Small RNA-mediated regulation of iPS cell generation

Li, Zhonghan; Yang, Chyun-Yu; Nakashima, Katsuhiko; Rana, Tariq M.

doi:10.1038/emboj.2011.2

Cited by 289 publications

(295 citation statements)

References 57 publications

(86 reference statements)

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“…34 p21 has previously been reported to be a target of miR-17 and miR-20a in MLL leukemia stem cells and gastric epithelial cells, and more recently in iPS cells. [35][36][37] STAT3 has also been found to be a target of miR-17 and miR-20a in mouse ES cells and mouse myeloid-derived suppressor cells. 38,39 Here, we show that miR-17 and miR-20a can target the p21 and STAT3 3 0 UTR to inhibit the expression of p21 and STAT3 in human cells.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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Section: Discussionmentioning

confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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“…The mir106b cluster is embedded within the MCM7 gene, which is a direct RB/E2F target gene. 16,[26][27][28][29][30] The mir106b cluster targets the expression of several genes that are directly disease-relevant and that provide a mechanism for cross-talk from the canonical RB pathway to PTEN and p21…”

Section: Discussionmentioning

confidence: 99%

Regulation of miR106b cluster through the RB pathway

et al. 2012

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“…54 Disruption of global miRNA biogenesis by ablation of Drosha, Dicer, or Ago2 substantially reduces OSKM-induced iPSC colonies in mouse embryonic fibroblasts. 54 Introduction of several members of miR-290 cluster may enhance the efficiency of OSK-induced cell reprogramming, comparable with that achieved by OSKM, demonstrating that miR-290s may substitute c-Myc (Figure 3). In this context, it should be noted that the promoter region of the miR-290-295 cluster may be bound by c-MYC.…”

Section: Mirnas In Cellular Reprogrammingmentioning

confidence: 99%