Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q15744 (C/EBP epsilon)
 82 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human C/EBP epsilon is a newly cloned CCAAT/enhancer-binding transcription factor. Initial studies indicated it may be an important regulator of human myelopoiesis. To elucidate the range of expression of C/EBP epsilon, we used reverse transcription-polymerase chain reaction (RT-PCR) analysis and examined its expression in 28 hematopoietic and 14 nonhematopoietic cell lines, 16 fresh myeloid leukemia samples, and normal human hematopoietic stem cells and their mature progeny. Prominent expression of C/EBP epsilon mRNA occurred in the late myeloblastic and promyelocytic cell lines (NB4, HL60, GFD8), the myelomonoblastic cell lines (U937 and THP-1), the early myeloblast cell lines (ML1, KCL22, MDS92), and the T-cell lymphoblastic leukemia cell lines CEM and HSB-2. For the acute promyelocytic leukemia cell line NB4, C/EBP epsilon was the only C/EBP family member that was easily detected by RT-PCR. No C/EBP epsilon mRNA was found in erythroid, megakaryocyte, basophil, B lymphoid, or nonhematopoietic cell lines. Most acute myeloid leukemia samples (11 of 12) from patients expressed C/EBP epsilon. Northern blot and RT-PCR analyses showed that C/EBP epsilon mRNA decreased when the HL60 and KG-1 myeloblast cell lines were induced to differentiate toward macrophages. Similarly, Western blot analysis showed that expression of C/EBP epsilon protein was either unchanged or decreased slightly as the promyelocytic cell line NB4 differentiated down the macrophage-like pathway after treatment with a potent vitamin D3 analog (KH1060). In contrast, C/EBP epsilon protein levels increased dramatically as NB4 cells were induced to differentiate down the granulocytic pathway after exposure to 9-cis retinoic acid. Furthermore, very early, normal hematopoietic stem cells (CD34+/CD38-), purified from humans had very weak expression of C/EBP epsilon mRNA, but levels increased as these cells differentiated towards granulocytes. Likewise, purified granulocytes appeared to express higher levels of C/EBP epsilon mRNA than purified macrophages. Addition of phosphothiolated antisense, but not sense oligonucleotides to C/EBP epsilon, decreased clonal growth of HL-60 and NB4 cells by about 50% compared with control cultures. Taken together, our results indicate that expression of C/EBP epsilon is restricted to hematopoietic tissues, especially myeloid cells as they differentiate towards granulocytes and inhibition of its expression in HL-60 and NB4 myeloblasts and promyelocytes decreased their proliferative capacity. Therefore, this transcriptional factor may play an important role in the process of normal myeloid development.
 ...
PMID:A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation. 932 25

The CCAAT enhancer binding protein alpha (C/EBP alpha) transcription factor plays a critical role in granulocytopoiesis. Mice with a disruption of the C/EBP alpha gene demonstrate an early block in granulocytic differentiation, and disruption of C/EBP alpha function is a common theme in many types of human acute myelogenous leukemia, which is characterized by a block in myeloid development. To characterize further the nature of this block, we derived cell lines from the fetal liver of C/EBP alpha-deficient animals. These lines resembled morphologically the immature myeloid blasts observed in C/EBP alpha(-/-) fetal livers and did not express messenger RNA encoding early myeloid genes such as myeloperoxidase. Similarly, granulocytic markers such as Mac-1 and Gr-1 were not expressed; nor were erythroid and lymphoid surface antigens. Introduction of an inducible C/EBP alpha gene into the line revealed that conditional expression of C/EBP alpha induced the C/EBP family members C/EBP beta and C/EBP epsilon and subsequent granulocyte differentiation. Similar results were obtained when C/EBP alpha(-/-) cells were stimulated with the cytokines interleukin-3 and granulocyte-macrophage colony-stimulating factor, but not with all-trans retinoic acid, supporting a model of at least 2 pathways leading to the differentiation of myeloid progenitors to granulocytes and implicating induction of other C/EBP family members in granulopoiesis.
 ...
PMID:Induction of granulocytic differentiation by 2 pathways. 1203 69

With the objective to correlate clonogenicity, gene expression and phenotype during differentiation, human bone marrow CD34(+) cells were cultured in vitro to stimulate erythroid or neutrophil development, and sorted into five subpopulations according to their surface expression of CD15/CD33 and blood group antigen A/CD117 respectively. Sorted cells were cultured in methylcellulose and analysed by real-time reverse transcription polymerase chain reaction for expression of neutrophil and erythroid marker genes. Surface expression of CD15 coincided with restriction to neutrophil/monocyte differentiation and A antigen with restriction to erythroid differentiation. GATA-2 mRNA was down-regulated during both neutrophil and erythroid maturation, whereas GATA-1, SCL, ABO, erythropoietin receptor, Kell, glycophorin A, beta-globin and alpha-haemoglobin stabilizing protein were up-regulated during erythroid differentiation and silenced during neutrophil differentiation. CCAAT/enhancer-binding protein (C/EBP)-alpha, PU.1, granulocyte colony-stimulating factor receptor, PR3, C/EBP-epsilon and lactoferrin were sequentially expressed during neutrophil differentiation but rapidly down-regulated during the early erythroid stages. Nuclear factor erythroid-derived 2 (NF-E2) and glycophorin C were expressed both during neutrophil and erythroid differentiation. Our data support the notion of early expression of several lineage-associated genes prior to actual lineage commitment, defined by surface expression of CD15 and A antigen as markers for definitive neutrophil/monocyte and erythroid differentiation respectively. Previous findings, primarily from cell lines and mouse models, have been extended to adult human haematopoiesis.
 ...
PMID:Clonogenicity, gene expression and phenotype during neutrophil versus erythroid differentiation of cytokine-stimulated CD34+ human marrow cells in vitro. 1552 24

CCAAT enhancer-binding protein-epsilon (C/EBP-epsilon) is required for the terminal differentiation of neutrophils and eosinophils. Human C/EBP-epsilon is expressed as 4 isoforms (32, 30, 27, and 14 kDa) through differential RNA splicing, and alternative promoters and translational start sites. The C/EBP-epsilon(32/30) isoforms are transcriptional activators, whereas C/EBP-epsilon(27) interacts with and represses GATA-1 transactivation of eosinophil promoters. C/EBP-epsilon(14) contains only DNA-binding and -dimerization domains and may function as a dominant-negative regulator. To define functional activities for these C/EBP-epsilon isoforms in myelopoiesis, human CD34(+) progenitors were transduced with internal ribosomal entry site-enhanced green fluorescent protein retroviral vectors encoding the 32/30, 27, and 14-kDa isoforms, purified by fluorescence-activated cell sorter, and analyzed in colony-forming assays and suspension cultures. Progenitors transduced with C/EBP-epsilon(32/30) default exclusively to eosinophil differentiation and gene expression, independent of interleukin-5, and regardless of inclusion of cytokines to induce other lineages. In contrast, the putative repressor C/EBP-epsilon(27) isoform strongly inhibits eosinophil differentiation and gene expression, including GATA-1, promoting granulocyte (neutrophil)-macrophage differen-tiation. The C/EBP-epsilon(14) repressor isoform strongly inhibits eosinophil development and gene expression, promoting erythroid differentiation, an effect enhanced by erythropoietin. Thus, C/EBP-epsilon isoforms can reprogram myeloid lineage commitment and differentiation consistent with their predicted activities based on activator and repressor domains and in vitro functional activities.
 ...
PMID:Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. 1883 58