Mechanism of Trib2 mediated degradation of C/EBP-ain acute myelogenous leukaemia

Lohan, F. M. and Keeshan, K. (2012) Mechanism of Trib2 mediated degradation of C/EBP-ain acute myelogenous leukaemia. British Journal of Haematology, 157(S1), p. 57. (doi:10.1111/j.1365-2141.2012.09071.x)

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Abstract

Tribbles 2 (Trib2) is a pseudokinase which is overexpressed in a subsetof human acute myelogenous leukemias (AMLs) and induces AMLwith 100% penetrance in murine models. Trib2 binds CCAAT/enhancer-binding-protein-a (C/EBP-a), a transcription factor whichregulates haematopoiesis. Functional inactivation of C/EBP-a has beenreported in 10–15% of AML cases. Trib2 binding of C/EBP-a whencomplexed with COP1 (E3-ligase) results in degradation of C/EBP-a1.Trib2 mediated degradation of C/EBP-a can be prevented by use of aproteasomal inhibitor, indicating proteasomal involvement. Proteaso-mal degradation is suggestive of potential ubiquitination of C/EBP-a,but is not conclusive evidence.In vivo ubiquitination assays analyzed the ubiquitination profile ofC/EBP-a in the presence and absence of Trib2. Our data shows thatTrib2 mediated ubiquitin-dependant-proteasomal-degradation of C/EBP-a. This ubiquitination was identified to be K48 species whichsignals proteasomal-mediated degradation and not K63 which specifiesintracellular signalling. Interestingly it has also been shown that C/EBP-b is also ubiquitinated in the presence of Trib2. Through peptidearray technology we have shown that Trib2 and C/EBP-a bind directly,the precise residues in Trib2 and C/EBP-a responsible for the bindinginteraction and ubiquitination are currently being assessed. Therequirement for direct binding and phosphorylation changes to triggerubiquitination of C/EBP-a will be presented and discussed.This is the first report of C/EBP-a K48 ubiquitin-dependant-proteasomal-degradation. These findings help to elucidate the prote-olytic relationship between leukemogenic Trib2 and C/EBP-a andhighlight their potential as therapeutic targets in AML.1Transformation by Tribbles homolog 2 (Trib2) requires both theTrib2 kinase domain and COP1 binding. Karen Keeshan, Will Bailis,Priya H. Dedhia, Maria E. Vega, Olga Shestova, Lanwei Xu, KristinToscano, Sacha N. Uljon, Stephen C. Blacklow and Warren S. Pear.(2010) Blood, Aug 30, 116, 4948–4957.

Item Type:Articles
Additional Information:(2012), Abstracts. British Journal of Haematology, 157: 1–88. doi: 10.1111/j.1365-2141.2012.09071.x
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen
Authors: Lohan, F. M., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:British Journal of Haematology
ISSN:0007-1048

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