Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions.
Several transcription factors have been implicated as playing a role in myelopoiesis. PU.1, an ets-family transcription factor, is required for the development of myeloid and lymphoid lineages, whereas the transcription factor CCAAT-enhancer binding protein family member C/EBPalpha is essential for granulocyte development. We present here the first evidence that C/EBPalpha blocks the function of PU.1. PU.1 and C/EBPalpha interact physically and colocalize in myeloid cells. As a consequence of this interaction, C/EBPalpha can inhibit the function of PU.1 to activate a minimal promoter containing only PU.1 DNA-binding sites. We further demonstrate that the leucine zipper in the DNA-binding domain of C/EBPalpha interacts with the beta3/beta4 region in the DNA-binding domain of PU.1 and as a result displaces the PU.1 coactivator c-Jun. Finally, C/EBPalpha blocks PU.1-induced dendritic cell development from CD34+ human cord blood cells. The functional blocking of PU.1 by C/EBPalpha could be the mechanism by which C/EBPalpha inhibits cell fates specified by PU.1 and directs cell development to the granulocyte lineage.
Reddy
Venkateshwar A
VA
Department of Medicine III, Ludwig-Maximilians-University and GSF-National Research Center for Environment and Health, Munich, Germany.
Iwama
Atsushi
A
Iotzova
Guergana
G
Schulz
Mathias
M
Elsasser
Annika
A
Vangala
Rajani K
RK
Tenen
Daniel G
DG
Hiddemann
Wolfgang
W
Behre
Gerhard
G
D000818:Animals; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D020239:Receptor Cross-Talk; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D020298:U937 Cells; D000099232:Proto-Oncogene Protein Spi-1
D022763:CCAAT-Enhancer-Binding Protein-alpha; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1