The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death
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 an...
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| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0224953 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0224953</identifier><identifier>PMID: 33370278</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activating transcription factor 3 ; Activating Transcription Factor 3 - genetics ; Activating Transcription Factor 3 - metabolism ; Animals ; Antibiotics ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - physiology ; Biflavonoids - pharmacology ; Bioflavonoids ; Biology ; Biology and Life Sciences ; Cell death ; Cell Death - drug effects ; Cell Death - physiology ; Cytotoxicity ; Drugs ; Embryo fibroblasts ; Epoxy Compounds - pharmacology ; Fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Flavones ; Flavonoids ; Gene expression ; Gene Expression - drug effects ; Gene Knockdown Techniques ; Genetic aspects ; Genetic research ; Health aspects ; HeLa Cells ; Humans ; Immunoglobulin G ; Inhibitors ; Introns ; Macrolides - pharmacology ; Membranes ; Mice ; Null cells ; Penicillin ; Proteins ; Research and analysis methods ; RNA splicing ; RNA, Small Interfering ; Sensitivity ; Spliceosomes ; Spliceosomes - metabolism ; Structure ; Toxicity ; Transcription factors ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2020-12, Vol.15 (12), p.e0224953</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Vanzyl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Vanzyl et al 2020 Vanzyl et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-b1a21261cfbed87560ded86ae88903a7607042dd578054ea88106266855601973</citedby><cites>FETCH-LOGICAL-c758t-b1a21261cfbed87560ded86ae88903a7607042dd578054ea88106266855601973</cites><orcidid>0000-0002-7921-1331</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769279/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769279/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33370278$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Larson, Daniel R.</contributor><creatorcontrib>Vanzyl, Erin J</creatorcontrib><creatorcontrib>Sayed, Hadil</creatorcontrib><creatorcontrib>Blackmore, Alex B</creatorcontrib><creatorcontrib>Rick, Kayleigh R C</creatorcontrib><creatorcontrib>Fernando, Pasan</creatorcontrib><creatorcontrib>McKay, Bruce C</creatorcontrib><title>The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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. 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Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.</description><subject>Activating transcription factor 3</subject><subject>Activating Transcription Factor 3 - genetics</subject><subject>Activating Transcription Factor 3 - metabolism</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Biflavonoids - pharmacology</subject><subject>Bioflavonoids</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - physiology</subject><subject>Cytotoxicity</subject><subject>Drugs</subject><subject>Embryo fibroblasts</subject><subject>Epoxy Compounds - pharmacology</subject><subject>Fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Flavones</subject><subject>Flavonoids</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Health aspects</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Immunoglobulin G</subject><subject>Inhibitors</subject><subject>Introns</subject><subject>Macrolides - pharmacology</subject><subject>Membranes</subject><subject>Mice</subject><subject>Null cells</subject><subject>Penicillin</subject><subject>Proteins</subject><subject>Research and analysis methods</subject><subject>RNA splicing</subject><subject>RNA, Small Interfering</subject><subject>Sensitivity</subject><subject>Spliceosomes</subject><subject>Spliceosomes - metabolism</subject><subject>Structure</subject><subject>Toxicity</subject><subject>Transcription factors</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNklGL1DAUhYso7rr6D0QLguDDjEmTJumLMC6uDiws6OiLDyGT3LYZM0ltWtF_b8bpLlNQkDwk3Hz35OZwsuwpRktMOH69C2PvlVt2wcMSFQWtSnIvO8cVKRasQOT-yfksexTjDqGSCMYeZmeEEI4KLs6zr5sW8tg5qyHEsIfc-tZu7RD6mNsYGuu_NTBYnytv8s4pY8EHZw3kbxNqRg35anNFFgY68Ab8kGtwLjeghvZx9qBWLsKTab_IPl-921x-WFzfvF9frq4XmpdiWGyxKnDBsK63YAQvGTJpZwqEqBBRnCGOaGFMyQUqKSghMGIFY6JMKK44ucieH3U7F6KcfImyoJxQKkqCErE-Eiaonex6u1f9LxmUlX8KoW-k6gerHcgKgcaCKFELTTmtVV1UTKitEbRClFRJ68302rjdg9Hpz71yM9H5jbetbMIPyTmrCn4QeDEJ9OH7CHH4x8gT1ag0lfV1SGJ6b6OWK0aZ4JTgg9byL1RaBvZWp2TUNtVnDa9mDYkZ4OfQqDFGuf708f_Zmy9z9uUJ24JyQxuDGwcbfJyD9AjqPsTYQ33nHEbyEOxbN-Qh2HIKdmp7dur6XdNtkslvZV7x0w</recordid><startdate>20201228</startdate><enddate>20201228</enddate><creator>Vanzyl, Erin J</creator><creator>Sayed, Hadil</creator><creator>Blackmore, Alex B</creator><creator>Rick, Kayleigh R C</creator><creator>Fernando, Pasan</creator><creator>McKay, Bruce C</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7921-1331</orcidid></search><sort><creationdate>20201228</creationdate><title>The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death</title><author>Vanzyl, Erin J ; Sayed, Hadil ; Blackmore, Alex B ; Rick, Kayleigh R C ; Fernando, Pasan ; McKay, Bruce C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-b1a21261cfbed87560ded86ae88903a7607042dd578054ea88106266855601973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Activating transcription factor 3</topic><topic>Activating Transcription Factor 3 - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33370278</pmid><doi>10.1371/journal.pone.0224953</doi><tpages>e0224953</tpages><orcidid>https://orcid.org/0000-0002-7921-1331</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Activating transcription factor 3 Activating Transcription Factor 3 - genetics Activating Transcription Factor 3 - metabolism Animals Antibiotics Apoptosis Apoptosis - drug effects Apoptosis - physiology Biflavonoids - pharmacology Bioflavonoids Biology Biology and Life Sciences Cell death Cell Death - drug effects Cell Death - physiology Cytotoxicity Drugs Embryo fibroblasts Epoxy Compounds - pharmacology Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Flavones Flavonoids Gene expression Gene Expression - drug effects Gene Knockdown Techniques Genetic aspects Genetic research Health aspects HeLa Cells Humans Immunoglobulin G Inhibitors Introns Macrolides - pharmacology Membranes Mice Null cells Penicillin Proteins Research and analysis methods RNA splicing RNA, Small Interfering Sensitivity Spliceosomes Spliceosomes - metabolism Structure Toxicity Transcription factors Tumor cell lines Tumors |
| title | The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death |
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