{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:09:01Z","timestamp":1790809741716,"version":"4.1.0"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:00:00Z","timestamp":1609113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002790","name":"Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2019-06146"],"award-info":[{"award-number":["RGPIN-2019-06146"]}],"id":[{"id":"10.13039\/501100002790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0224953","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T13:47:11Z","timestamp":1609163231000},"page":"e0224953","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death"],"prefix":"10.1371","volume":"15","author":[{"given":"Erin J.","family":"Vanzyl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadil","family":"Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex B.","family":"Blackmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayleigh R. C.","family":"Rick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasan","family":"Fernando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7921-1331","authenticated-orcid":true,"given":"Bruce C.","family":"McKay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,28]]},"reference":[{"key":"pone.0224953.ref001","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.14166","article-title":"Single molecule analysis reveals reversible and irreversible steps during spliceosome activation","volume":"5","author":"AA Hoskins","year":"2016","journal-title":"Elife"},{"issue":"1","key":"pone.0224953.ref002","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S1097-2765(03)00270-3","article-title":"Pre-mRNA splicing: awash in a sea of 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Yokoi","year":"2011","journal-title":"FEBS J"},{"issue":"11","key":"pone.0224953.ref006","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/1535-7163.MCT-06-0321","article-title":"Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase\/Akt-dependent matrix metalloproteinase-9 expression","volume":"5","author":"SO Yoon","year":"2006","journal-title":"Molecular cancer therapeutics"},{"issue":"49","key":"pone.0224953.ref007","doi-asserted-by":"crossref","first-page":"7488","DOI":"10.1038\/sj.onc.1205896","article-title":"ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth","volume":"21","author":"F Fan","year":"2002","journal-title":"Oncogene"},{"issue":"13","key":"pone.0224953.ref008","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1038\/onc.2011.353","article-title":"Pancreatic beta-cells activate a JunB\/ATF3-dependent survival pathway during 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