C/EBPε Is a Myeloid-specific Activator of Cytokine, Chemokine, and Macrophage-Colony-stimulating Factor Receptor Genes

Williams, Simon C.; Du, Yang; Schwartz, Richard C.; Weiler, Sarah R.; Ortiz, Mariaestela; Keller, Jonathan R.; Johnson, Peter F.

doi:10.1074/jbc.273.22.13493

Cited by 65 publications

(61 citation statements)

References 41 publications

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“…The rat C/EBP⑀ promoter contains potential C/EBP-binding sites at Ϫ157 and Ϫ454, and the human gene contains a near-perfect C/EBP consensus 324 bp upstream of the initiation site of the more highly used P␤ promoter. 43,52 Future experiments will determine whether C/EBP␣ or C/EBP␤ activates the C/EBP⑀ gene via these or other binding sites.…”

Section: Discussionmentioning

confidence: 99%

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CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

Wang

Friedman

2002

Blood

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Section: Discussionmentioning

confidence: 99%

“…The murine myeloperoxidase (MPO), lactoferrin (LF), lysozyme, PU.1, G-CSFR, C/EBP⑀, and ␤-actin cDNA probes have been described. 40,[42][43][44] Assessment of G-CSFR expression was performed as described. 44 In brief, human G-CSF was biotinylated by means of a kit (Pierce, Rockford, IL).…”

Section: Western Northern and Facs Analysesmentioning

confidence: 99%

CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

Wang

Friedman

2002

Blood

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“…6 MCP and MIP-1 alpha have been implicated as target genes of C/EBP⑀ in monocytes. 34 A reduced or absent expression of these myelosuppressive cytokines or chemokines by C/EBP⑀ −/− monocytes/macrophages could be an additional or alternative mechanism for the enhanced myelopoiesis in C/EBP⑀ −/− mice. Mature C/EBP⑀ −/− granulocytic cells rapidly underwent apoptosis when recruited to the peritoneal cavity.…”

Section: Figurementioning

confidence: 99%

C/EBPε −/− mice: increased rate of myeloid proliferation and apoptosis

et al. 2001

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CCAAT/enhancer binding protein epsilon (C/EBP⑀) is essential for terminal granulocytic differentiation. Its expression begins at the transition between the proliferative and non-proliferative compartments of myelopoiesis. We studied the effect of targeted disruption of the C/EBP⑀ gene on murine myeloid proliferation and apoptosis. Bone marrow cellularity of C/EBP⑀ −/− and wild-type mice was 95% and 65%, respectively. The C/EBP⑀ −/− mice had an expansion in the number of their CFU-GM/femur. The number of myeloid committed progenitor cells in the peripheral blood and the spleen of these mice was also increased. Bromodeoxyuridine (BrDU) pulse labeling studies demonstrated that the fraction of actively proliferating cells was two-fold higher in the bone marrow of C/EBP⑀ −/− mice. However, the number of myeloid colonies arising from purified Sca-1+/lin− early hematopoietic progenitor cells and from bone marrow mononuclear cells grown in different cytokine combinations was not significantly different between wild-type and knock-out mice. Also, long-term marrow growth, and CFU were not different between the wild-type and C/EBP⑀ −/− mice. The sensitivity to induction of apoptosis in the committed progenitor cell compartment after either withdrawal of growth factor or brief exposure to etoposide was normal. However, Gr-1 antigen-positive C/EBP⑀ −/− granulocytic cells showed an increased rate of apoptosis in comparison to their wild-type counterparts. In summary, the myeloid compartment appears to be expanded in mice lacking C/EBP⑀. However, this is not the consequence of an intrinsic myeloproliferation but due to an indirect, possibly cytokine-mediated stimulation of myelopoiesis in vivo. C/EBP⑀ may have a role in the inhibition of apoptosis in maturing granulocytic cells. Leukemia (2001) 15, 103-111.

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“…This block can be overcome by culturing in the presence of the multifunctional cytokine interleukin-3 (IL-3) and pharmacological doses of all-trans-retinoic acid (atRA) (17,22). Under these conditions, EML cells differentiate into promyelocytes over a period of 6 -7 days, and differentiation-specific genes are expressed in patterns similar to those seen in bona fide hematopoietic progenitors (17,24,25). Terminal granulocytic differentiation can be achieved by removing IL-3 after 3 days and replacing it with granulocyte/macrophage colony-stimulating factor (GM-CSF) (22,25).…”

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confidence: 99%

“…mAKRa mRNA levels were calculated after normalization to the level of glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA. The mAKRa probe was a DpnII fragment that was isolated in the RDA procedure (see below), and the GAPDH probe was a 200-bp fragment amplified by PCR using the following oligonucleotide primers: GAPDH 5Ј-AAGGTCGGAGTCAACGGATT, and GAPDH 3Ј-TTGATGA-CAAGCTTCCCGTT (24). The C/EBP⑀ probe was an 850-bp NcoI/HindIII fragment containing the entire murine cDNA (24).…”

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Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis

Du¹,

Tsai²,

Keller³

et al. 2000

Journal of Biological Chemistry

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The EML hematopoietic progenitor cell line is a model system for studying molecular events regulating myeloid commitment and terminal differentiation. We used representational difference analysis to identify genes that are expressed differentially during myeloid differentiation of EML cells. One gene (named mAKRa) encoded a novel member of the aldoketo reductase (AKR) superfamily of cytosolic NAD(P)(H)-dependent oxidoreductases. mAKRa mRNA was detected in murine hematopoietic tissues including bone marrow, spleen, and thymus. In myeloid cell lines, mAKRa was expressed at highest levels in cells representative of promyelocytes. mAKRa mRNA levels increased rapidly in response to interleukin-3 over the first 24 h of EML cell differentiation when the cells undergo lineage commitment and extensive proliferation. mAKRa mRNA levels decreased later in the differentiation process particularly when the EML cells were cultured with granulocyte/macrophage colony-stimulating factor and retinoic acid to induce terminal granulocytic maturation. mAKRa mRNA levels decreased during retinoic acidinduced terminal granulocytic differentiation of the MPRO promyelocyte cell line. AKRs act as molecular switches by catalyzing the interconversion or inactivation of bioactive molecules including steroids and prostaglandins. We propose that mAKRa may catalyze the production or catabolism of autocrine factors that promote the proliferation and/or lineage commitment of early myeloid progenitors.

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C/EBPε Is a Myeloid-specific Activator of Cytokine, Chemokine, and Macrophage-Colony-stimulating Factor Receptor Genes

Cited by 65 publications

References 41 publications

CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

C/EBPε −/− mice: increased rate of myeloid proliferation and apoptosis

Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis

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