miRNA-130a regulates C/EBP-ε expression during granulopoiesis

Larsen, Maria Torp; Häger, Mattias; Glenthøj, Andreas; Asmar, Fazila; Clemmensen, Stine Novrup; Mora-Jensen, Helena; Borregaard, Niels; Cowland, Jack B.

doi:10.1182/blood-2013-08-523233

Cited by 40 publications

(41 citation statements)

References 38 publications

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“…Transcription of miR-130a is governed by the proto-oncogene c-Myc [34,35], a wellcharacterized driver of cell proliferation through induction of cyclins and repression of p21Kip1 transcription [36,37]. Expression of c-Myc is high in MB/PMs and low in more mature cells as seen also for miR-130a further indicating a role for miR-130a as regulator of cell proliferation [25].…”

Section: Mirnas and Transcription Factorsmentioning

confidence: 94%

“…The CEBPE transcript, on the other hand, is present also in MB/PMs, and to avoid premature translation of C/EBP-ε downregulation by miR-130a is required. This is demonstrated by the untimely expression of C/EBP-ε in MB/PMs transfected with a Locked Nucleic Acid (LNA) oligo against miR-130a and by repression of C/EBP-ε and genes encoding secondary granule proteins, by forced expression of miR-130a [25]. During normal granulopoiesis the level of miR-130a is 8-10 times higher in MB/PMs than in more mature neutrophil precursors in accordance with a role as fine-tuner of C/EBP-ε expression in MB/PMs [13].…”

Section: Mirnas and Transcription Factorsmentioning

confidence: 95%

“…No miRNA affecting C/EBP-α expression in neutrophils has yet been identified, whereas C/EBP-ε, that like C/EBP-α is obligate for neutrophil development [24], has been shown to be repressed by miR-130a [25]. C/EBP-α is a key factor for commitment of CMPs and GMPs towards the granulocytic lineage as demonstrated by the selective and complete block in neutrophil differentiation in Cebpa knockout mice [26].…”

Section: Mirnas and Transcription Factorsmentioning

confidence: 96%

“…These mice also lack expression of secondary and tertiary granule proteins such as lactoferrin, cathelin B9, and MMP9 [27], a trait mimicked in humans with specific granule deficiency (SGD) due to an inactivating point mutation of the CEBPE gene [28]. In the course of normal granulopoiesis, C/EBP-ε protein is highly expressed in MC/MMs and almost absent in both more immature and more mature cells [16,25]. The CEBPE transcript, on the other hand, is present also in MB/PMs, and to avoid premature translation of C/EBP-ε downregulation by miR-130a is required.…”

Section: Mirnas and Transcription Factorsmentioning

confidence: 97%

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MicroRNA Regulation of Neutrophil Function

Cowland

2014

MicroRNAs and Other Non-Coding RNAs in Inflammation

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Neutrophil maturation in the bone marrow, granulopoiesis, is a tightly regulated process governed by a temporal and successive expression of transcription factors and appropriate stimulation by cytokines from the surrounding stromal tissue of the bone marrow. Observations published over the last decade have, however, made it increasingly clear that posttranscriptional fine-tuning of protein expression by microRNAs (miRNAs) also plays a very important role in this process. In this chapter the influence of miRNAs on normal neutrophil development and biology is reviewed. The majority of miRNAs alter their expression profile at the point in granulopoiesis where proliferation ceases and terminal differentiation commences indicating a major role of miRNAs in fine-tuning of cell cycle regulatory proteins and transcription factors governing this transition. Some miRNAs are induced by external stimuli of the mature neutrophil and act to fine-tune the innate immune action of the cell.

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Section: Mirnas and Transcription Factorsmentioning

confidence: 94%

Section: Mirnas and Transcription Factorsmentioning

confidence: 95%

Section: Mirnas and Transcription Factorsmentioning

confidence: 96%

Section: Mirnas and Transcription Factorsmentioning

confidence: 97%

See 2 more Smart Citations

MicroRNA Regulation of Neutrophil Function

Cowland

2014

MicroRNAs and Other Non-Coding RNAs in Inflammation

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“…miR-130a was observed to be downregulated in pancreatic cancer and CML (5,6). miR-130a is a c-myc-responsive gene, which has been identified to regulate CCAAT/enhancer-binding protein β, homeobox A5, runt-related transcription factor 3 and Wnt signaling (33)(34)(35). Previous studies have demonstrated that the expression of miR-130a is increased in non-small cell lung cancer (36), whereas in glioblastoma patients, increased levels of miR-130a are associated with long-term survival (37).…”

Section: Mir-15 Mir-15 Was Identified To Be Downregulated In Screensmentioning

confidence: 99%

Diverse microRNAs with convergent functions regulate tumorigenesis

2015

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Abstract. MicroRNAs (miRNAs) regulate several biological processes, including tumorigenesis. In order to comprehend the roles of miRNAs in cancer, various screens were performed to investigate the changes in the expression levels of miRNAs that occur in different types of cancer. The present review focuses on the results of five recent screens, whereby a number of overlapping miRNAs were identified to be downregulated or differentially regulated, whereas no miRNAs were observed to be frequently upregulated. Furthermore, the majority of the miRNAs that were common to >1 screen were involved in signaling networks, including wingless-related integration site, receptor tyrosine kinase and transforming growth factor-β, or in cell cycle checkpoint control. The present review will discuss the aforementioned miRNAs implicated in cell cycle checkpoint control and signaling networks. IntroductionMicroRNAs (miRNAs) are small non-coding RNAs of 21-25 nucleotides in length that control gene expression via post-transcriptional regulation (1). Contrasting with the maturation process of normal coding RNAs, the miRNA genes are initially transcribed by RNA polymerase II into a primary transcript in the nucleus, where the hairpin structure is processed into precursor miRNA by a microprocessing complex that includes Drosha and DiGeorge syndrome chromosomal (or critical) region 8 (DGCR8) (1). Subsequently, the ~70 nucleotide-long precursor miRNA is exported into the cytoplasm, where it undergoes secondary processing by Dicer, and one strand of the hairpin is then incorporated into a ribonucleoprotein complex known as miRNA-induced silencing complex (1). Once matured, a single miRNA may target miscellaneous messenger RNAs (mRNAs), and an individual mRNA may be regulated by various miRNAs (1). miRNAs have significant roles during stem cell maintenance and differentiation (2). In addition, they have frequently been used as markers for certain types of cancer cells, by comparing the measured levels of known miRNAs with those present in their wild-type counterparts (2,3). Screens investigating differential expression of miRNAs in various cancer cell populations have been previously performed. The present review will focus on the results of five screens conducted in the past recent years, which investigated prostate cancer (3), neuroblastoma (4), pancreatic cancer (5), chronic myeloid leukemia (CML) (6) and osteosarcoma cells (7). Specifically, Liu et al (3) used three prostate cancer metastatic cell lines, namely LAPC9, LAPC4 and Du145 [bone cluster of differentiation (CD)44 + /CD44 -subpopulation sorting based on LAPC9, LAPC4 and Du145 cell lines; side population (SP)/non-SP sorting based on LAPC9 cell line; and CD133 + /CD133 -subpopulation sorting based on LAPC4 cell line], and compared the expression levels of miscellaneous miRNAs (with vs. without markers) in these cells. Following testing for 324 DGCR8 miRNAs by reverse transcription-quantitative polymerase chain reaction, 137 miRNAs were identified to be expressed in the three ce...

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Stable miRNA overexpression in human CAP cells: Engineering alternative production systems for advanced manufacturing of biologics using miR‐136 and miR‐3074

Weis

Guth

Fischer

et al. 2018

Biotech & Bioengineering

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Chinese hamster ovary (CHO) cells still represent the major production host for therapeutic proteins. However, multiple limitations have been acknowledged leading to the search for alternative expression systems. CEVEC's amniocyte production (CAP) cells are human production cells demonstrated to enable efficient overexpression of recombinant proteins with human glycosylation pattern. However, CAP cells have not yet undergone any engineering approaches to optimize process parameters for a cheaper and more sustainable production of biopharmaceuticals. Thus, we assessed the possibility to enhance CAP cell production capacity via cell engineering using miRNA technology. Based on a previous high-content miRNA screen in CHO-SEAP cells, selected pro-productive miRNAs including, miR-99b-3p, 30a-5p, 329-3p, 483-3p, 370-3p, 219-1-3p, 3074-5p, 136-3p, 30e-5p, 1a-3p, and 484-5p, were shown to act pro-productive and product independent upon transient transfection in CAP and CHO antibody expressing cell lines. Stable expression of miRNAs established seven CAP cell pools with an overexpression of the pro-productive miRNA strand. Subsequent small-scale screening as well as upscaling batch experiments identified miR-136 and miR-3074 to significantly increase final mAb concentration in CAP-mAb cells. Transcriptomic changes analyzed by microarrays identified several lncRNAs as well as growth and apoptosis-related miRNAs to be differentially regulated in CAP-mAb-miR-136 and -miR-3074. This study presents the first engineering approach to optimize the alternative human expression system of CAP-cells.

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miRNA-130a regulates C/EBP-ε expression during granulopoiesis

Abstract: Key Points miRNA-130a is expressed in myeloblasts and promyelocytes and inhibits translation of CEBPE mRNA encoding transcription factor C/EBP-ε. Regulation of CEBPE mRNA by miRNA-130a is required for timed expression of secondary granule proteins and cell cycle exit.

Cited by 40 publications

References 38 publications

MicroRNA Regulation of Neutrophil Function

MicroRNA Regulation of Neutrophil Function

Diverse microRNAs with convergent functions regulate tumorigenesis

Stable miRNA overexpression in human CAP cells: Engineering alternative production systems for advanced manufacturing of biologics using miR‐136 and miR‐3074

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