Human C/EBP-ϵ activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation

Bedi, Richa; Du, Jian; Sharma, Arun K.; Gomes, Ignatius; Ackerman, Steven J.

doi:10.1182/blood-2008-02-139741

Cited by 68 publications

(77 citation statements)

References 50 publications

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“…Bedi et al previously demonstrated that enforced expression of the transcriptional activator isoforms C/EBPe 32/30 in hematopoietic progenitor cells stimulated eosinophil differentiation at the expense of granulocyte/ macrophage differentiation, whereas overexpression of the C/EBPe 27 or C/EBPe 14 isoforms inhibited eosinophil differentiation. 20 In agreement with these data, we observed disturbed neutrophil maturation accompanied by an increase in eosinophil precursors in some, but not all, donors, suggesting this is dependent on C/EBPe 32/30 expression levels. Intriguingly, compared with the lysine dead mutant, enforced expression of C/EBPe R121/198K rescued neutrophil differentiation, yet induced no increase in eosinophil precursors or aberrant neutrophil maturation, suggesting these lysines are selectively important for terminal neutrophil differentiation (supplemental Figure 7).…”

Section: Discussionsupporting

confidence: 90%

“…These functional differences, transcriptional activation by C/EBPe 32/30 , transcriptional repression by C/EBPe 27 , and dominant negative regulation by C/EBPe 14 , can, at least partly, be explained by analysis of the functional domains of human-C/EBPe. [20][21][22][23] In addition to using activation and repression domains to regulate transcriptional activity, the expression and function of transcription factors is regulated by posttranslational modifications. Concerning C/EBP transcription factors, several posttranslational modification sites have been characterized, primarily on C/EBPa and C/EBPb.…”

Section: Introductionmentioning

confidence: 99%

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Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Bartels

Govers

Fleskens

et al. 2015

Blood

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Bartels

Govers

Fleskens

et al. 2015

Blood

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“…Other examples are C/EBP«, whose different isoforms are endowed with the ability to specifically reprogram myeoid lineage commitment (Bedi et al, 2009;Halene et al, 2010) and Irf8, which extinguishes neutrophil production and promotes DC lineage commitment (Becker et al, 2012). These and other studies have clearly shown that hematopoietic cell fate is dependent on several key transcription factors, and .…”

Section: Discussionmentioning

confidence: 96%

The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation

et al. 2014

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The stilbene derivative (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine) amino]phenyl}acrylonitrile (DG172) was developed as a highly selective inhibitory peroxisome proliferator-activated receptor (PPAR)b/d ligand. Here, we describe a novel PPARb/d-independent, yet highly specific, effect of DG172 on the differentiation of bone marrow cells (BMCs). DG172 strongly augmented granulocytemacrophage-colony-stimulating factor (GM-CSF)-induced differentiation of primary BMCs from Ppard null mice into two specific populations, characterized as mature (CD11c Ly6B1 cells. In agreement with these findings, transcriptome analyses showed a strong DG172-mediated repression of genes encoding neutrophilic markers in both differentiating wild-type and Ppard null cells, while macrophage/DC marker genes were up-regulated. DG172 also inhibited the expression of transcription factors driving granulocytic differentiation (Cebpe, Gfi1, and Klf5), and increased the levels of transcription factors promoting macrophage/DC differentiation (Irf4, Irf8, Spib, and Spic). DG172 exerted these effects only at an early stage of BMC differentiation induced by GM-CSF, did not affect macrophage-colony-stimulating factortriggered differentiation to macrophages and had no detectable PPARb/d-independent effect on other cell types tested. Structurefunction analyses demonstrated that the 4-methylpiperazine moiety in DG172 is required for its effect on DC differentiation, but is dispensable for PPARb/d binding. Based on these data we developed a new compound, (Z)-2-(4-chlorophenyl)-3-[4-(4-methylpiperazine-1-yl)phenyl]acrylonitrile (DG228), which enhances DC differentiation in the absence of significant PPARb/d binding.

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“…[27][28][29] Interestingly, this type of regulation of various cellular processes was all dependent on proteinprotein interactions. Previous co-immunoprecipitation assays, 7 together with the co-localization of isoforms 1 and 2 proteins reflected by immunohistochemistry and subcellular immunofluorescence analyses, also support an inhibition by heteromeric interaction.…”

Section: Discussionmentioning

confidence: 99%

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

et al. 2009

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The UDP-glucuronosyltransferase UGT1A gene is a major biotransformation gene involved in the metabolism of a vast array of molecules. Recently, we uncovered a new series of alternative spliced isoforms referred to as isoforms 2 or UGT1As_i2 that use an alternative exon 5 (5b). The function of such mRNAs and the corresponding 45 kDa proteins still remains unclear. Although devoid of glucuronosyltransferase activity, UGT1As_i2 are widely co-expressed with the enzymatically active and classical UGT1A isoforms (UGT1As_i1). In this study, we observed abundant signal in human colon tissue samples, predominantly along intestinal crypts. In human cells, UGT1A_i2 proteins are expressed in similar subcellular compartments as UGT1As_i1. Cellular properties of i2-spliced forms were then studied using synthetic small-interfering RNA (siRNA) in two human colon cancer cell lines that show a significant amount of exon 5a-and exon 5b-containing mRNAs and that display enzymatic activities for UGT1As substrates. We observed that siRNA-mediated knockdown of endogenous i2 upregulates cellular glucuronidation activities by 120-170% (Po0.01) for all substrates tested. Functional data support a dominant-negative function for endogenous exon 5b-spliced forms of UGT1A, hence potentially affecting in vivo glucuronidation capacity. This new regulatory strategy may ensure an additional mean to modulate cellular response to endo/xeno stimulus.

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Human C/EBP-ϵ activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation

Cited by 68 publications

References 50 publications

Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

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