The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest

Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACTdependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been report...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cell cycle (Georgetown, Tex.) Tex.), 2012-01, Vol.11 (2), p.407-417
Hauptverfasser: Bennett, Richard, Pan, Yu, Christian, Jaime, Hui, Teng, May Jr, W. Stratford
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 417
container_issue 2
container_start_page 407
container_title Cell cycle (Georgetown, Tex.)
container_volume 11
creator Bennett, Richard
Pan, Yu
Christian, Jaime
Hui, Teng
May Jr, W. Stratford
description Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACTdependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFκB. Here, we report that RAX/PACT interacts with the SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in G 1 . In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G1 arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G 1 growth arrest and expression of RAX/PACT in pkr+/+ but not pkr-/- MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to G 1 cell cycle arrest.
doi_str_mv 10.4161/cc.11.2.18999
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3293386</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>920232103</sourcerecordid><originalsourceid>FETCH-LOGICAL-i312t-62cca03b985994d3c6adfcae3803a9a6afaaea3467ff4956fac9e8d430199e643</originalsourceid><addsrcrecordid>eNqFkkFv1DAQhSMEoqVw5Ip840K2Hjtx4wvSEkFBVKKqFombNetMukaJHWxvq_33ZHdLBScutkd-33uWZ4riNfBFBQrOrV0ALMQCGq31k-IU6hrKivP66f4sm7ICDifFi5R-ci6aCw3PixMhBFRKidOiX22I3Sx_nF8v21V5_fWGpRwpJTYvU_CJ2IR5c487NsUwhkyJTbVkaTuG3YDZBc_QdwxtdneH8h0bCDvnb1kO7BIYxtkpvyye9TgkevWwnxXfP31ctZ_Lq2-XX9rlVekkiFwqYS1yudZNrXXVSauw6y2SbLhEjQp7REJZqYu-r3SterSamq6SHLQmVcmz4v3Rd9quR-os-RxxMFN0I8adCejMvzfebcxtuDNSaCkbNRu8fTCI4dd2frkZXbI0DOgpbJPRggspgMtZ-ebvqMeMP387C-AomNmO0tqFZB15S4_SD-Q95dy2AEaYqetnhv-HsdZgzM4OZA4tn5HmiDjfhzjifYhDZzLuhhD7iN66ZCRws5-WPX3IOqK_ATBTs9E</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>920232103</pqid></control><display><type>article</type><title>The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Bennett, Richard ; Pan, Yu ; Christian, Jaime ; Hui, Teng ; May Jr, W. Stratford</creator><creatorcontrib>Bennett, Richard ; Pan, Yu ; Christian, Jaime ; Hui, Teng ; May Jr, W. Stratford</creatorcontrib><description>Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACTdependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFκB. Here, we report that RAX/PACT interacts with the SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in G 1 . In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G1 arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G 1 growth arrest and expression of RAX/PACT in pkr+/+ but not pkr-/- MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to G 1 cell cycle arrest.</description><identifier>ISSN: 1538-4101</identifier><identifier>EISSN: 1551-4005</identifier><identifier>DOI: 10.4161/cc.11.2.18999</identifier><identifier>PMID: 22214662</identifier><language>eng</language><publisher>United States: Taylor &amp; Francis</publisher><subject>Binding ; Biology ; Bioscience ; Calcium ; Cancer ; Cell ; Cell Line, Tumor ; Cycle ; eIF-2 Kinase - metabolism ; Eukaryotic Initiation Factor-2 - metabolism ; Eye Proteins - metabolism ; G1 Phase Cell Cycle Checkpoints ; Gene Expression Profiling ; Gene Expression Regulation ; Homeodomain Proteins - metabolism ; Humans ; Landes ; Organogenesis ; Phosphorylation ; Protein Binding ; Protein Biosynthesis ; Protein Processing, Post-Translational ; Proteins ; Real-Time Polymerase Chain Reaction ; RNA-Binding Proteins - metabolism ; Signal Transduction ; Stress, Physiological ; Sumoylation ; Transcription Factors - metabolism ; Transcriptional Activation ; Tumor Suppressor Protein p53 - metabolism ; Two-Hybrid System Techniques ; Ubiquitin-Conjugating Enzymes - metabolism</subject><ispartof>Cell cycle (Georgetown, Tex.), 2012-01, Vol.11 (2), p.407-417</ispartof><rights>Copyright © 2012 Landes Bioscience 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293386/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293386/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22214662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bennett, Richard</creatorcontrib><creatorcontrib>Pan, Yu</creatorcontrib><creatorcontrib>Christian, Jaime</creatorcontrib><creatorcontrib>Hui, Teng</creatorcontrib><creatorcontrib>May Jr, W. Stratford</creatorcontrib><title>The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest</title><title>Cell cycle (Georgetown, Tex.)</title><addtitle>Cell Cycle</addtitle><description>Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACTdependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFκB. Here, we report that RAX/PACT interacts with the SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in G 1 . In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G1 arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G 1 growth arrest and expression of RAX/PACT in pkr+/+ but not pkr-/- MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to G 1 cell cycle arrest.</description><subject>Binding</subject><subject>Biology</subject><subject>Bioscience</subject><subject>Calcium</subject><subject>Cancer</subject><subject>Cell</subject><subject>Cell Line, Tumor</subject><subject>Cycle</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Eye Proteins - metabolism</subject><subject>G1 Phase Cell Cycle Checkpoints</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Landes</subject><subject>Organogenesis</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Biosynthesis</subject><subject>Protein Processing, Post-Translational</subject><subject>Proteins</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Stress, Physiological</subject><subject>Sumoylation</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional Activation</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Two-Hybrid System Techniques</subject><subject>Ubiquitin-Conjugating Enzymes - metabolism</subject><issn>1538-4101</issn><issn>1551-4005</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkkFv1DAQhSMEoqVw5Ip840K2Hjtx4wvSEkFBVKKqFombNetMukaJHWxvq_33ZHdLBScutkd-33uWZ4riNfBFBQrOrV0ALMQCGq31k-IU6hrKivP66f4sm7ICDifFi5R-ci6aCw3PixMhBFRKidOiX22I3Sx_nF8v21V5_fWGpRwpJTYvU_CJ2IR5c487NsUwhkyJTbVkaTuG3YDZBc_QdwxtdneH8h0bCDvnb1kO7BIYxtkpvyye9TgkevWwnxXfP31ctZ_Lq2-XX9rlVekkiFwqYS1yudZNrXXVSauw6y2SbLhEjQp7REJZqYu-r3SterSamq6SHLQmVcmz4v3Rd9quR-os-RxxMFN0I8adCejMvzfebcxtuDNSaCkbNRu8fTCI4dd2frkZXbI0DOgpbJPRggspgMtZ-ebvqMeMP387C-AomNmO0tqFZB15S4_SD-Q95dy2AEaYqetnhv-HsdZgzM4OZA4tn5HmiDjfhzjifYhDZzLuhhD7iN66ZCRws5-WPX3IOqK_ATBTs9E</recordid><startdate>20120115</startdate><enddate>20120115</enddate><creator>Bennett, Richard</creator><creator>Pan, Yu</creator><creator>Christian, Jaime</creator><creator>Hui, Teng</creator><creator>May Jr, W. Stratford</creator><general>Taylor &amp; Francis</general><general>Landes Bioscience</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120115</creationdate><title>The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest</title><author>Bennett, Richard ; Pan, Yu ; Christian, Jaime ; Hui, Teng ; May Jr, W. Stratford</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i312t-62cca03b985994d3c6adfcae3803a9a6afaaea3467ff4956fac9e8d430199e643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Binding</topic><topic>Biology</topic><topic>Bioscience</topic><topic>Calcium</topic><topic>Cancer</topic><topic>Cell</topic><topic>Cell Line, Tumor</topic><topic>Cycle</topic><topic>eIF-2 Kinase - metabolism</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Eye Proteins - metabolism</topic><topic>G1 Phase Cell Cycle Checkpoints</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Landes</topic><topic>Organogenesis</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Biosynthesis</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteins</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>Stress, Physiological</topic><topic>Sumoylation</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional Activation</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Two-Hybrid System Techniques</topic><topic>Ubiquitin-Conjugating Enzymes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bennett, Richard</creatorcontrib><creatorcontrib>Pan, Yu</creatorcontrib><creatorcontrib>Christian, Jaime</creatorcontrib><creatorcontrib>Hui, Teng</creatorcontrib><creatorcontrib>May Jr, W. Stratford</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell cycle (Georgetown, Tex.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bennett, Richard</au><au>Pan, Yu</au><au>Christian, Jaime</au><au>Hui, Teng</au><au>May Jr, W. Stratford</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest</atitle><jtitle>Cell cycle (Georgetown, Tex.)</jtitle><addtitle>Cell Cycle</addtitle><date>2012-01-15</date><risdate>2012</risdate><volume>11</volume><issue>2</issue><spage>407</spage><epage>417</epage><pages>407-417</pages><issn>1538-4101</issn><eissn>1551-4005</eissn><abstract>Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACTdependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFκB. Here, we report that RAX/PACT interacts with the SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in G 1 . In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G1 arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G 1 growth arrest and expression of RAX/PACT in pkr+/+ but not pkr-/- MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to G 1 cell cycle arrest.</abstract><cop>United States</cop><pub>Taylor &amp; Francis</pub><pmid>22214662</pmid><doi>10.4161/cc.11.2.18999</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1538-4101
ispartof Cell cycle (Georgetown, Tex.), 2012-01, Vol.11 (2), p.407-417
issn 1538-4101
1551-4005
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3293386
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Line, Tumor
Cycle
eIF-2 Kinase - metabolism
Eukaryotic Initiation Factor-2 - metabolism
Eye Proteins - metabolism
G1 Phase Cell Cycle Checkpoints
Gene Expression Profiling
Gene Expression Regulation
Homeodomain Proteins - metabolism
Humans
Landes
Organogenesis
Phosphorylation
Protein Binding
Protein Biosynthesis
Protein Processing, Post-Translational
Proteins
Real-Time Polymerase Chain Reaction
RNA-Binding Proteins - metabolism
Signal Transduction
Stress, Physiological
Sumoylation
Transcription Factors - metabolism
Transcriptional Activation
Tumor Suppressor Protein p53 - metabolism
Two-Hybrid System Techniques
Ubiquitin-Conjugating Enzymes - metabolism
title The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T17%3A56%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20RAX/PACT-PKR%20stress%20response%20pathway%20promotes%20p53%20sumoylation%20and%20activation,%20leading%20to%20G1%20arrest&rft.jtitle=Cell%20cycle%20(Georgetown,%20Tex.)&rft.au=Bennett,%20Richard&rft.date=2012-01-15&rft.volume=11&rft.issue=2&rft.spage=407&rft.epage=417&rft.pages=407-417&rft.issn=1538-4101&rft.eissn=1551-4005&rft_id=info:doi/10.4161/cc.11.2.18999&rft_dat=%3Cproquest_pubme%3E920232103%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=920232103&rft_id=info:pmid/22214662&rfr_iscdi=true