title: The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia.
abstract: C/EBPα (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/EBPα 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/EBPα, TRIB2 was unable to induce AML. Only in the presence of C/EBPα 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/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBPα. 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/EBPα p42 is required for TRIB2-mediated AML.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: C
authors.initials: C
authors.lastname: O'Connor
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: F
authors.initials: F
authors.lastname: Lohan
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Campos
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.|Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Ohlsson
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: M
authors.initials: M
authors.lastname: Salomè
authors.affiliation: University College Cork, Cork, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Forde
authors.affiliation: School of Chemistry, University of Glasgow, Glasgow, UK.
authors.forename: R
authors.initials: R
authors.lastname: Artschwager
authors.affiliation: School of Chemistry, University of Glasgow, Glasgow, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Liskamp
authors.affiliation: Department of Haematology, Cork University Hospital, Cork, Ireland.
authors.forename: M R
authors.initials: MR
authors.lastname: Cahill
authors.affiliation: Department of Life Sciences, Materials and Surface Science Institute and Stokes Institute, University of Limerick, Limerick, Ireland.
authors.forename: P A
authors.initials: PA
authors.lastname: Kiely
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.|Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Porse
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: K
authors.initials: K
authors.lastname: Keeshan
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D047908:Intracellular Signaling Peptides and Proteins; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human