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Modulation of mRNA Expression of a Novel Human Myeloid-Selective CCAAT/Enhancer Binding Protein Gene (C/EBP )
Doris Y. Chih,
Alexey M. Chumakov,
Dorothy J. Park,
Agnes G. Silla, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA.
Human C/EBP is a newly cloned gene coding for a CCAAT/enhancer binding protein that may be involved in the regulation of myeloid differentiation. Our studies showed that levels of C/EBP mRNA were markedly increased in NB4 cells (promyelocytic leukemia line), because they were induced by 9-cis retinoic acid (9-cis RA) to differentiate towards granulocytes. Accumulation of C/EBP mRNA occurred as early as 1 hour after exposure of NB4 cells to 9-cis RA (5 × 10-7 mol/L); and at 48 hours, levels were increased by 5.1-fold. Dose-response studies showed that 10-7 to 10-6 mol/L 9-cis RA (12 hours) resulted in peak levels of C/EBP mRNA; but even 10-10 mol/L 9-cis RA increased levels of these transcripts. NB4 cells pulse-exposed (30 minutes) to all-trans retinoic acid (ATRA), washed, and cultured (3 days) with either dimethylsulfoxide (DMSO) or hexamethylene bisacetamide (HMBA) had a prominent increase in levels of C/EBP mRNA and an increase in granulocytic differentiation, but exposure to either DMSO or HMBA alone had no effect on base levels of C/EBP and did not induce differentiation. Macrophage-differentiation of NB4 reduced levels of C/EBP mRNA. Nuclear run-off assays and half-life studies showed that accumulation of C/EBP mRNA by 9-cis RA was due to enhanced transcription. Furthermore, this C/EBP mRNA accumulation did not require synthesis of new protein factors because 9-cis RA induced C/EBP mRNA accumulation in the absence of new protein synthesis. ATRA also induced expression of C/EBP protein in NB4 cells, as shown by Western blotting. In contrast to the increase of C/EBP in 9-cis RA-mediated granulocytic differentiation, the DMSO-induced differentiation of HL-60 cells down the granulocytic pathway was associated with an initial reduction of C/EBP mRNA levels. In summary, we have discovered that expression of C/EBP mRNA is markedly enhanced as the NB4 promyelocytes are induced by retinoids to differentiate towards granulocytes. This induction of C/EBP mRNA expression is transcriptionally mediated and occurs in the absence of synthesis of additional protein factors. We suspect that the C/EBP promoter/enhancer contains a retinoic acid-response element that is directly stimulated by retinoids.
Blood, Vol. 90 No. 8 (July 15), 1997:
pp. 2987-2994
© 1997 by The American Society of Hematology.
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