C/EBPα and the G-CSF receptor gene – partners in granulopoiesis?

The C/EBPs are a protein family with highly homologous leucine zipper domains designed to allow dimerization within the family. The finding that C/EBPs bind DNA as obligate homodimers or heterodimers made combinatorial diversity relevant to the regulation of developmental programs by transcription factors, just as antibody diversity generated via combinations of light and heavy chains is a key component of the immune response. The additional discovery that C/EBPs bind a common DNA motif raises a question: Is there selectivity in gene regulation by C/EBPs? The observation that C/EBPα (−/−) neonates lack both neutro-phils and G-CSF–responsive progenitors combined with evidence implicating C/EBPs as activators of the G-CSF receptor gene answered this question in the affirmative. However, in this issue (page 2382) Collins and his colleagues demonstrate high-level G-CSF receptor expression in hematopoietic cells immortalized from C/EBPα (−/−) mice. How might these new data be reconciled with the lack of CFU-G in the knockout mice? One possibility, perhaps the simplest, is that while C/EBPα is the most prominent C/EBP isoform in normal granu-locytic progenitors, their immortalization via expression of a dominant-negative retinoic acid receptor increases expression of other family members, such as C/EBPβ or C/EBPδ. Alternatively, the immortalized stem cells may have altered expression of other factors capable of activating the G-CSF receptor promoter. Regardless of the true explanation, C/EBPα and the G-CSF receptor gene can no longer be considered obligate partners.