cam a22 4 4500 52897047X CHVBK 20201202100920.0 180926s2018 sz a m 00 0deng d urn:nbn:ch:bel-1688506 urn (SNL)991017731639703976 (SNL)991018082626803976 (NEBIS)011251715 (Sz)1952001-41snl_51 (Sz)vtls001952001 (Sz)001952001 (Sz)991018082626803976 Sz ger rda eng eng ger 570 23sdnb Markolin Philipp 1987- (DE-588)1163225886 Verfasser aut Discovery of hypoxia-mediated alternative splicing isoforms with impact in cellular metabolism and cancer presented by Philipp Markolin Zurich 2018 89 Seiten Illustrationen 30 cm Dissertation No. 25052 ETH Zurich, 2018 Literaturverzeichnis application/pdf Oxygen is essential for eukaryotic life. Over millions of years, it was necessary for organisms to evolve and integrate elaborate oxygen sensing and adaptation systems into cellular pathways to ensure cellular survival during periods of oxygen deprivation (hypoxia). Cellular hypoxia occurs both physiologically, e.g. during embryonic development and tissue growth, as well as in various disease contexts ranging from stroke or heart failure to cancer biology. Especially solid tumors are often poorly vascularized and thus harbor cancer cells experiencing intra-tumor hypoxia. These hypoxic cancer cells are of high interest in oncology research with respect to their roles in tumor survival, immune system evasion, metastasis and resistance to therapy. The most important and well-studied proteins involved in oxygen sensing and signaling include hypoxia-inducible factors (HIFs) and their biochemical regulators. HIF proteins are a class of transcriptional activators which, under hypoxic conditions, accumulate in the nucleus and bind to hypoxia-responsive elements in DNA to regulate gene expression of thousands of genes involved in varied cellular pathways, including angiogenesis, proliferation, metabolism, apoptosis and DNA repair. Although many transcriptional targets of hypoxia-inducible factors (HIFs) have been quite well characterized, hypoxia is also reported to impact on multiple post-transcriptional processes, including alternative splicing of RNA. Recently discovered hypoxia-dependent alternative splicing events are thought to introduce an additional layer of complexity to hypoxia biology but their overall contribution to cancer development, survival and resistance to therapy remain poorly understood. In this study, we set out to identify HIF dependent alternative splicing events after whole transcriptome sequencing in pancreatic cancer cells exposed to hypoxia with and without downregulation of the aryl hydrocarbon receptor -nuclear-translocator (ARNT), a protein required for HIFs to form a transcriptionally active dimer. We discover and validate a set of hypoxia-dependent alternative splicing events in detail in human pancreatic cancer cells as well as patient-derived human pancreatic cancer organoids. We investigate potential biological functions in these novel, hypoxia-dependent RNA transcripts. Finally, we report the discovery of a hypoxia-dependent long isoform of the UDP-N-acetylglucosamine transporter SLC35A3 with potential impact on cellular metabolism. Englischer Text mit englischer und deutscher Zusammenfassung KREBSZELLEN (CYTOPATHOLOGIE) ger (ETHUDK)000021695 ethudk RNA-SPLICING (MOLEKULARE GENETIK) ger (ETHUDK)000022845 ethudk SAUERSTOFFMANGEL (PHYSIOLOGIE) ger (ETHUDK)000040854 ethudk TRANSKRIPTIONSFAKTOREN (MOLEKULARE GENETIK) ger (ETHUDK)000048941 ethudk ZELLMETABOLISMUS + ZELLERNÄHRUNG (CYTOLOGIE) ger (ETHUDK)000021656 ethudk Hochschulschrift (DE-588)4113937-9 gnd-content Hochschulschrift gnd-content sb 2018/21 570 zh snl-sb xehelv xediss 2020 570 610 5 snl ehelv u SAUERSTOFFMANGEL (PHYSIOLOGIE) ger 612.232 nebis E1 u ZELLMETABOLISMUS + ZELLERNÄHRUNG (CYTOLOGIE) ger 576.34 nebis E1 u TRANSKRIPTIONSFAKTOREN (MOLEKULARE GENETIK) ger 577.214.6.052.042 nebis E1 u RNA-SPLICING (MOLEKULARE GENETIK) ger 577.214.7,1 nebis E1 u KREBSZELLEN (CYTOPATHOLOGIE) ger 576.385.5*2 nebis E1 u LACK OF OXYGEN (PHYSIOLOGY) eng 612.232 nebis E1 u MANQUE D'OXYGÈNE (PHYSIOLOGIE) fre 612.232 nebis E1 u CELL NUTRITION + CELL METABOLISM (CYTOLOGY) eng 576.34 nebis E1 u MÉTABOLISME CELLULAIRE + NUTRITION CELLULAIRE (CYTOLOGIE) fre 576.34 nebis E1 u TRANSCRIPTION FACTORS (MOLECULAR GENETICS) eng 577.214.6.052.042 nebis E1 u FACTEURS DE TRANSCRIPTION (GÉNÉTIQUE MOLÉCULAIRE) fre 577.214.6.052.042 nebis E1 u ÉPISSAGE D'ARN (GÉNÉTIQUE MOLÉCULAIRE) fre 577.214.7,1 nebis E1 u RNA SPLICING (MOLECULAR GENETICS) eng 577.214.7,1 nebis E1 u CELLULES CANCEREUSES (CYTOPATHOLOGIE) fre 576.385.5*2 nebis E1 u CANCER CELLS (CYTOPATHOLOGY) eng 576.385.5*2 nebis E1 Eidgenössische Technische Hochschule Zürich (DE-588)2023928-2 Grad-verleihende Institution dgg SNL NB001 NB999 - chb99 - https://opac.admin.ch/toc/toc1902038334.pdf Inhaltsverzeichnis BK020300 XK020000 XK020000 031 E01-20180813 130 E01-20180813 SNL NB001 NB001 Nbq 117633 NB10010 NEBIS E16 E16 RH Diss ETH 25052 SNL 100 1- Markolin Philipp 1987- (DE-588)1163225886 Verfasser aut SNL 856 41 https://opac.admin.ch/toc/toc1902038334.pdf Inhaltsverzeichnis SNL 710 2- Eidgenössische Technische Hochschule Zürich (DE-588)2023928-2 Grad-verleihende Institution dgg SNL 100 1- Markolin Philipp Verfasser aut SNL 856 40 http://hdl.handle.net/20.500.11850/274086 SNL 856 4- https://nbn-resolving.org/urn:nbn:ch:bel-1688506 SNL 856 42 http://www.e-helvetica.nb.admin.ch/directAccess?callnumber=bel-1688506 NEBIS 100 1- Markolin Philipp 1987- (DE-588)1163225886 Verfasser aut NEBIS 700 1- Krek Wilhelm 1962-2018 (DE-588)1089356005 Akademischer Betreuer dgs NEBIS 700 1- Theurillat Jean-Philippe Akademischer Betreuer dgs