dc.date.accessioned | 2019-04-03T10:02:34Z | |
dc.date.available | 2019-09-17T22:46:15Z | |
dc.date.created | 2018-09-23T11:19:36Z | |
dc.date.issued | 2018 | |
dc.identifier.citation | Szalai, Paula Parys, Jan B Bultynck, Geert Christensen, Søren Brøgger Nissen, Poul Møller, Jesper Vuust Engedal, Nikolai . Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death. Cell Calcium. 2018, 76, 48-61 | |
dc.identifier.uri | http://hdl.handle.net/10852/67509 | |
dc.description.abstract | Endoplasmic reticulum (ER) Ca2+ depletion activates the unfolded protein response (UPR), inhibits bulk autophagy and eventually induces cell death in mammalian cells. However, the extent and duration of ER Ca2+ depletion required is unknown. We instigated a detailed study in two different cell lines, using sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors to gradually reduce ER Ca2+ levels in a controlled manner. Remarkably, UPR induction (as assessed by expression analyses of UPR-regulated proteins) and autophagy inhibition (as assessed by analyses of effects on starvation-induced bulk autophagy) required substantially higher drug concentrations than those needed to strongly decrease total ER Ca2+ levels. In fact, even when ER Ca2+ levels were so low that we could hardly detect any release of Ca2+ upon challenge with ER Ca2+ purging agents, UPR was not induced, and starvation-induced bulk autophagy was still fully supported. Moreover, although we observed reduced cell proliferation at this very low level of ER Ca2+, cells could tolerate prolonged periods (days) without succumbing to cell death. Addition of increasing concentrations of extracellular EGTA also gradually depleted the ER of Ca2+, and, as with the SERCA inhibitors, EGTA-induced activation of UPR and cell death required higher EGTA concentrations than those needed to strongly reduce ER Ca2+ levels. We conclude that ER Ca2+ depletion-induced effects on UPR, autophagy and cell death require either an extreme general depletion of ER Ca2+ levels, or Ca2+ depletion in areas of the ER that have a higher resistance to Ca2+ drainage than the bulk of the ER. | en_US |
dc.language | EN | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Szalai, Paula | |
dc.creator.author | Parys, Jan B | |
dc.creator.author | Bultynck, Geert | |
dc.creator.author | Christensen, Søren Brøgger | |
dc.creator.author | Nissen, Poul | |
dc.creator.author | Møller, Jesper Vuust | |
dc.creator.author | Engedal, Nikolai | |
cristin.unitcode | 185,57,11,0 | |
cristin.unitname | Mills/Engedal Group - Prostate Cancer | |
cristin.ispublished | true | |
cristin.fulltext | postprint | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 1612491 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Cell Calcium&rft.volume=76&rft.spage=48&rft.date=2018 | |
dc.identifier.jtitle | Cell Calcium | |
dc.identifier.volume | 76 | |
dc.identifier.startpage | 48 | |
dc.identifier.endpage | 61 | |
dc.identifier.doi | http://dx.doi.org/10.1016/j.ceca.2018.09.005 | |
dc.identifier.urn | URN:NBN:no-70683 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0143-4160 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/67509/2/Szalai_et_al_Cell_Calcium_2018_Accepted_manuscript.pdf | |
dc.type.version | AcceptedVersion | |
dc.relation.project | NFR/187615 | |
dc.relation.project | NFR/230686 | |
dc.relation.project | NFR/144182 | |