University of Limerick Institutional Repository

The presence of C/EBP alpha and its degradation are both required for TRIB2-mediated leukaemia

DSpace Repository

Show simple item record O'Connor, Caitríona Lohan, Fíona Campos, Joana Ohlsson, Ewa Salomé, Mara Forde, Ciarán Artschwager, Raik Liskamp, Robert M. Cahill, Mary R. Kiely, Patrick A. Porse, Bo Keeshan, Karen 2018-10-18T14:32:11Z 2018-10-18T14:32:11Z 2016
dc.description peer-reviewed en_US
dc.description.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. en_US
dc.language.iso eng en_US
dc.publisher Springer Nature en_US
dc.relation.ispartofseries Oncogene;35 (40), pp. 5272-5281
dc.relation.uri 10.1038/onc.2016.66
dc.subject C/EBPα en_US
dc.subject p42 en_US
dc.subject p30 en_US
dc.subject TRIB2 en_US
dc.subject proteasome en_US
dc.title The presence of C/EBP alpha and its degradation are both required for TRIB2-mediated leukaemia en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US 2018-10-18T14:22:01Z
dc.identifier.doi 10.1038/onc.2016.66
dc.contributor.sponsor Cancer Research UK Glasgow Centre en_US
dc.contributor.sponsor Cancer Research UK Beatson Institute en_US
dc.relation.projectid C596/A18076 en_US
dc.relation.projectid C596/A17196 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US
dc.internal.rssid 2692305
dc.internal.copyrightchecked Yes
dc.identifier.journaltitle Oncogene
dc.description.status peer-reviewed

Files in this item

This item appears in the following Collection(s)

Show simple item record

Search ULIR


My Account