Document Detail


Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1.
MedLine Citation:
PMID:  22972988     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, one of three E-protein-encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif that as previously been implicated in E-protein silencing, and the KIX domain of the transcriptional co-activator CBP/p300 is critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here, we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important both binding KIX and for bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET:KIX interaction as a therapeutic target for E2A-PBX1-induced leukemia.
Authors:
Christopher M Denis; Seth Chitayat; Michael J Plevin; Feng Wang; Patrick Thompson; Shuang Li; Holly L Spencer; Mitsuhiko Ikura; David P Lebrun; Steven P Smith
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-12
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada;
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