Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation
The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene express...
Gespeichert in:
| Veröffentlicht in: | PLoS pathogens 2017-07, Vol.13 (7), p.e1006517 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 7 |
| container_start_page | e1006517 |
| container_title | PLoS pathogens |
| container_volume | 13 |
| creator | Tikhmyanova, Nadezhda Tutton, Steve Martin, Kayla A Lu, Fang Kossenkov, Andrew V Paparoidamis, Nicholas Kenney, Shannon Salvino, Joseph M Lieberman, Paul M |
| description | The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53. |
| doi_str_mv | 10.1371/journal.ppat.1006517 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1929416892</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A499694185</galeid><doaj_id>oai_doaj_org_article_ca2c3f0a7f4f4920a17b63dcf34364fe</doaj_id><sourcerecordid>A499694185</sourcerecordid><originalsourceid>FETCH-LOGICAL-c727t-2028cc3055bd81f6b52c7a02ee54b3af6956ea655faa4d182f58f322e28c30483</originalsourceid><addsrcrecordid>eNqVkk1v1DAQhiMEoqXwDxBY4sQhiz_zcUFalgIrVUWicLYmjp16lY1T21lRxI_H7aZVV4ID8sHW-HnfGY8ny14SvCCsJO82bvID9ItxhLggGBeClI-yYyIEy0tW8scPzkfZsxA2GHPCSPE0O6JVSQSv6XH2-2ILfY-2rtdq6jUatY-TbyBaNyBnULzUaLU8_0jy1dT3diD51NiryUY7IHWtkiJEaGxvf-mARsEQDC2K3nad9gGdjiFqO-QfwHu0s34KyGtQ0e5uEzzPnhjog34x7yfZj0-n31df8rOvn9er5VmuSlrGnGJaKcWwEE1bEVM0gqoSMNVa8IaBKWpRaCiEMAC8JRU1ojKMUp1kDPOKnWSv975j74KcGxckqWnNSVHVNBHrPdE62MjR2y34a-nAytuA850EH216r1RAFTMYSsNNaiEGUjYFa5VhnBXc6OT1fs42NVvdKj1ED_2B6eHNYC9l53Yy_RYpRJ0M3swG3l1NOsR_lDxTHaSq7GBcMlNbG5Rc8rouEleJRC3-QqXV6q1VbtDGpviB4O2BIDFR_4wdTCHI9cW3_2DPD1m-Z5V3IXht7htCsLwZ6LtHypuBlvNAJ9mrh828F91NMPsDJnLyyA</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1929416892</pqid></control><display><type>article</type><title>Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><source>Public Library of Science (PLoS)</source><creator>Tikhmyanova, Nadezhda ; Tutton, Steve ; Martin, Kayla A ; Lu, Fang ; Kossenkov, Andrew V ; Paparoidamis, Nicholas ; Kenney, Shannon ; Salvino, Joseph M ; Lieberman, Paul M</creator><creatorcontrib>Tikhmyanova, Nadezhda ; Tutton, Steve ; Martin, Kayla A ; Lu, Fang ; Kossenkov, Andrew V ; Paparoidamis, Nicholas ; Kenney, Shannon ; Salvino, Joseph M ; Lieberman, Paul M</creatorcontrib><description>The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1006517</identifier><identifier>PMID: 28715492</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antiviral Agents - pharmacology ; Biology and life sciences ; Buckminsterfullerene ; Cullin ; Cullin Proteins - genetics ; Cullin Proteins - metabolism ; Deoxyribonucleic acid ; DNA ; Enzymes ; Epstein-Barr virus ; Epstein-Barr Virus Infections - genetics ; Epstein-Barr Virus Infections - metabolism ; Epstein-Barr Virus Infections - virology ; Fullerenes ; Fullerenes - pharmacology ; Funding ; Gene expression ; Gene Expression Regulation, Viral - drug effects ; Genetic aspects ; Herpesvirus 4, Human - drug effects ; Herpesvirus 4, Human - genetics ; Herpesvirus 4, Human - physiology ; Humans ; Infections ; Kinases ; Latency ; Libraries ; Lymphoma ; Medicine ; Medicine and health sciences ; p53 Protein ; Perturbation methods ; Phosphorylation ; Protein Binding - drug effects ; Proteins ; Research and Analysis Methods ; Stabilization ; Substrates ; Supervision ; Transcription activation ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor proteins ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Ubiquitin ; Ubiquitin - genetics ; Ubiquitin - metabolism ; Virus Activation - drug effects ; Viruses</subject><ispartof>PLoS pathogens, 2017-07, Vol.13 (7), p.e1006517</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Tikhmyanova N, Tutton S, Martin KA, Lu F, Kossenkov AV, Paparoidamis N, et al. (2017) Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation. PLoS Pathog 13(7): e1006517. https://doi.org/10.1371/journal.ppat.1006517</rights><rights>2017 Tikhmyanova et al 2017 Tikhmyanova et al</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Tikhmyanova N, Tutton S, Martin KA, Lu F, Kossenkov AV, Paparoidamis N, et al. (2017) Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation. PLoS Pathog 13(7): e1006517. https://doi.org/10.1371/journal.ppat.1006517</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c727t-2028cc3055bd81f6b52c7a02ee54b3af6956ea655faa4d182f58f322e28c30483</citedby><cites>FETCH-LOGICAL-c727t-2028cc3055bd81f6b52c7a02ee54b3af6956ea655faa4d182f58f322e28c30483</cites><orcidid>0000-0003-3143-4277 ; 0000-0001-9118-8245 ; 0000-0003-1856-224X ; 0000-0002-3935-9921 ; 0000-0002-2184-5980 ; 0000-0002-1536-0418</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/PMC5531659/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531659/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28715492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tikhmyanova, Nadezhda</creatorcontrib><creatorcontrib>Tutton, Steve</creatorcontrib><creatorcontrib>Martin, Kayla A</creatorcontrib><creatorcontrib>Lu, Fang</creatorcontrib><creatorcontrib>Kossenkov, Andrew V</creatorcontrib><creatorcontrib>Paparoidamis, Nicholas</creatorcontrib><creatorcontrib>Kenney, Shannon</creatorcontrib><creatorcontrib>Salvino, Joseph M</creatorcontrib><creatorcontrib>Lieberman, Paul M</creatorcontrib><title>Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.</description><subject>Antiviral Agents - pharmacology</subject><subject>Biology and life sciences</subject><subject>Buckminsterfullerene</subject><subject>Cullin</subject><subject>Cullin Proteins - genetics</subject><subject>Cullin Proteins - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Enzymes</subject><subject>Epstein-Barr virus</subject><subject>Epstein-Barr Virus Infections - genetics</subject><subject>Epstein-Barr Virus Infections - metabolism</subject><subject>Epstein-Barr Virus Infections - virology</subject><subject>Fullerenes</subject><subject>Fullerenes - pharmacology</subject><subject>Funding</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Viral - drug effects</subject><subject>Genetic aspects</subject><subject>Herpesvirus 4, Human - drug effects</subject><subject>Herpesvirus 4, Human - genetics</subject><subject>Herpesvirus 4, Human - physiology</subject><subject>Humans</subject><subject>Infections</subject><subject>Kinases</subject><subject>Latency</subject><subject>Libraries</subject><subject>Lymphoma</subject><subject>Medicine</subject><subject>Medicine and health sciences</subject><subject>p53 Protein</subject><subject>Perturbation methods</subject><subject>Phosphorylation</subject><subject>Protein Binding - drug effects</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Stabilization</subject><subject>Substrates</subject><subject>Supervision</subject><subject>Transcription activation</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Ubiquitin</subject><subject>Ubiquitin - genetics</subject><subject>Ubiquitin - metabolism</subject><subject>Virus Activation - drug effects</subject><subject>Viruses</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVkk1v1DAQhiMEoqXwDxBY4sQhiz_zcUFalgIrVUWicLYmjp16lY1T21lRxI_H7aZVV4ID8sHW-HnfGY8ny14SvCCsJO82bvID9ItxhLggGBeClI-yYyIEy0tW8scPzkfZsxA2GHPCSPE0O6JVSQSv6XH2-2ILfY-2rtdq6jUatY-TbyBaNyBnULzUaLU8_0jy1dT3diD51NiryUY7IHWtkiJEaGxvf-mARsEQDC2K3nad9gGdjiFqO-QfwHu0s34KyGtQ0e5uEzzPnhjog34x7yfZj0-n31df8rOvn9er5VmuSlrGnGJaKcWwEE1bEVM0gqoSMNVa8IaBKWpRaCiEMAC8JRU1ojKMUp1kDPOKnWSv975j74KcGxckqWnNSVHVNBHrPdE62MjR2y34a-nAytuA850EH216r1RAFTMYSsNNaiEGUjYFa5VhnBXc6OT1fs42NVvdKj1ED_2B6eHNYC9l53Yy_RYpRJ0M3swG3l1NOsR_lDxTHaSq7GBcMlNbG5Rc8rouEleJRC3-QqXV6q1VbtDGpviB4O2BIDFR_4wdTCHI9cW3_2DPD1m-Z5V3IXht7htCsLwZ6LtHypuBlvNAJ9mrh828F91NMPsDJnLyyA</recordid><startdate>20170717</startdate><enddate>20170717</enddate><creator>Tikhmyanova, Nadezhda</creator><creator>Tutton, Steve</creator><creator>Martin, Kayla A</creator><creator>Lu, Fang</creator><creator>Kossenkov, Andrew V</creator><creator>Paparoidamis, Nicholas</creator><creator>Kenney, Shannon</creator><creator>Salvino, Joseph M</creator><creator>Lieberman, Paul M</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>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-3143-4277</orcidid><orcidid>https://orcid.org/0000-0001-9118-8245</orcidid><orcidid>https://orcid.org/0000-0003-1856-224X</orcidid><orcidid>https://orcid.org/0000-0002-3935-9921</orcidid><orcidid>https://orcid.org/0000-0002-2184-5980</orcidid><orcidid>https://orcid.org/0000-0002-1536-0418</orcidid></search><sort><creationdate>20170717</creationdate><title>Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation</title><author>Tikhmyanova, Nadezhda ; Tutton, Steve ; Martin, Kayla A ; Lu, Fang ; Kossenkov, Andrew V ; Paparoidamis, Nicholas ; Kenney, Shannon ; Salvino, Joseph M ; Lieberman, Paul M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c727t-2028cc3055bd81f6b52c7a02ee54b3af6956ea655faa4d182f58f322e28c30483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antiviral Agents - pharmacology</topic><topic>Biology and life sciences</topic><topic>Buckminsterfullerene</topic><topic>Cullin</topic><topic>Cullin Proteins - genetics</topic><topic>Cullin Proteins - metabolism</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Enzymes</topic><topic>Epstein-Barr virus</topic><topic>Epstein-Barr Virus Infections - genetics</topic><topic>Epstein-Barr Virus Infections - metabolism</topic><topic>Epstein-Barr Virus Infections - virology</topic><topic>Fullerenes</topic><topic>Fullerenes - pharmacology</topic><topic>Funding</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Viral - drug effects</topic><topic>Genetic aspects</topic><topic>Herpesvirus 4, Human - drug effects</topic><topic>Herpesvirus 4, Human - genetics</topic><topic>Herpesvirus 4, Human - physiology</topic><topic>Humans</topic><topic>Infections</topic><topic>Kinases</topic><topic>Latency</topic><topic>Libraries</topic><topic>Lymphoma</topic><topic>Medicine</topic><topic>Medicine and health sciences</topic><topic>p53 Protein</topic><topic>Perturbation methods</topic><topic>Phosphorylation</topic><topic>Protein Binding - drug effects</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Stabilization</topic><topic>Substrates</topic><topic>Supervision</topic><topic>Transcription activation</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><topic>Ubiquitin</topic><topic>Ubiquitin - genetics</topic><topic>Ubiquitin - metabolism</topic><topic>Virus Activation - drug effects</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tikhmyanova, Nadezhda</creatorcontrib><creatorcontrib>Tutton, Steve</creatorcontrib><creatorcontrib>Martin, Kayla A</creatorcontrib><creatorcontrib>Lu, Fang</creatorcontrib><creatorcontrib>Kossenkov, Andrew V</creatorcontrib><creatorcontrib>Paparoidamis, Nicholas</creatorcontrib><creatorcontrib>Kenney, Shannon</creatorcontrib><creatorcontrib>Salvino, Joseph M</creatorcontrib><creatorcontrib>Lieberman, Paul M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tikhmyanova, Nadezhda</au><au>Tutton, Steve</au><au>Martin, Kayla A</au><au>Lu, Fang</au><au>Kossenkov, Andrew V</au><au>Paparoidamis, Nicholas</au><au>Kenney, Shannon</au><au>Salvino, Joseph M</au><au>Lieberman, Paul M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2017-07-17</date><risdate>2017</risdate><volume>13</volume><issue>7</issue><spage>e1006517</spage><pages>e1006517-</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28715492</pmid><doi>10.1371/journal.ppat.1006517</doi><orcidid>https://orcid.org/0000-0003-3143-4277</orcidid><orcidid>https://orcid.org/0000-0001-9118-8245</orcidid><orcidid>https://orcid.org/0000-0003-1856-224X</orcidid><orcidid>https://orcid.org/0000-0002-3935-9921</orcidid><orcidid>https://orcid.org/0000-0002-2184-5980</orcidid><orcidid>https://orcid.org/0000-0002-1536-0418</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2017-07, Vol.13 (7), p.e1006517 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_1929416892 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Public Library of Science (PLoS) |
| subjects | Antiviral Agents - pharmacology Biology and life sciences Buckminsterfullerene Cullin Cullin Proteins - genetics Cullin Proteins - metabolism Deoxyribonucleic acid DNA Enzymes Epstein-Barr virus Epstein-Barr Virus Infections - genetics Epstein-Barr Virus Infections - metabolism Epstein-Barr Virus Infections - virology Fullerenes Fullerenes - pharmacology Funding Gene expression Gene Expression Regulation, Viral - drug effects Genetic aspects Herpesvirus 4, Human - drug effects Herpesvirus 4, Human - genetics Herpesvirus 4, Human - physiology Humans Infections Kinases Latency Libraries Lymphoma Medicine Medicine and health sciences p53 Protein Perturbation methods Phosphorylation Protein Binding - drug effects Proteins Research and Analysis Methods Stabilization Substrates Supervision Transcription activation Transcription Factors - genetics Transcription Factors - metabolism Tumor proteins Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Ubiquitin Ubiquitin - genetics Ubiquitin - metabolism Virus Activation - drug effects Viruses |
| title | Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T10%3A36%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Small%20molecule%20perturbation%20of%20the%20CAND1-Cullin1-ubiquitin%20cycle%20stabilizes%20p53%20and%20triggers%20Epstein-Barr%20virus%20reactivation&rft.jtitle=PLoS%20pathogens&rft.au=Tikhmyanova,%20Nadezhda&rft.date=2017-07-17&rft.volume=13&rft.issue=7&rft.spage=e1006517&rft.pages=e1006517-&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1006517&rft_dat=%3Cgale_plos_%3EA499694185%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1929416892&rft_id=info:pmid/28715492&rft_galeid=A499694185&rft_doaj_id=oai_doaj_org_article_ca2c3f0a7f4f4920a17b63dcf34364fe&rfr_iscdi=true |