Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia

Pulikkan, John Anto; Dengler, Viola; Peramangalam, Philomina Sona; Zada, Abdul Ali Peer; Müller‐Tidow, Carsten; Bohlander, Stefan K.; Tenen, Daniel G.; Behre, Gerhard

doi:10.1182/blood-2009-08-240101

Cited by 261 publications

(246 citation statements)

References 39 publications

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“…MiR-223 is deregulated in acute myeloid leukemia (14,15). We find that miR-223 is also expressed in the nervous system and we demonstrate that miR-223 controls the expression and function of GluR2 and NR2B subunits of the glutamate receptor.…”

mentioning

confidence: 64%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

183

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Stroke is a major cause of mortality and morbidity worldwide. Extracellular glutamate accumulation leading to overstimulation of the ionotropic glutamate receptors mediates neuronal injury in stroke and in neurodegenerative disorders. Here we show that miR-223 controls the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowers the levels of GluR2 and NR2B by targeting 3′-UTR target sites (TSs) in GluR2 and NR2B, inhibits NMDA-induced calcium influx in hippocampal neurons, and protects the brain from neuronal cell death following transient global ischemia and excitotoxic injury. MiR-223 deficiency results in higher levels of NR2B and GluR2, enhanced NMDA-induced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 leads to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity. These data identify miR-223 as a major regulator of the expression of GluR2 and NR2B, and suggest a therapeutic role for miR-223 in stroke and other excitotoxic neuronal disorders.

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mentioning

confidence: 64%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

183

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“…Most of these TFs are also present in transcriptional regulatory miR-223 circuitries necessary for the correct maturation of HSC/HPC. 25,[41][42][43][44] Therefore, in hematopoietic cells, miR-223 activity and TF networks appear extensively dynamic, thus calling for a tight regulation of miR-223 levels during developmental transitions and lineage fate decisions.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional fine-tuning of microRNA-223 levels directs lineage choice of human hematopoietic progenitors

et al. 2013

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MicroRNAs (miRNAs) regulate cell proliferation, differentiation and death during development and postnatal life. The expression level of mature miRNAs results from complex molecular mechanisms, including the transcriptional regulation of their genes. MiR-223 is a hematopoietic-specific miRNA participating in regulatory signaling networks involving lineage-specific transcription factors (TFs). However, the transcriptional mechanisms governing its expression levels and its functional role in lineage fate decision of human hematopoietic progenitors (HPCs) have not yet been clarified. We found that in CD34þ HPCs undergoing unilineage differentiation/maturation, miR-223 is upregulated more than 10-fold during granulopoiesis, 3-fold during monocytopoiesis and maintained at low levels during erythropoiesis. Chromatin immunoprecipitation and promoter luciferase assays showed that the lineage-specific expression level of mature miR-223 is controlled by the coordinated binding of TFs to their DNA-responsive elements located in 'distal' and 'proximal' regulatory regions of the miR-223 gene, differentially regulating the transcription of two primary transcripts (pri-miRs). All this drives myeloid progenitor maturation into specific lineages. Accordingly, modulation of miR-223 activity in CD34þ HPCs and myeloid cell lines significantly affects their differentiation/ maturation into erythroid, granulocytic and monocytic/macrophagic lineages. MiR-223 overexpression increases granulopoiesis and impairs erythroid and monocytic/macrophagic differentiation. Its knockdown, meanwhile, impairs granulopoiesis and facilitates erythropoiesis and monocytic/macrophagic differentiation. Overall, our data reveal that transcriptional pathways acting on the differential regulation of two pri-miR transcripts results in the fine-tuning of a single mature miRNA expression level, which dictates the lineage fate decision of hematopoietic myeloid progenitors.

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“…The rest of the members of the miR-17-92 and miR-106b/93 clusters also interact with the E2F family members and form autoregulatory feedback loops [17,25] . In addition to the miR-17-92 family members, E2F1 also binds to the promoter of miR-223 and represses its transcription, and E2F1 is also targeted by miR-223 [94] .…”

Section: Myc and E2f Familymentioning

confidence: 99%

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

Liang

2011

Acta Pharmacol Sin

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The cell cycle, which is precisely controlled by a number of regulators, including cyclins and cyclin-dependent kinases (CDKs), is crucial for the life cycle of mammals. Cell cycle dysregulation is implicated in many diseases, including cancer. Recently, compelling evidence has been found that microRNAs play important roles in the regulation of cell cycle progression by modulating the expression of cyclins, CDKs and other cell cycle regulators. Herein, the recent findings on the regulation of the cell cycle by microRNAs are summarized, and the potential implications of miRNAs in anti-cancer therapies are discussed.

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Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia

Cited by 261 publications

References 39 publications

MicroRNA-223 is neuroprotective by targeting glutamate receptors

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Transcriptional fine-tuning of microRNA-223 levels directs lineage choice of human hematopoietic progenitors

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

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