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.