ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim
Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is...
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| Veröffentlicht in: | Cell 2007-06, Vol.129 (7), p.1337-1349 |
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| creator | Puthalakath, Hamsa O'Reilly, Lorraine A. Gunn, Priscilla Lee, Lily Kelly, Priscilla N. Huntington, Nicholas D. Hughes, Peter D. Michalak, Ewa M. McKimm-Breschkin, Jennifer Motoyama, Noburo Gotoh, Tomomi Akira, Shizuo Bouillet, Philippe Strasser, Andreas |
| description | Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPα-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases. |
| doi_str_mv | 10.1016/j.cell.2007.04.027 |
| format | Article |
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Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPα-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2007.04.027</identifier><identifier>PMID: 17604722</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apoptosis - physiology ; Apoptosis Regulatory Proteins - metabolism ; Bcl-2-Like Protein 11 ; CELLBIO ; Cells, Cultured ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; Endoplasmic Reticulum - ultrastructure ; Enzyme Inhibitors - pharmacology ; Membrane Proteins - metabolism ; Mice ; Phosphoprotein Phosphatases - metabolism ; Phosphorylation ; Protein Phosphatase 2 ; Protein Structure, Tertiary - physiology ; Proto-Oncogene Proteins - metabolism ; Regulatory Elements, Transcriptional - physiology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors ; Signal Transduction - drug effects ; Signal Transduction - physiology ; SIGNALING ; Thapsigargin - pharmacology ; Transcription Factor CHOP - genetics ; Transcription Factor CHOP - metabolism ; Up-Regulation - drug effects ; Up-Regulation - physiology</subject><ispartof>Cell, 2007-06, Vol.129 (7), p.1337-1349</ispartof><rights>2007 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-42b2187f85180d62242d584e8c5cf8e27543a9770267162674e5d3ef17a6939c3</citedby><cites>FETCH-LOGICAL-c398t-42b2187f85180d62242d584e8c5cf8e27543a9770267162674e5d3ef17a6939c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867407005375$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17604722$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Puthalakath, Hamsa</creatorcontrib><creatorcontrib>O'Reilly, Lorraine A.</creatorcontrib><creatorcontrib>Gunn, Priscilla</creatorcontrib><creatorcontrib>Lee, Lily</creatorcontrib><creatorcontrib>Kelly, Priscilla N.</creatorcontrib><creatorcontrib>Huntington, Nicholas D.</creatorcontrib><creatorcontrib>Hughes, Peter D.</creatorcontrib><creatorcontrib>Michalak, Ewa M.</creatorcontrib><creatorcontrib>McKimm-Breschkin, Jennifer</creatorcontrib><creatorcontrib>Motoyama, Noburo</creatorcontrib><creatorcontrib>Gotoh, Tomomi</creatorcontrib><creatorcontrib>Akira, Shizuo</creatorcontrib><creatorcontrib>Bouillet, Philippe</creatorcontrib><creatorcontrib>Strasser, Andreas</creatorcontrib><title>ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim</title><title>Cell</title><addtitle>Cell</addtitle><description>Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. 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These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Bcl-2-Like Protein 11</subject><subject>CELLBIO</subject><subject>Cells, Cultured</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endoplasmic Reticulum - ultrastructure</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Phosphoprotein Phosphatases - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Phosphatase 2</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Regulatory Elements, Transcriptional - physiology</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>SIGNALING</subject><subject>Thapsigargin - pharmacology</subject><subject>Transcription Factor CHOP - genetics</subject><subject>Transcription Factor CHOP - metabolism</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - physiology</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFFLwzAUhYMobk7_gA_SJ99ab9KkSUGQbUwnDCY6n0OX3o6Mrq1JN9i_t2UD34TLuS_nHDgfIfcUIgo0edpGBssyYgAyAh4BkxdkSCGVIaeSXZIhQMpClUg-IDfebwFACSGuyYDKBLhkbEheZp_BV-vQ-2Dl7GaDzgfjpm7a2lsfrI_B2LT2kLW22gSTeRwuq_IYfLi6RVsFE7u7JVdFVnq8O_8R-X6drabzcLF8e5-OF6GJU9WGnK0ZVbJQgirIE8Y4y4XiqIwwhUImBY-zVEpgiaRJJxxFHmNBZZakcWriEXk89Tau_tmjb_XO-n5-VmG991pCIkTc3Yiwk9G42nuHhW6c3WXuqCnoHpve6j6ne2wauO6wdaGHc_t-vcP8L3Lm1BmeTwbsNh4sOu2Nxcpgbh2aVue1_a__F9xye1Y</recordid><startdate>20070629</startdate><enddate>20070629</enddate><creator>Puthalakath, Hamsa</creator><creator>O'Reilly, Lorraine A.</creator><creator>Gunn, Priscilla</creator><creator>Lee, Lily</creator><creator>Kelly, Priscilla N.</creator><creator>Huntington, Nicholas D.</creator><creator>Hughes, Peter D.</creator><creator>Michalak, Ewa M.</creator><creator>McKimm-Breschkin, Jennifer</creator><creator>Motoyama, Noburo</creator><creator>Gotoh, Tomomi</creator><creator>Akira, Shizuo</creator><creator>Bouillet, Philippe</creator><creator>Strasser, Andreas</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope></search><sort><creationdate>20070629</creationdate><title>ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim</title><author>Puthalakath, Hamsa ; O'Reilly, Lorraine A. ; Gunn, Priscilla ; Lee, Lily ; Kelly, Priscilla N. ; Huntington, Nicholas D. ; Hughes, Peter D. ; Michalak, Ewa M. ; McKimm-Breschkin, Jennifer ; Motoyama, Noburo ; Gotoh, Tomomi ; Akira, Shizuo ; Bouillet, Philippe ; Strasser, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-42b2187f85180d62242d584e8c5cf8e27543a9770267162674e5d3ef17a6939c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Bcl-2-Like Protein 11</topic><topic>CELLBIO</topic><topic>Cells, Cultured</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Endoplasmic Reticulum - ultrastructure</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Phosphoprotein Phosphatases - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Phosphatase 2</topic><topic>Protein Structure, Tertiary - physiology</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Regulatory Elements, Transcriptional - physiology</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>SIGNALING</topic><topic>Thapsigargin - pharmacology</topic><topic>Transcription Factor CHOP - genetics</topic><topic>Transcription Factor CHOP - metabolism</topic><topic>Up-Regulation - drug effects</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Puthalakath, Hamsa</creatorcontrib><creatorcontrib>O'Reilly, Lorraine A.</creatorcontrib><creatorcontrib>Gunn, Priscilla</creatorcontrib><creatorcontrib>Lee, Lily</creatorcontrib><creatorcontrib>Kelly, Priscilla N.</creatorcontrib><creatorcontrib>Huntington, Nicholas D.</creatorcontrib><creatorcontrib>Hughes, Peter D.</creatorcontrib><creatorcontrib>Michalak, Ewa M.</creatorcontrib><creatorcontrib>McKimm-Breschkin, Jennifer</creatorcontrib><creatorcontrib>Motoyama, Noburo</creatorcontrib><creatorcontrib>Gotoh, Tomomi</creatorcontrib><creatorcontrib>Akira, Shizuo</creatorcontrib><creatorcontrib>Bouillet, Philippe</creatorcontrib><creatorcontrib>Strasser, Andreas</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Puthalakath, Hamsa</au><au>O'Reilly, Lorraine A.</au><au>Gunn, Priscilla</au><au>Lee, Lily</au><au>Kelly, Priscilla N.</au><au>Huntington, Nicholas D.</au><au>Hughes, Peter D.</au><au>Michalak, Ewa M.</au><au>McKimm-Breschkin, Jennifer</au><au>Motoyama, Noburo</au><au>Gotoh, Tomomi</au><au>Akira, Shizuo</au><au>Bouillet, Philippe</au><au>Strasser, Andreas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2007-06-29</date><risdate>2007</risdate><volume>129</volume><issue>7</issue><spage>1337</spage><epage>1349</epage><pages>1337-1349</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPα-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17604722</pmid><doi>10.1016/j.cell.2007.04.027</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Apoptosis - physiology Apoptosis Regulatory Proteins - metabolism Bcl-2-Like Protein 11 CELLBIO Cells, Cultured Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism Endoplasmic Reticulum - ultrastructure Enzyme Inhibitors - pharmacology Membrane Proteins - metabolism Mice Phosphoprotein Phosphatases - metabolism Phosphorylation Protein Phosphatase 2 Protein Structure, Tertiary - physiology Proto-Oncogene Proteins - metabolism Regulatory Elements, Transcriptional - physiology Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors Signal Transduction - drug effects Signal Transduction - physiology SIGNALING Thapsigargin - pharmacology Transcription Factor CHOP - genetics Transcription Factor CHOP - metabolism Up-Regulation - drug effects Up-Regulation - physiology |
| title | ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim |
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