C/EBPalpha downregualtes c-jun expression

The transcription factor C/EBPa is crucial for the differentiation of granulocytes. Conditional expression of C/EBPa triggers neutrophilic differentiation and C/EBPa can block TPA induced monocytic differentiation of bipotential myeloid cells. In C/EBPa knockout mice, no mature granulocytes are present. A dramatic increase of c-jun mRNA in C/EBPa knockout mice fetal liver was observed. c-jun, a component of the AP-1 transcription factor complex and a co-activator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPa downregulates c-jun expression to drive granulocytic differentiation. Ectopic increase of C/EBPa expression decreases c-jun mRNA level, and the human c-jun promoter activity is downregulated 8 fold in presence of C/EBPa. C/EBPa and c-jun interact through their leucine zipper domains and this interaction prevents c-jun from binding to DNA. This results in downregulation of c-jun’s capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-jun prevents C/EBPa induced granulocytic differentiation. c-jun expression was higher in AML M2 patients with dominant negative C/EBPa mutations in comparison to AML M2 patients without C/EBPa mutations. Thus, we propose a model in which C/EBPa needs to downregulate c-jun expression and transactivation capacity for promoting granulocytic differentiation.