Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins
The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x L inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistanc...
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| Veröffentlicht in: | Cell death and differentiation 2018-03, Vol.25 (4), p.721-734 |
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| container_title | Cell death and differentiation |
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| creator | Hockings, Colin Alsop, Amber E. Fennell, Stephanie C. Lee, Erinna F. Fairlie, W. Douglas Dewson, Grant Kluck, Ruth M. |
| description | The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x
L
inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x
L
and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-x
L
preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x
L
could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x
L
. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics. |
| doi_str_mv | 10.1038/s41418-017-0010-6 |
| format | Article |
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L
inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x
L
and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-x
L
preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x
L
could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x
L
. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-017-0010-6</identifier><identifier>PMID: 29459767</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1244 ; 631/80 ; Apoptosis ; Bax protein ; Bcl-2 protein ; Bcl-x protein ; BIM protein ; Biochemistry ; Biomedical and Life Sciences ; Cancer ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Life Sciences ; Mcl-1 protein ; Proteins ; Stem Cells</subject><ispartof>Cell death and differentiation, 2018-03, Vol.25 (4), p.721-734</ispartof><rights>ADMC Associazione Differenziamento e Morte Cellulare 2017</rights><rights>Copyright Nature Publishing Group Apr 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c377t-fb7ed7cf16af3bb4cc0686a2284d20b14d5221447f215c1b20f1fad28b5add953</citedby><cites>FETCH-LOGICAL-c377t-fb7ed7cf16af3bb4cc0686a2284d20b14d5221447f215c1b20f1fad28b5add953</cites><orcidid>0000-0002-7101-1925 ; 0000-0001-7894-7294</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/PMC5864222/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864222/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41488,42557,51319,53791,53793</link.rule.ids></links><search><creatorcontrib>Hockings, Colin</creatorcontrib><creatorcontrib>Alsop, Amber E.</creatorcontrib><creatorcontrib>Fennell, Stephanie C.</creatorcontrib><creatorcontrib>Lee, Erinna F.</creatorcontrib><creatorcontrib>Fairlie, W. Douglas</creatorcontrib><creatorcontrib>Dewson, Grant</creatorcontrib><creatorcontrib>Kluck, Ruth M.</creatorcontrib><title>Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><description>The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x
L
inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x
L
and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-x
L
preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x
L
could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x
L
. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.</description><subject>631/67/1244</subject><subject>631/80</subject><subject>Apoptosis</subject><subject>Bax protein</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>BIM protein</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell death</subject><subject>Life Sciences</subject><subject>Mcl-1 protein</subject><subject>Proteins</subject><subject>Stem Cells</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUtvFDEQhC0EIg_4AdwsceFi6PZ47JkLEhsBQdqIS3LhYnn8CA6z9mLPouTfx5uNQCBx6pb6q1KXipBXCG8RuuFdFShwYICKASAw-YQco1CS9QK6p23vemAjCHVETmq9AQCpRvmcHPFR9KOS6ph8u7AzQ2qSo6u23a5p9T93vi7FLDEnmgNdmR_U5hR8qdTF0KZPSzQzLb7GuphkPV0yXZ13LKf5jm5LXnxM9QV5Fsxc_cvHeUquPn28PDtn66-fv5x9WDPbKbWwMCnvlA0oTeimSVgLcpCG80E4DhMK13OOQqjAsbc4cQgYjOPD1Bvnxr47Je8PvtvdtPHOtu-KmfW2xI0pdzqbqP--pPhdX-dfuh-k4Jw3gzePBiU_ZNebWK2fZ5N83lXNARSiVMMeff0PepN3JbV4jerkABL7oVF4oGzJtRYffj-DoPfN6UNzujWn981p2TT8oKmNTde-_HH-v-geSRKaIQ</recordid><startdate>20180301</startdate><enddate>20180301</enddate><creator>Hockings, Colin</creator><creator>Alsop, Amber E.</creator><creator>Fennell, Stephanie C.</creator><creator>Lee, Erinna F.</creator><creator>Fairlie, W. 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Douglas ; Dewson, Grant ; Kluck, Ruth M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c377t-fb7ed7cf16af3bb4cc0686a2284d20b14d5221447f215c1b20f1fad28b5add953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>631/67/1244</topic><topic>631/80</topic><topic>Apoptosis</topic><topic>Bax protein</topic><topic>Bcl-2 protein</topic><topic>Bcl-x protein</topic><topic>BIM protein</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell death</topic><topic>Life Sciences</topic><topic>Mcl-1 protein</topic><topic>Proteins</topic><topic>Stem Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hockings, Colin</creatorcontrib><creatorcontrib>Alsop, Amber E.</creatorcontrib><creatorcontrib>Fennell, Stephanie C.</creatorcontrib><creatorcontrib>Lee, Erinna F.</creatorcontrib><creatorcontrib>Fairlie, W. 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Douglas</au><au>Dewson, Grant</au><au>Kluck, Ruth M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><date>2018-03-01</date><risdate>2018</risdate><volume>25</volume><issue>4</issue><spage>721</spage><epage>734</epage><pages>721-734</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x
L
inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x
L
and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-x
L
preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x
L
could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x
L
. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29459767</pmid><doi>10.1038/s41418-017-0010-6</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-7101-1925</orcidid><orcidid>https://orcid.org/0000-0001-7894-7294</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Cell death and differentiation, 2018-03, Vol.25 (4), p.721-734 |
| issn | 1350-9047 1476-5403 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5864222 |
| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SpringerNature Journals; PubMed Central |
| subjects | 631/67/1244 631/80 Apoptosis Bax protein Bcl-2 protein Bcl-x protein BIM protein Biochemistry Biomedical and Life Sciences Cancer Cell Biology Cell Cycle Analysis Cell death Life Sciences Mcl-1 protein Proteins Stem Cells |
| title | Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins |
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