C/EBPα and DEK coordinately regulate myeloid differentiation.
Blood
; 119(21): 4878-88, 2012 May 24.
Article
in En
| MEDLINE
| ID: mdl-22474248
ABSTRACT
The transcription factor C/EBPα is a critical mediator of myeloid differentiation and is often functionally impaired in acute myeloid leukemia. Recent studies have suggested that oncogenic FLT3 activity disrupts wild-type C/EBPα function via phosphorylation on serine 21 (S21). Despite the apparent role of pS21 as a negative regulator of C/EBPα transcription activity, the mechanism by which phosphorylation tips the balance between transcriptionally competent and inhibited forms remains unresolved. In the present study, we used immuno-affinity purification combined with quantitative mass spectrometry to delineate the proteins associated with C/EBPα on chromatin. We identified DEK, a protein with genetic links to leukemia, as a member of the C/EBPα complexes, and demonstrate that this association is disrupted by S21 phosphorylation. We confirmed that DEK is recruited specifically to chromatin with C/EBPα to enhance GCSFR3 promoter activation. In addition, we demonstrated that genetic depletion of DEK reduces the ability of C/EBPα to drive the expression of granulocytic target genes in vitro and disrupts G-CSF-mediated granulocytic differentiation of fresh human BM-derived CD34(+) cells. Our data suggest that C/EBPα and DEK coordinately activate myeloid gene expression and that S21 phosphorylation on wild-type C/EBPα mediates protein interactions that regulate the differentiation capacity of hematopoietic progenitors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chromosomal Proteins, Non-Histone
/
Cell Differentiation
/
Oncogene Proteins
/
Myeloid Cells
/
CCAAT-Enhancer-Binding Proteins
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Blood
Year:
2012
Document type:
Article
Affiliation country:
United States