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dc.contributor.author
Bluwstein, Andrej
dc.contributor.author
Kumar, Nitin
dc.contributor.author
Léger, Karolin
dc.contributor.author
Traenkle, Jens
dc.contributor.author
van Oostrum, Jan
dc.contributor.author
Rehrauer, Hubert K.
dc.contributor.author
Baudis, Michael
dc.contributor.author
Hottiger, Michael O.
dc.date.accessioned
2019-09-09T08:07:11Z
dc.date.available
2017-06-11T03:41:50Z
dc.date.available
2019-09-09T08:07:11Z
dc.date.issued
2013
dc.identifier.issn
2041-4889
dc.identifier.other
10.1038/cddis.2013.15
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/78934
dc.identifier.doi
10.3929/ethz-b-000078934
dc.description.abstract
Primary cells respond to irradiation by activation of the DNA damage response and cell cycle arrest, which eventually leads to senescence or apoptosis. It is not clear in detail which signaling pathways or networks regulate the induction of either apoptosis or senescence. Primary human fibroblasts are able to withstand high doses of irradiation and to prevent irradiation-induced apoptosis. However, the underlying regulatory basis for this phenotype is not well understood. Here, a kinetic network analysis based on reverse phase protein arrays (RPPAs) in combination with extensive western blot and cell culture analyses was employed to decipher the cytoplasmic and nuclear signaling networks and to identify possible antiapoptotic pathways. This analysis identified activation of known DNA damage response pathways (e.g., phosphorylation of MKK3/6, p38, MK2, Hsp27, p53 and Chk1) as well as of prosurvival (e.g., MEK-ERK, cAMP response element-binding protein (CREB), protein kinase C (PKC)) and antiapoptotic markers (e.g., Bad, Bcl-2). Interestingly, PKC family members were activated early upon irradiation, suggesting a regulatory function in the ionizing radiation (IR) response of these cells. Inhibition or downregulation of PKC in primary human fibroblasts caused IR-dependent downregulation of the identified prosurvival (CREB phosphorylation) and antiapoptotic (Bad phosphorylation, Bcl-2) markers and thus lead to a proliferation stop and to apoptosis. Taken together, our analysis suggests that cytoplasmic PKC signaling conditions IR-stressed MRC-5 and IMR-90 cells to prevent irradiation-induced apoptosis. These findings contribute to the understanding of the cellular and nuclear IR response and may thus eventually improve the efficacy of radiotherapy and help overcome tumor radioresistance.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject
Apoptosis
en_US
dc.subject
DNA damage response
en_US
dc.subject
PKC signaling
en_US
dc.subject
Primary human fibroblast
en_US
dc.subject
Radiation sensitivity
en_US
dc.subject
Reverse phase protein array
en_US
dc.title
PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported
dc.date.published
2013-02-14
ethz.journal.title
Cell Death & Disease
ethz.journal.volume
4
en_US
ethz.pages.start
e498
en_US
ethz.size
10 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.nebis
006029226
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
ethz.date.deposited
2017-06-11T03:42:29Z
ethz.source
ECIT
ethz.identifier.importid
imp59365184cd6bd27958
ethz.ecitpid
pub:124051
ethz.eth
no
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-19T08:35:49Z
ethz.rosetta.lastUpdated
2021-02-15T05:50:50Z
ethz.rosetta.versionExported
true
ethz.COinS
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