Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3′UTR

Sun, Guihua; Li, Haitang; Rossi, John J.

doi:10.1093/nar/gkp870

Cited by 66 publications

(60 citation statements)

References 66 publications

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“…29 Although eNOS levels were decreased in pre-miR-223-overexpressing cells, there was no identifiable miR-223 seeding sequence in the eNOS 3′UTR, and it seems that miR-223, like miR-221 and miR-222, 29 has only an indirect effect on eNOS expression. The 3′UTR of RhoB was reported previously to be targeted by miR-223 in different cell lines, 21 and the protein has been implicated in angiogenesis. [22][23][24] Therefore, we concentrated on determining a link between miR-223 and β1 integrin expression.…”

Section: Discussionmentioning

confidence: 98%

“…However, no obvious seeding sequence for miR-223 could be detected within the eNOS 3′UTR, indicating that eNOS is likely to be an indirect rather than a direct target. Given that RhoB has already been identified as a miR-223 target 21 and has been implicated in angiogenesis, [22][23][24] we concentrated on β1 integrin.…”

Section: Identification Of Mir-223 Target Proteins In Endothelial Cellsmentioning

confidence: 99%

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MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

Shi

Fißlthaler

Zippel

et al. 2013

Circulation Research

120

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Rationale: Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype. Objective: To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors. Methods and Results: Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223 −/y animals were enhanced. MiR-223 overexpression had no effect on the growth factor–induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced phosphorylation of their receptors and activation of Akt. β1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of β1 integrin into miR-223–ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis. Conclusions: These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting β1 integrin.

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Section: Discussionmentioning

confidence: 98%

Section: Identification Of Mir-223 Target Proteins In Endothelial Cellsmentioning

confidence: 99%

MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

Shi

Fißlthaler

Zippel

et al. 2013

Circulation Research

120

View full text Add to dashboard Cite

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“…Though miR-132 and miR-212 share the same seed sequence, the rest of their nucleotide sequences differ from one another. These non-seed regions play an important role in directing mRNA targeting, and therefore potentially have a dramatic effect on the regulatory capacity of each miRNA (Breving and Esquela-Kerscher 2010;Sun et al 2010). Furthermore, while their transcriptional expression may be quite similar, miR-132 and miR-212 may undergo substantially different posttranscriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

et al. 2016

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miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in a complex, nonredundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR-132/-212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders.

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“…Previous studies demonstrated that miRNA-mediated regulation might require the presence of an ARE sequence [42][43][44]. As the miR-101 and miR-600 binding sites overlap with the ARE-6074 motif and the miR-384 binding site overlaps with the ARE-5698 motif ( fig.…”

Section: Transcription Factors Involved In the Regulation Of Cftr Temmentioning

confidence: 95%

Transcription factors and miRNAs that regulate fetal to adultCFTRexpression change are new targets for cystic fibrosis

Viart¹,

Bergougnoux²,

Bonini³

et al. 2014

Eur Respir J

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The CFTR gene displays a tightly regulated tissue-specific and temporal expression. Mutations in this gene cause cystic fibrosis (CF). In this study we wanted to identify trans-regulatory elements responsible for CFTR differential expression in fetal and adult lung, and to determine the importance of inhibitory motifs in the CFTR-3′UTR with the aim of developing new tools for the correction of disease-causing mutations within CFTR.We show that lung development-specific transcription factors (FOXA, C/EBP) and microRNAs (miR-101, miR-145, miR-384) regulate the switch from strong fetal to very low CFTR expression after birth. By using miRNome profiling and gene reporter assays, we found that miR-101 and miR-145 are specifically upregulated in adult lung and that miR-101 directly acts on its cognate site in the CFTR-3′UTR in combination with an overlapping AU-rich element. We then designed miRNA-binding blocker oligonucleotides (MBBOs) to prevent binding of several miRNAs to the CFTR-3′UTR and tested them in primary human nasal epithelial cells from healthy individuals and CF patients carrying the p.Phe508del CFTR mutation. These MBBOs rescued CFTR channel activity by increasing CFTR mRNA and protein levels.Our data offer new understanding of the control of the CFTR gene regulation and new putative correctors for cystic fibrosis. @ERSpublications Transcription factors/miRNAs that regulate fetal to adult CFTR expression change are new targets for CF treatment

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Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3′UTR

Cited by 66 publications

References 66 publications

MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

Transcription factors and miRNAs that regulate fetal to adultCFTRexpression change are new targets for cystic fibrosis

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