Modulation of mRNA Expression of a Novel Human Myeloid-Selective CCAAT/Enhancer Binding Protein Gene (C/EBPε)
10.1182/blood.v90.8.2987
Crossref journal-article
American Society of Hematology
Blood (234)
Abstract

Abstract Human C/EBPε 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/EBPε 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/EBPε 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/EBPε 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/EBPε mRNA and an increase in granulocytic differentiation, but exposure to either DMSO or HMBA alone had no effect on base levels of C/EBPε and did not induce differentiation. Macrophage-differentiation of NB4 reduced levels of C/EBPε mRNA. Nuclear run-off assays and half-life studies showed that accumulation of C/EBPε mRNA by 9-cis RA was due to enhanced transcription. Furthermore, this C/EBPε mRNA accumulation did not require synthesis of new protein factors because 9-cis RA induced C/EBPε mRNA accumulation in the absence of new protein synthesis. ATRA also induced expression of C/EBPε protein in NB4 cells, as shown by Western blotting. In contrast to the increase of C/EBPε 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/EBPε mRNA levels. In summary, we have discovered that expression of C/EBPε mRNA is markedly enhanced as the NB4 promyelocytes are induced by retinoids to differentiate towards granulocytes. This induction of C/EBPε mRNA expression is transcriptionally mediated and occurs in the absence of synthesis of additional protein factors. We suspect that the C/EBPε promoter/enhancer contains a retinoic acid-response element that is directly stimulated by retinoids.

Bibliography

Chih, D. Y., Chumakov, A. M., Park, D. J., Silla, A. G., & Koeffler, H. P. (1997). Modulation of mRNA Expression of a Novel Human Myeloid-Selective CCAAT/Enhancer Binding Protein Gene (C/EBPε). Blood, 90(8), 2987–2994.

Authors 5
  1. Doris Y. Chih (first)
  2. Alexey M. Chumakov (additional)
  3. Dorothy J. Park (additional)
  4. Agnes G. Silla (additional)
  5. H. Phillip Koeffler (additional)
References 40 Referenced 65
  1. {'key': '2019111907480956200_B1', 'first-page': '149', 'article-title': 'Regulation of immature myeloid cell differentiation by PEPB2/CBP, myb, C/EBP and Ets family members.', 'volume': '211', 'author': 'Friedman', 'year': '1996', 'journal-title': 'Curr Top Microbiol Immunol'} / Curr Top Microbiol Immunol / Regulation of immature myeloid cell differentiation by PEPB2/CBP, myb, C/EBP and Ets family members. by Friedman (1996)
  2. 10.1128/MCB.16.3.1231 / Mol Cell Biol / CCAAT enhancer binding protein (C/EBP) and AML1 (CBF alpha 2) synergistically activate the macrophage colony-stimulating factor receptor promoter. by Zhang (1996)
  3. 10.1101/gad.7.5.749 / Genes Dev / Myb and NF-M: Combinatorial acticvators of myeloid genes in heterologous cell types. by Ness (1993)
  4. {'key': '2019111907480956200_B4', 'first-page': '113', 'article-title': 'Terminal myeloid gene expression and differentiation requires the transcription factor PU.1.', 'volume': '211', 'author': 'Simon', 'year': '1996', 'journal-title': 'Curr Top Microbiol Immunol'} / Curr Top Microbiol Immunol / Terminal myeloid gene expression and differentiation requires the transcription factor PU.1. by Simon (1996)
  5. 10.1182/blood.V77.5.909.909 / Blood / Expression and regulation of myeloid-specific genes in normal and leukemic myeloid cells. by Lubbert (1991)
  6. 10.1182/blood.V80.12.2953.2953 / Blood / Transcriptional factors, translocations and leukemia. by Nichols (1992)
  7. 10.1038/372143a0 / Nature / Chromosomal translocations in human cancer. by Simon (1994)
  8. 10.1002/j.1460-2075.1990.tb08316.x / EMBO J / A nuclear factor for IL-6 expression (NF-IL6) is a member of C/EBP family. by Akira (1990)
  9. 10.1073/pnas.90.7.2584 / Proc Natl Acad Sci USA / Participation of the transcription factor C/EBP delta in acute-phase regulation of the human gene for complement component C3. by Juan (1993)
  10. 10.1016/0092-8674(90)90459-R / Cell / IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. by Poli (1990)
  11. 10.1126/science.7652557 / Science / Impaired energy homeostasis in C/EBP alpha knockout mice. by Wang (1995)
  12. 10.1182/blood.V80.7.1725.1725 / Blood / A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. by Scott (1992)
  13. 10.1016/0092-8674(95)90418-2 / Cell / Targeted disruption of the NF-IL6 gene discloses its essential role in bacterial killing and tumor cytotoxicity by macrophages. by Tanaka (1995)
  14. 10.1073/pnas.94.2.569 / Proc Natl Acad Sci USA / Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. by Zhang (1997)
  15. 10.1101/gad.4.8.1404 / Genes Dev / Ig/EBP-1: A ubiquitously expressed immunoglobulin enhancer binding protein that is similar to C/EBP and heterodimerizes with C/EBP. by Roman (1990)
  16. 10.1016/0378-1119(95)00271-7 / Gene / Cloning of the cDNA encoding human C/EBP gamma, a protein binding to the PRE-I enhancer element of the human interleukin-4 promoter. by Davydov (1995)
  17. 10.1006/geno.1996.0319 / Genomics / A novel human CCAAT/enhancer binding protein gene, C/EBPε, is expressed in cells of lymphoid and myeloid lineages and is localized on chromosome 14q11.2 close to the T-cell receptor α/δ locus. by Antonson (1996)
  18. 10.1128/MCB.17.3.1375 / Mol Cell Biol / Cloning of the novel human myeloid-specific C/EBP transcription factor (C/EBPε). by Chumakov (1997)
  19. 10.1126/science.2202050 / Science / Evidence of changes in protease sensitivity and subunit exchange rate on DNA binding by C/EBP. by Shuman (1990)
  20. 10.1126/science.2683088 / Science / Scissors-grips model for DNA recognition by a family of leucine zipper proteins. by Vinson (1989)
  21. 10.1084/jem.149.4.969 / J Exp Med / Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentaition by dimethylsulfoxide. by Collins (1979)
  22. {'key': '2019111907480956200_B22', 'first-page': '3570', 'article-title': 'Combination of potent 20-epi-vitamin D3 analog (KH1060) and 9-cis-retinoic acid inhibits irreversibly clonal growth, decreases bcl-2 expression and induces apoptosis in HL-60 leukemic cells.', 'volume': '56', 'author': 'Elstner', 'year': '1996', 'journal-title': 'Cancer Res'} / Cancer Res / Combination of potent 20-epi-vitamin D3 analog (KH1060) and 9-cis-retinoic acid inhibits irreversibly clonal growth, decreases bcl-2 expression and induces apoptosis in HL-60 leukemic cells. by Elstner (1996)
  23. {'key': '2019111907480956200_B23'}
  24. {'key': '2019111907480956200_B24'}
  25. 10.1182/blood.V82.4.1317.1317 / Blood / Molecular analysis of myeloperoxidase deficiency shows heterogeneous patterns of the complete deficiency state manifested at the genomic, mRNA, and protein levels. by Selsted (1993)
  26. 10.1182/blood.V84.7.2122.2122 / Blood / Retinoic acid is required for and potentiates differentiation of acute promyelocytic leukemia cells by nonretinoid agents. by Chen (1994)
  27. 10.1182/blood.V77.5.1080.1080 / Blood / NB4, a maturation-inducible cell line with t(15; 17) marker isolated from a humanacute promyelocytic leukemia (M3). by Lanotte (1991)
  28. 10.1073/pnas.91.18.8428 / Proc Natl Acad Sci USA / Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line. by Ruchaud (1994)
  29. 10.1182/blood.V84.1.294.294 / Blood / NB4 cells show bilineage potential and an aberrant pattern of neutrophil secondary granule protein gene expression. by Khana-Gupta (1994)
  30. {'key': '2019111907480956200_B30', 'first-page': '1744', 'article-title': 'M-CSF and 1,25-dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbal-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells.', 'volume': '8', 'author': 'Bhatia', 'year': '1994', 'journal-title': 'Leukemia'} / Leukemia / M-CSF and 1,25-dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbal-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells. by Bhatia (1994)
  31. 10.1182/blood.V88.1.114.114 / Blood / Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells. by Matikainen (1996)
  32. {'key': '2019111907480956200_B32', 'first-page': '3924', 'article-title': 'Induction of differentiation of the human histiocytic lymphoma cell line U-937 by retinoic acid and cyclic adenosine 3′,5′-monophosphate-inducing agents.', 'volume': '42', 'author': 'Olsson', 'year': '1982', 'journal-title': 'Cancer Res'} / Cancer Res / Induction of differentiation of the human histiocytic lymphoma cell line U-937 by retinoic acid and cyclic adenosine 3′,5′-monophosphate-inducing agents. by Olsson (1982)
  33. {'key': '2019111907480956200_B33'}
  34. 10.1073/pnas.94.12.6462 / Proc Natl Acad Sci USA / CCAAT/enhancer binding proteinε is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. by Yamaka (1997)
  35. 10.1182/blood.V70.5.1233.bloodjournal7051233 / Blood / The HL-60 promyelocytic leukemia cell line: Proliferation, differentiation and cellular oncogene expression. by Collins (1987)
  36. 10.1093/carcin/17.8.1543 / Carcinogenesis / Relationship between the intracellular reactive oxygen species and the induction of oxidative DNA damage in human neutrophil-like cells. by Takeuchi (1996)
  37. 10.1038/347558a0 / Nature / The t(15; 17) translocation of acute promyelocytic leukemia fuses the retinoic acid receptor α gene to a novel transcribed locus. by de The (1990)
  38. 10.1126/science.2218500 / Science / Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. by Borrow (1990)
  39. 10.1016/0092-8674(91)90113-D / Cell / The PML-RARα fusion mRNA generated by the t(15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. by de The (1991)
  40. 10.1182/blood.V82.6.1858.1858 / Blood / PML protein expression in hematopoietic and acute promyelocytic leukemia cells. by Daniel (1993)
Dates
Type When
Created 5 years, 10 months ago (Oct. 12, 2019, 7:18 p.m.)
Deposited 5 years, 9 months ago (Nov. 19, 2019, 7:48 a.m.)
Indexed 4 months, 2 weeks ago (April 10, 2025, 7:13 a.m.)
Issued 27 years, 10 months ago (Oct. 15, 1997)
Published 27 years, 10 months ago (Oct. 15, 1997)
Published Print 27 years, 10 months ago (Oct. 15, 1997)
Funders 0

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@article{Chih_1997, title={Modulation of mRNA Expression of a Novel Human Myeloid-Selective CCAAT/Enhancer Binding Protein Gene (C/EBPε)}, volume={90}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v90.8.2987}, DOI={10.1182/blood.v90.8.2987}, number={8}, journal={Blood}, publisher={American Society of Hematology}, author={Chih, Doris Y. and Chumakov, Alexey M. and Park, Dorothy J. and Silla, Agnes G. and Koeffler, H. Phillip}, year={1997}, month=oct, pages={2987–2994} }