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Blood, 15 August 2001, Vol. 98, No. 4, pp. 897-905
PLENARY PAPER
Granulocyte colony-stimulating factor regulates myeloid
differentiation through CCAAT/enhancer-binding protein 
Hideaki Nakajima and
James
N. Ihle
From the Howard Hughes Medical Institute, Department of
Biochemistry, St Jude Children's Research Hospital, Memphis, TN; and
the University of Tennessee Medical School, Memphis, TN.
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)  and
C/EBP , respectively, in the early and mid-late stages of granulocyte differentiation. The expression of C/EBP in 32Dcl3 cells and FDCP1
cells expressing mutant G-CSF receptors was examined and it was found
that G-CSF up-regulates C/EBP. 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/EBP, indicating that
these proteins work in different pathways. It was also found that
overexpression of C/EBP greatly facilitated granulocytic differentiation by G-CSF and, surprisingly, that expression of C/EBP
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/EBP is completely abrogated. Ectopic expression of
C/EBP in these cells induced features of differentiation, including
changes in nuclear morphologic characteristics and the appearance of
granules. These data show that C/EBP 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/EBP.
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