The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia
C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event...
Gespeichert in:
| Veröffentlicht in: | Oncogene 2016-10, Vol.35 (40), p.5272 |
|---|---|
| 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 | 40 |
| container_start_page | 5272 |
| container_title | Oncogene |
| container_volume | 35 |
| creator | O'Connor, C Lohan, F Campos, J Ohlsson, E Salomè, M Forde, C Artschwager, R Liskamp, R M Cahill, M R Kiely, P A Porse, B Keeshan, K |
| description | C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP[alpha], TRIB2 was unable to induce AML. Only in the presence of C/EBP[alpha] p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP[alpha] p42 requires site-specific direct interaction between TRIB2 and C/EBP[alpha] p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP[alpha] p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP[alpha]. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP[alpha] p42 is required for TRIB2-mediated AML. Oncogene (2016) 35, 5272-5281; doi: 10.1038/onc.2016.66; published online 21 March 2016 |
| doi_str_mv | 10.1038/onc.2016.66 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_journals_1826238169</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A465660151</galeid><sourcerecordid>A465660151</sourcerecordid><originalsourceid>FETCH-LOGICAL-g959-6109dbaf4fde9fea094c851e66606bceea8a720044eb5563f460c51ed23725763</originalsourceid><addsrcrecordid>eNptj1FLwzAUhYMoOKdP_oGAz92SNEmbx21MHQwU6ZtISZObLbNrtrT9_wYU9EHuw4Vzv3MOF6F7SmaU5OU8dGbGCJUzKS_QhPJCZkIofokmRAmSKZaza3TT9wdCSKEIm6C62gM-ReihM4CDw6v5evn6rtvTXn9g3Vnshx5b2EVt9eBDh3UE3IRhjyOcRx_BYhcirt42S5YdwXo9JKmF8VPD0etbdOV028Pdz56i6nFdrZ6z7cvTZrXYZjslVCYpUbbRjjsLyoEmiptSUJBSEtkYAF3qghHCOTRCyNxxSUy6W5YXTBQyn6KH79hTDOcR-qE-hDF2qbGmJZMsL6lUv9ROt1D7zoUhanP0vakXXIpURgVN1OwfKo1ND5nQgfNJ_2P4AncMb2M</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1826238169</pqid></control><display><type>article</type><title>The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia</title><source>Nature</source><source>SpringerNature Journals</source><creator>O'Connor, C ; Lohan, F ; Campos, J ; Ohlsson, E ; Salomè, M ; Forde, C ; Artschwager, R ; Liskamp, R M ; Cahill, M R ; Kiely, P A ; Porse, B ; Keeshan, K</creator><creatorcontrib>O'Connor, C ; Lohan, F ; Campos, J ; Ohlsson, E ; Salomè, M ; Forde, C ; Artschwager, R ; Liskamp, R M ; Cahill, M R ; Kiely, P A ; Porse, B ; Keeshan, K</creatorcontrib><description>C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP[alpha], TRIB2 was unable to induce AML. Only in the presence of C/EBP[alpha] p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP[alpha] p42 requires site-specific direct interaction between TRIB2 and C/EBP[alpha] p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP[alpha] p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP[alpha]. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP[alpha] p42 is required for TRIB2-mediated AML. Oncogene (2016) 35, 5272-5281; doi: 10.1038/onc.2016.66; published online 21 March 2016</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2016.66</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>New York: Nature Publishing Group</publisher><subject>Amino acids ; Animal genetics ; Leukemia ; Molecular biology ; Mutation ; Ubiquitin</subject><ispartof>Oncogene, 2016-10, Vol.35 (40), p.5272</ispartof><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 6, 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>O'Connor, C</creatorcontrib><creatorcontrib>Lohan, F</creatorcontrib><creatorcontrib>Campos, J</creatorcontrib><creatorcontrib>Ohlsson, E</creatorcontrib><creatorcontrib>Salomè, M</creatorcontrib><creatorcontrib>Forde, C</creatorcontrib><creatorcontrib>Artschwager, R</creatorcontrib><creatorcontrib>Liskamp, R M</creatorcontrib><creatorcontrib>Cahill, M R</creatorcontrib><creatorcontrib>Kiely, P A</creatorcontrib><creatorcontrib>Porse, B</creatorcontrib><creatorcontrib>Keeshan, K</creatorcontrib><title>The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia</title><title>Oncogene</title><description>C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP[alpha], TRIB2 was unable to induce AML. Only in the presence of C/EBP[alpha] p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP[alpha] p42 requires site-specific direct interaction between TRIB2 and C/EBP[alpha] p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP[alpha] p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP[alpha]. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP[alpha] p42 is required for TRIB2-mediated AML. Oncogene (2016) 35, 5272-5281; doi: 10.1038/onc.2016.66; published online 21 March 2016</description><subject>Amino acids</subject><subject>Animal genetics</subject><subject>Leukemia</subject><subject>Molecular biology</subject><subject>Mutation</subject><subject>Ubiquitin</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptj1FLwzAUhYMoOKdP_oGAz92SNEmbx21MHQwU6ZtISZObLbNrtrT9_wYU9EHuw4Vzv3MOF6F7SmaU5OU8dGbGCJUzKS_QhPJCZkIofokmRAmSKZaza3TT9wdCSKEIm6C62gM-ReihM4CDw6v5evn6rtvTXn9g3Vnshx5b2EVt9eBDh3UE3IRhjyOcRx_BYhcirt42S5YdwXo9JKmF8VPD0etbdOV028Pdz56i6nFdrZ6z7cvTZrXYZjslVCYpUbbRjjsLyoEmiptSUJBSEtkYAF3qghHCOTRCyNxxSUy6W5YXTBQyn6KH79hTDOcR-qE-hDF2qbGmJZMsL6lUv9ROt1D7zoUhanP0vakXXIpURgVN1OwfKo1ND5nQgfNJ_2P4AncMb2M</recordid><startdate>20161006</startdate><enddate>20161006</enddate><creator>O'Connor, C</creator><creator>Lohan, F</creator><creator>Campos, J</creator><creator>Ohlsson, E</creator><creator>Salomè, M</creator><creator>Forde, C</creator><creator>Artschwager, R</creator><creator>Liskamp, R M</creator><creator>Cahill, M R</creator><creator>Kiely, P A</creator><creator>Porse, B</creator><creator>Keeshan, K</creator><general>Nature Publishing Group</general><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20161006</creationdate><title>The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia</title><author>O'Connor, C ; Lohan, F ; Campos, J ; Ohlsson, E ; Salomè, M ; Forde, C ; Artschwager, R ; Liskamp, R M ; Cahill, M R ; Kiely, P A ; Porse, B ; Keeshan, K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g959-6109dbaf4fde9fea094c851e66606bceea8a720044eb5563f460c51ed23725763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Amino acids</topic><topic>Animal genetics</topic><topic>Leukemia</topic><topic>Molecular biology</topic><topic>Mutation</topic><topic>Ubiquitin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>O'Connor, C</creatorcontrib><creatorcontrib>Lohan, F</creatorcontrib><creatorcontrib>Campos, J</creatorcontrib><creatorcontrib>Ohlsson, E</creatorcontrib><creatorcontrib>Salomè, M</creatorcontrib><creatorcontrib>Forde, C</creatorcontrib><creatorcontrib>Artschwager, R</creatorcontrib><creatorcontrib>Liskamp, R M</creatorcontrib><creatorcontrib>Cahill, M R</creatorcontrib><creatorcontrib>Kiely, P A</creatorcontrib><creatorcontrib>Porse, B</creatorcontrib><creatorcontrib>Keeshan, K</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</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>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</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>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</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>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>O'Connor, C</au><au>Lohan, F</au><au>Campos, J</au><au>Ohlsson, E</au><au>Salomè, M</au><au>Forde, C</au><au>Artschwager, R</au><au>Liskamp, R M</au><au>Cahill, M R</au><au>Kiely, P A</au><au>Porse, B</au><au>Keeshan, K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia</atitle><jtitle>Oncogene</jtitle><date>2016-10-06</date><risdate>2016</risdate><volume>35</volume><issue>40</issue><spage>5272</spage><pages>5272-</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP[alpha], TRIB2 was unable to induce AML. Only in the presence of C/EBP[alpha] p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP[alpha] p42 requires site-specific direct interaction between TRIB2 and C/EBP[alpha] p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP[alpha] p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP[alpha]. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP[alpha] p42 is required for TRIB2-mediated AML. Oncogene (2016) 35, 5272-5281; doi: 10.1038/onc.2016.66; published online 21 March 2016</abstract><cop>New York</cop><pub>Nature Publishing Group</pub><doi>10.1038/onc.2016.66</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2016-10, Vol.35 (40), p.5272 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_journals_1826238169 |
| source | Nature; SpringerNature Journals |
| subjects | Amino acids Animal genetics Leukemia Molecular biology Mutation Ubiquitin |
| title | The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-30T06%3A08%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20presence%20of%20C/EBP%5Balpha%5D%20and%20its%20degradation%20are%20both%20required%20for%20TRIB2-mediated%20leukaemia&rft.jtitle=Oncogene&rft.au=O'Connor,%20C&rft.date=2016-10-06&rft.volume=35&rft.issue=40&rft.spage=5272&rft.pages=5272-&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2016.66&rft_dat=%3Cgale_proqu%3EA465660151%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1826238169&rft_id=info:pmid/&rft_galeid=A465660151&rfr_iscdi=true |