C/EBPε is an integrator of multiple signaling pathways that induce myeloid differentiation.

(A) Expression of C/EBPε is up-regulated not only by G-CSF but also by retinoic acid and other differentiation-inducing chemicals. Retinoic acid (RA) acts through the retinoic acid responsive element (RARE) on the promoter of C/EBPε. IL-3 and c-myc suppress C/EBPε expression at the transcriptional level. (B) A model of G-CSF–induced granulocytic differentiation. C/EBPα up-regulates G-CSF receptor and enhances signals to induce STAT3 and C/EBPε. Expression of G-CSF receptor can also be induced by C/EBPε as a positive feedback regulation. C/EBPε induces morphologic and functional differentiation to granulocytes and may be involved in cell-cycle arrest. STAT3 is critical for cell-cycle arrest, cooperatively or independently with C/EBPε. STAT3 may also be essential for differentiation, and C/EBPα is one possible downstream target of the STAT3-dependent pathway.