Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε

Hideaki Nakajima, James N. Ihle

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a major cytokine that regulates proliferation and differentiation of myeloid cells, although the underlying mechanisms by which G-CSF controls myeloid differentiation are largely unknown. Differentiation of hematopoietic cells is regulated by lineage-specific transcription factors, and gene-targeting studies previously revealed the critical roles of CCAAT/enhancer-binding protein (C/EBP) α and C/EBPε, respectively, in the early and mid-late stages of granulocyte differentiation. The expression of C/EBPε in 32Dcl3 cells and FDCP1 cells expressing mutant G-CSF receptors was examined and it was found that G-CSF up-regulates C/EBPε. The signal for this expression required the region containing the first tyrosine residue of G-CSF receptor. Dominant-negative signal transducers and activators of transcription 3 blocked G-CSF-induced granulocytic differentiation in 32D cells but did not block induction of C/EBPε, indicating that these proteins work in different pathways. It was also found that overexpression of C/EBPε greatly facilitated granulocytic differentiation by G-CSF and, surprisingly, that expression of C/EBPε alone was sufficient to make cells differentiate into morphologically and functionally mature granulocytes. Overexpression of c-myc inhibits differentiation of hematopoietic cells, but the molecular mechanisms of this inhibition are not fully understood. In 32Dcl3 cells overexpressing c-myc that do not differentiate by means of G-CSF, induction of C/EBPε is completely abrogated. Ectopic expression of C/EBPε in these cells induced features of differentiation, including changes in nuclear morphologic characteristics and the appearance of granules. These data show that C/EBPε constitutes a rate-limiting step in G-CSF-regulated granulocyte differentiation and that c-myc antagonizes G-CSF-induced myeloid differentiation, at least partly by suppressing induction of C/EBPε.

Original languageEnglish
Pages (from-to)897-905
Number of pages9
JournalBlood
Volume98
Issue number4
DOIs
Publication statusPublished - 2001 Aug 15

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CCAAT-Enhancer-Binding Proteins
Granulocyte Colony-Stimulating Factor
Granulocyte Colony-Stimulating Factor Receptors
Cells
Granulocytes
Cell Differentiation
STAT3 Transcription Factor
Gene Targeting
Myeloid Cells
Tyrosine
Transcription Factors
Up-Regulation
Genes

ASJC Scopus subject areas

  • Hematology

Cite this

Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε. / Nakajima, Hideaki; Ihle, James N.

In: Blood, Vol. 98, No. 4, 15.08.2001, p. 897-905.

Research output: Contribution to journalArticle

Nakajima, Hideaki ; Ihle, James N. / Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε. In: Blood. 2001 ; Vol. 98, No. 4. pp. 897-905.
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