HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis

Glorian, Valérie; Maillot, Gérard; Polès, Sophie; Iacovoni, Jason S.; Favre, Gilles; Vagner, Stéphan

doi:10.1038/cdd.2011.35

Cited by 83 publications

(64 citation statements)

References 37 publications

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“…S2B). In addition, we immunoprecipitated Argonaute 2 (AGO2), a core component of RNA-induced silencing complex (RISC), as previously described (25), and demonstrated the binding of miR-125a/b to endogenous TNFAIP3 (Fig. 1B and Fig.…”

Section: Resultsmentioning

confidence: 62%

MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 ( TNFAIP3, A20 )

Kim

Ramasamy

Bouamar

et al. 2012

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

290

232

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Constitutive activation of the NF-κB pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether micro-RNA dysfunction can contribute to these events remains unclear. Starting from an integrative screening strategy, we uncovered that the negative NF-κB regulator TNFAIP3 is a direct target of miR-125a and miR-125b, which are commonly gained and/or overexpressed in DLBCL. Ectopic expression of these microRNAs in multiple cell models enhanced K63-linked ubiquitination of proximal signaling complexes and elevated NF-κB activity, leading to aberrant expression of its transcriptional targets and the development of a proproliferative and antiapoptotic phenotype in malignant B cells. Concordantly, genetic inhibition of miR-125a/miR-125b blunted NF-κB signals, whereas rescue assays and genetic modulation of a TNFAIP3-null model defined the essential role of the TNFAIP3 targeting on miR-125a/ miR-125b-mediated lymphomagenesis. Importantly, miR-125a/mir125b effects on TNFAIP3 expression and NF-κB activity were confirmed in a well-characterized cohort of primary DLBCLs. Our data delineate a unique epigenetic model for aberrant activation of the NF-κB pathway in cancer and provide a coherent mechanism for the role of these miRNAs in immune cell activation and hematopoiesis. Further, as miR-125b is a direct NF-κB transcriptional target, our results suggest the presence of a positive self-regulatory loop whereby termination of TNFAIP3 function by miR-125 could strengthen and prolong NF-κB activity.

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Section: Resultsmentioning

confidence: 62%

MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 ( TNFAIP3, A20 )

Kim

Ramasamy

Bouamar

et al. 2012

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

290

232

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“…RhoB mRNA contains a HuR binding site in its 3= untranslated region (UTR) (28), and a constitutive HuRRhoB mRNA interaction has been found by RNA immunoprecipitation coupled with microarray analyses (RIP-chip) (37,38). To test the potential role of HuR in the enhanced stability of RhoB mRNA, we tested whether HuR inhibition affected CPT-induced RhoB mRNA.…”

Section: Resultsmentioning

confidence: 99%

RhoB Promotes γH2AX Dephosphorylation and DNA Double-Strand Break Repair

Mamouni

Cristini

Guirouilh‐Barbat

et al. 2014

Molecular and Cellular Biology

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c Unlike other Rho GTPases, RhoB is rapidly induced by DNA damage, and its expression level decreases during cancer progression. Because inefficient repair of DNA double-strand breaks (DSBs) can lead to cancer, we investigated whether camptothecin, an anticancer drug that produces DSBs, induces RhoB expression and examined its role in the camptothecin-induced DNA damage response. We show that in camptothecin-treated cells, DSBs induce RhoB expression by a mechanism that depends notably on Chk2 and its substrate HuR, which binds to RhoB mRNA and protects it against degradation. RhoB-deficient cells fail to dephosphorylate ␥H2AX following camptothecin removal and show reduced efficiency of DSB repair by homologous recombination. These cells also show decreased activity of protein phosphatase 2A (PP2A), a phosphatase for ␥H2AX and other DNA damage and repair proteins. Thus, we propose that DSBs activate a Chk2-HuR-RhoB pathway that promotes PP2A-mediated dephosphorylation of ␥H2AX and DSB repair. Finally, we show that RhoB-deficient cells accumulate endogenous ␥H2AX and chromosomal abnormalities, suggesting that RhoB loss increases DSB-mediated genomic instability and tumor progression.

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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: 94%

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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HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis

Cited by 83 publications

References 37 publications

MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 ( TNFAIP3, A20 )

MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 ( TNFAIP3, A20 )

RhoB Promotes γH2AX Dephosphorylation and DNA Double-Strand Break Repair

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

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