CCAAT/enhancer binding protein ɛ is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing

Abstract

Hematopoietic stem cells have the ability to promote continuous self-renewal by controlled proliferation and expansive differentiation into all cells of hematopoietic lineages. Regulation of the molecular mechanisms that direct cellular proliferation and differentiation during hematopoiesis depends, partly, on the action of certain transcription factors (1-3).Several members of the basic region-leucine zipper (bZIP) class of transcription factors, including the CCAAT͞enhancer binding protein (C͞EBP) family have been implicated in the differentiation of hematopoietic cells (1-5). C͞EBP proteins have highly conserved bZIP C-terminal regions, but differ in their N-terminal regions (6, 7). A consensus site,

Increased expression of CCAAT/enhancer binding protein β correlates with prognosis in glioma patients

“…The expression of these proteins is influenced by a variety of external stimuli such as growth factors, hormones or cytokines (3,16). In addition, by using different start codons, the translation of C/EBPs results in two or more protein products which differ in their biological activities (3,12,17,18). As an additional level of regulation, posttranslational phosphorylation influences DNA binding and transactivation properties (3,19).…”

“…All of these distinct interactions result in the differential transcriptional activity of the C/EBP isoforms. At present, six members (C/EBP ·, -ß, -Á, -‰, -Â, and -˙) with different tissue-specific expression patterns have been characterized (3,(6)(7)(8)(9)(10)(11)(12)(13)(14). C/EBPs exert pleiotropic effects based on tissue-and stage-specific gene expression, alternative translation of various protein isoforms, interaction with other transcription factors, and variable DNA-binding specificities.…”

Eicosapentaenoic Acid Demethylates a Single CpG That Mediates Expression of Tumor Suppressor CCAAT/Enhancer-binding Protein δ in U937 Leukemia Cells

“…Members of the C/EBP family are structurally related, each consisting of an N-terminal transactivating region, a central basic DNA-binding domain, and a C-terminal leucine zipper motif for dimerization (20). During hematopoiesis, C/EBP␣, C/EBP␤, and C/EBP␦ are predominantly expressed in the granulocyte and monocyte lineages, whereas C/EBP⑀ is found in the middle to later stages of differentiation of granulocytes and T cells (21)(22)(23)(24)(25). The most compelling evidence for a crucial role of the C/EBPs in myeloid cell differentiation and maturation has come from studies on knock-out mice.…”

Regulation of granulopoiesis by transcription factors and cytokine signals

“…43,44 C/EBP⑀ is expressed in Tlineage cells and predominantly in late-stage granulocytes. 15,45,46 C/EBP⑀ null mice show defects in neutrophil function, suggesting that C/EBP⑀ controls the expression of a number of key genes. 16 This is consistent with a recent study showing that neutrophil-specific granule deficiency results from a loss of function in C/EBP⑀.…”

“…Furthermore, other studies have implicated several additional transcription factors in the control of granulopoiesis. For example, C/EBP⑀ is expressed predominantly in latestage granulocytic differentiation and contributes to the expression of a number of key genes, 15,16 family members are restricted in their expression, within hematopoiesis, to myeloid cells, [17][18][19] while the WT-1 gene is expressed in immature hematopoietic cells and in a subset of acute myeloid leukemias. 20,21 Finally, a number of more ubiquitous transcription factors are known to perform important roles in granulopoiesis in responses to external stimuli: for example, Stat proteins, Myc, and Mad in response to cytokines and the retinoic acid receptor (RAR) in response to retinoic acid.…”