Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε
2001
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/EBPe, respectively, in the early and mid-late stages of granulocyte differentiation. The expression of C/EBPe in 32Dcl3 cells and FDCP1 cells expressing mutant G-CSF receptors was examined and it was found that G-CSF up-regulates C/EBPe. 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/EBPe, indicating that these proteins work in different pathways. It was also found that overexpression of C/EBPe greatly facilitated granulocytic differentiation by G-CSF and, surprisingly, that expression of C/EBPe 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/EBPe is completely abrogated. Ectopic expression of C/EBPe in these cells induced features of differentiation, including changes in nuclear morphologic characteristics and the appearance of granules. These data show that C/EBPe 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/EBPe.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
46
References
74
Citations
NaN
KQI