Smad Proteins Bind a Conserved RNA Sequence to Promote MicroRNA Maturation by Drosha

Davis, Brandi N.; Hilyard, Aaron C.; Nguyen, Peter H.; Lagna, Giorgio; Hata, Akiko

doi:10.1016/j.molcel.2010.07.011

Cited by 353 publications

(353 citation statements)

References 28 publications

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“…30,31 The signal transducers of the transforming growth factor β/bone morphogenetic protein, the Smads, promote the expression of a subset of miRNAs, including miR-21 and miR-199a, by facilitating the cleavage reaction by Drosha. 16,32 In response to DNA damage, p53 interacts with the Drosha processing complex through its association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs, which enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145. 18 Tumor suppressor BRCA1 regulates the biogenesis of a group of miRNA biogenesis, including let-7a-1, miR-16-1, miR-145 and miR-34a, via direct association with the Drosha microprocessor complex and Smad3/p53/DHX9.…”

Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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Radioresistance is a major obstacle in successful clinical cancer radiotherapy, and the underlying mechanisms are not clear. Here we show that IKKα-mediated miR-196a biogenesis via interaction with Drosha regulates the sensitivity of nasopharyngeal carcinoma (NPC) cells to radiotherapy. Phosphorylation of IKKα at T23 site (p-IKKαT23) promotes the binding of IKKα to Drosha that accelerates the processing of miR-196a primary transcripts, leading to increased expressions of both precursor and mature miR-196a. Dephosphorylation of p-IKKαT23 downregulates miR-196a expression and promotes the resistance of NPC cells to radiation treatment. The miR-196a mimic suppresses while its inhibitor promotes the resistance of NPC to radiation treatment. Importantly, the expression of p-IKKαT23 is positively related to the expression of miR-196a in human NPC tissues, and expression of p-IKKαT23 and miR-196a is inversely correlated with NPC clinical radioresistance. Thus, our studies establish a novel mechanistic link between the inactivation of IKKαT23-Drosha-miR-196a pathway and NPC radioresistance, and de-inactivation of IKKαT23-Drosha-miR-196a pathway would be an efficient way to restore the sensitivity of radioresistant NPC to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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“…19,31 Some miRNAs are regulated by BMP4 through a posttranscriptional mechanism, involving Smad proteins that engage miRNAs and promote their maturation by Drosha. 35 miR-23a and 23b are among the miRs that are target of this mechanism, as they are induced in PASM cells on treatment with TGFβ or BMP4. This mechanism could be active in ESCs too, and, therefore, it could be responsible for the posttranscriptional accumulation of miR-23b.…”

Section: Discussionmentioning

confidence: 99%

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4. Cell Death and Differentiation (2015) 22, 1047-1057 doi:10.1038/cdd.2014; published online 5 December 2014ESCs represent a precious experimental model of the early stages of embryo development. They can be grown indefinitely in vitro and induced to differentiate, thus mimicking two events taking place in the blastocyst: (i) the differentiation of the cells of the inner cell mass into epiblast cells and (ii) the commitment of epiblast cells to neuroectodermal or mesendodermal precursors. 1,2 These differentiation events are regulated by extrinsic signals. BMP4, a member of the TGF-β superfamily of cytokines, has a crucial role in ESCs. Many results indicate that it is able, together with LIF, to maintain mouse ESCs in the pluripotent state. 3 This effect is mediated by the regulation of many direct targets of Smad1, 5 and 8, the transcription factors downstream of the BMP4 receptor. 4 BMP4 also contributes to govern early steps of differentiation. First, BMP4 acts by regulating ESC-epiblast transition and then by suppressing neural differentiation and promoting non-neural lineage formation. 2 Moreover, BMP4 promotes the differentiation towards mesendodermal lineages and also regulates, either positively or negatively, the further commitment of mesendodermal precursors into their different fates. [5][6][7][8] Gene expression in ESCs is regulated by a complex network of transcription factors. 9,10 In addition, numerous results indicate that miRNAs are crucial regulators of the gene expression programs that drive ESC differentiation. Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differenti...

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“…Proteins that can bind both DNA and RNA are ideal candidates for transcriptional and/or epigenetic regulators, in an RNAguiding manner. Like the multifunction protein EZH2, there are some well-studied DNA-binding proteins, such as DNA methylase [108], Smad [109], p53 [110,111], and others [112], that bind RNAs. Similarly, some RBPs can also bind DNA [113115].…”

Section: Studying Epigenetic Modification-associated Rnasmentioning

confidence: 99%

CLIP: viewing the RNA world from an RNA-protein interactome perspective

Zhang

Xie²,

Xu³

et al. 2015

Sci. China Life Sci.

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The pervasive transcription of the genome creates many types of non-coding RNAs (ncRNAs). However, we know very little regarding the functions and the regulatory mechanisms of these ncRNAs. Exploring the interactions of RNA and RNA binding proteins (RBPs) is vital because it can allow us to truly understand how these ncRNAs behave in vivo. High-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP or CLIP-seq) and its variants have been successfully used as systemic techniques to study RBP binding sites. In this review, we will explain the major differences between the CLIP techniques, summarize successful applications of these techniques, discuss limitations of CLIP, present some suggested solutions and project their promising future roles in studying the RNA world. CLIP, CLASH, RPBs, ncRNAs, functional RNomics Citation:Zhang

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Smad Proteins Bind a Conserved RNA Sequence to Promote MicroRNA Maturation by Drosha

Cited by 353 publications

References 28 publications

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

CLIP: viewing the RNA world from an RNA-protein interactome perspective

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