C/EBPalpha induces PU.1 and interacts with AP-1 and NF-kappaB to regulate myeloid development.

C/EBPalpha and PU.1 are key regulators of early myeloid development. Mice lacking C/EBPalpha or PU.1 have reduced granulocytes and monocytes. Consistent with a model in which induction of PU.1 by C/EBPalpha contributes to monocyte lineage specification, mice with reduced PU.1 have diminished monocytes but retain granulocytes, C/EBPalpha directly activates PU.1 gene transcription, and exogenous C/EBPalpha increases monocytic lineage commitment from bipotential myeloid progenitors. In addition to C/EBPalpha, AP-1 proteins also have the capacity to induce monocytic maturation. C/EBPalpha:c-Jun or C/EBPalpha:c-Fos leucine zipper heterodimers induce monopoiesis more potently than C/EBPalpha or c-Jun homodimers or c-Fos:c-Jun heterodimers. C/EBPs and NF-kappaB cooperatively regulate numerous genes during the inflammatory response. The C/EBPalpha basic region interacts with NF-kappaB p50, but not p65, to induce bcl-2, and this interaction may be relevant to myeloid cell survival and development.