Downregulation of c-Jun expression by transcription factor C/EBPalpha is critical for granulocytic lineage commitment.
The transcription factor C/EBPalpha is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and C/EBPalpha can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPalpha knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPalpha 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/EBPalpha downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPalpha expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPalpha. C/EBPalpha 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/EBPalpha-induced granulocytic differentiation. Thus, we propose a model in which C/EBPalpha needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.
Rangatia
Janki
J
Department of Medicine III, Ludwig Maximilians University Munich, and GSF-National Research Center, Munich, Germany.
Vangala
Rajani Kanth
RK
Treiber
Nicolai
N
Zhang
Pu
P
Radomska
Hanna
H
Tenen
Daniel G
DG
Hiddemann
Wolfgang
W
Behre
Gerhard
G
D000818:Animals; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage; D015536:Down-Regulation / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006098:Granulocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D016350:Leucine Zippers; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D015032:Zinc