop new strategies to target this therapeutically challenging tumor\r\ncell population."^^ . "2025" . . . . . . . "Milica"^^ . "Velimirovic"^^ . "Milica Velimirovic"^^ . . . . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (PDF)"^^ . . . "Thesis Milica Velimirovic.pdf"^^ . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Senescence Control in Normoxic and Hypoxic\r\nHPV-Positive Cancer Cells:\r\nThe Interplay between B-MYB and A-MYB (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #37467 \n\nSenescence Control in Normoxic and Hypoxic \nHPV-Positive Cancer Cells: \nThe Interplay between B-MYB and A-MYB\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .