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- Title
Cell cycle inhibition mediated by the outer surface of the C/EBPa basic region is required but not sufficient for granulopoiesis.
- Authors
Wang, Qian-Fei; Cleaves, Rebecca; Kummalue, Tanawan; Nerlov, Claus; Friedman, Alan D
- Abstract
CCAAT/enhancer binding protein a (C/EBPa) transactivates target genes dependent upon DNA binding via its basic region-leucine zipper domain and slows G1 progression by interaction with E2F, cdk2, or cdk4. E2F interacts with the non-DNA-binding surface of the C/EBPa basic region and C/EBPa residues 1-70 are required for repressing E2F targets, while cdk2 and cdk4 bind residues 177-191. C/EBPa-ER induces the 32D cl3 myeloblast cell line to differentiate to granulocytes. C/EBPa-ER variants incapable of binding DNA slowed G1, but did not induce early or late granulopoiesis, indicating that cell cycle inhibition as mediated by C/EBPa is not sufficient for differentiation. C/EBPa-ER variants lacking residues 11-70 or residues 11-70 and 178-200 both slowed the G1 to S transition. C/EBPa(GZ)-ER, containing the GCN4 rather than the C/EBPa leucine zipper, also slowed G1. In contrast, C/EBPa(BRM2)-ER, carrying mutations in the outer surface of the basic region required for interaction with E2F, did not slow G1. C/EBPa(BRM2)-ER induced early markers of granulopoiesis much less efficiently than C/EBPa-ER and did not direct terminal maturation. Inhibition of G1 progression using mimosine increased induction of late markers by G-CSF. Thus, both DNA binding and cell cycle arrest, mediated by opposite surfaces of the C/EBPa basic region, are required for granulopoiesis.Oncogene (2003) 22, 2548-2557. doi:10.1038/sj.onc.1206360
- Publication
Oncogene, 2003, Vol 22, Issue 17, p2548
- ISSN
0950-9232
- Publication type
Academic Journal
- DOI
10.1038/sj.onc.1206360