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Downregulation of c-Jun Expression by Transcription Factor C/EBP Is Critical for Granulocytic Lineage Commitment

Department of Medicine III, Ludwig Maximilians University Munich, and GSF-National Research Center, Munich, Germany,¹ Harvard Institutes of Medicine and Harvard Medical School, Boston, Massachusetts²

Received 29 May 2002/ Returned for modification 1 July 2002/ Accepted 15 September 2002

The transcription factor C/EBP is crucial for the differentiation of granulocytes. Conditional expression of C/EBP triggers neutrophilic differentiation, and C/EBP can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBP knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBP knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBP downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBP expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBP. C/EBP 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/EBP-induced granulocytic differentiation. Thus, we propose a model in which C/EBP needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.

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