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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3327-3337
C/EBP Directly Interacts With the DNA Binding Domain of c-myb
and Cooperatively Activates Transcription of Myeloid Promoters
Walter Verbeek,
Adrian F. Gombart,
Alexey M. Chumakov,
Carsten Müller,
Alan D. Friedman, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Department of Medicine,
Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles CA;
and the Division of Pediatric Oncology, The Johns-Hopkins University,
Baltimore, MD.
C/EBP is essential for granulocytic differentiation. We
investigated the role of C/EBP in the transcriptional activation of
various myeloid-specific genes. We found that two C/EBP isoforms, p32 and p30, possessing transcriptional activation domains were coexpressed in myeloid cells. Interestingly, isoform C/EBP p30 but
not p32 was differentially upregulated in NB-4 promyelocytic leukemia
cells treated with retinoids. Both isoforms bound specifically to C/EBP
sites in myeloid promoters. The kd for C/EBP binding to the C/EBP site of the neutrophil elastase promoter was 4.2 nmol/L.
In transfection assays using the nonhematopoietic cell line, CV-1, the
p32 isoform activated promoters from the myeloid-specific mim-1,
neutrophil elastase, and granulocyte colony-stimulating factor (G-CSF)
receptor genes by 2.5-, 1.8-, and 1.6-fold, respectively. The p30
isoform lacked significant transcriptional activity, suggesting that
other hematopoietic-specific factors were required for its function.
Consistent with this prediction, transfections into the hematopoietic
cell line Jurkat showed a 9.0- and 2.5-fold activation of the mim-1
promoter by the p32 and p30 isoforms, respectively. The additional 32 NH2-terminal residues made p32 a significantly more potent
transcriptional activator than p30. T lymphoblasts (Jurkat cells) and
immature myeloid cells (eg, Kcl22 cells) expressed high levels of the
c-myb hematopoietic transcription factor. Cotransfection of c-myb with
either the p32 or p30 isoform of C/EBP in CV-1 cells cooperatively
transactivated the mim-1 promoter by 20- and 16-fold, respectively, and
the neutrophil elastase promoter by 10-and 7-fold, respectively.
Pulldown assays showed that each C/EBP isoform interacted directly
with the DNA binding domain of the c-myb protein. Further studies
showed that Kcl22 myeloid cells only contained active C/EBP, but not
C/EBP , C/EBP , or C/EBP . A mutation of the C/EBP site in the
neutrophil elastase promoter markedly decreased the transactivation of
the promoter in Kcl22 myeloblasts. These results demonstrate a role for
C/EBP in regulating myeloid promoters, such as neutrophil elastase,
probably through a direct interaction with c-myb.
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