Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis

Qian Fei Wang, Rebecca Cleaves, Tanawan Kummalue, Claus Nerlov, Alan David Friedman

Research output: Contribution to journalArticle

Abstract

CCAAT/enhancer binding protein α (C/EBPα) 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/EBPα basic region and C/EBPα residues 1-70 are required for repressing E2F targets, while cdk2 and cdk4 bind residues 177-191. C/EBPα-ER induces the 32D c13 myeloblast cell line to differentiate to granulocytes. C/EBPα-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/EBPα is not sufficient for differentiation. C/EBPα-ER variants lacking residues 11-70 or residues 11-70 and 178-200 both slowed the G1 to S transition. C/EBPα(GZ)-ER, containing the GCN4 rather than the C/EBPα leucine zipper, also slowed G1. In contrast, C/EBPα(BRM2)-ER, carrying mutations in the outer surface of the basic region required for interaction with E2F, did not slow G1. C/EBPα(BRM2)-ER induced early markers of granulopoiesis much less efficiently than C/EBPα-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/EBPα basic region, are required for granulopoiesis.

Original languageEnglish (US)
Pages (from-to)2548-2557
Number of pages10
JournalOncogene
Volume22
Issue number17
DOIs
StatePublished - May 1 2003

Fingerprint

CCAAT-Enhancer-Binding Proteins
Cell Cycle
Leucine Zippers
DNA
Mimosine
Granulocyte Precursor Cells
Granulocyte Colony-Stimulating Factor
Cell Cycle Checkpoints
Granulocytes

Keywords

  • C/EBPα
  • Cell cycle
  • Differentiation
  • E2F
  • Granulopoiesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis. / Wang, Qian Fei; Cleaves, Rebecca; Kummalue, Tanawan; Nerlov, Claus; Friedman, Alan David.

In: Oncogene, Vol. 22, No. 17, 01.05.2003, p. 2548-2557.

Research output: Contribution to journalArticle

Wang, Qian Fei ; Cleaves, Rebecca ; Kummalue, Tanawan ; Nerlov, Claus ; Friedman, Alan David. / Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis. In: Oncogene. 2003 ; Vol. 22, No. 17. pp. 2548-2557.
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AB - CCAAT/enhancer binding protein α (C/EBPα) 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/EBPα basic region and C/EBPα residues 1-70 are required for repressing E2F targets, while cdk2 and cdk4 bind residues 177-191. C/EBPα-ER induces the 32D c13 myeloblast cell line to differentiate to granulocytes. C/EBPα-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/EBPα is not sufficient for differentiation. C/EBPα-ER variants lacking residues 11-70 or residues 11-70 and 178-200 both slowed the G1 to S transition. C/EBPα(GZ)-ER, containing the GCN4 rather than the C/EBPα leucine zipper, also slowed G1. In contrast, C/EBPα(BRM2)-ER, carrying mutations in the outer surface of the basic region required for interaction with E2F, did not slow G1. C/EBPα(BRM2)-ER induced early markers of granulopoiesis much less efficiently than C/EBPα-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/EBPα basic region, are required for granulopoiesis.

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