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dc.contributor.author
Markolin, Philipp
dc.contributor.supervisor
Krek, Wilhelm
dc.contributor.supervisor
Theurillat, Jean-Philippe
dc.contributor.supervisor
Schwank, Gerald
dc.date.accessioned
2018-07-09T11:04:35Z
dc.date.available
2018-07-05T12:40:02Z
dc.date.available
2018-07-05T13:49:38Z
dc.date.available
2018-07-09T11:04:35Z
dc.date.issued
2018
dc.identifier.uri
http://hdl.handle.net/20.500.11850/274086
dc.identifier.doi
10.3929/ethz-b-000274086
dc.description.abstract
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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.subject
Hypoxia-inducible factors
en_US
dc.subject
splicing regulation
en_US
dc.subject
SLC35A3
en_US
dc.subject
Alternative splicing
en_US
dc.subject
Pancreatic cancer
en_US
dc.subject
Oxygen signaling
en_US
dc.title
Discovery of hypoxia-mediated alternative splicing isoforms with impact in cellular metabolism and cancer
en_US
dc.type
Doctoral Thesis
dc.date.published
2018-07-05
ethz.size
89 p.
en_US
ethz.code.ddc
::DDC - DDC::5 - Science
en_US
ethz.identifier.diss
25052
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::03630 - Krek, Wilhelm / Krek, Wilhelm
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::03630 - Krek, Wilhelm / Krek, Wilhelm
en_US
ethz.date.deposited
2018-07-05T12:40:03Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Embargoed
en_US
ethz.date.embargoend
2020-07-05
ethz.rosetta.installDate
2018-07-05T13:49:47Z
ethz.rosetta.lastUpdated
2019-02-03T04:45:36Z
ethz.rosetta.versionExported
true
ethz.COinS
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