Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype

doi:10.1038/NM.2054

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Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype

Journal Article•DOI•

Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype

Daniel T. Starczynowski¹, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan D. Morin, Andrew L Muranyi, Martin Hirst, Donna E. Hogge, Marco A. Marra, Richard A. Wells², Rena Buckstein², Wan L. Lam¹, R. Keith Humphries¹, Aly Karsan¹ - Show less +10 more•Institutions (2)

University of British Columbia¹, Sunnybrook Research Institute²

01 Jan 2010-Nature Medicine (Nature Research)-Vol. 16, Iss: 1, pp 49-58

TL;DR: Deletes chromosome 5q and identifies Toll–interleukin-1 receptor domain–containing adaptor protein (TIRAP) and tumor necrosis factor receptor–associated factor-6 (TRAF6) as respective targets of these miRNAs.

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Abstract: 5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome.

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Journal Article•DOI•

Non-coding RNAs in human disease

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Manel Esteller

18 Nov 2011-Nature Reviews Genetics

TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.

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Abstract: The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.

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4,016 citations

Cites background from "Identification of miR-145 and miR-1..."

...In addition, specific miRNA defects have been shown to underlie particular diseases; for example, miR-145 and miR-146a deletions are involved in the 5q syndrome phenotyp...
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Journal Article•DOI•

MicroRNAs: the fine-tuners of Toll-like receptor signalling

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Luke A. J. O'Neill¹, Frederick J. Sheedy², Claire E. McCoy³•Institutions (3)

Trinity College, Dublin¹, New York University², Monash Institute of Medical Research³

01 Mar 2011-Nature Reviews Immunology

TL;DR: MicroRNAs have emerged as important controllers of TLR signalling and are proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammation.

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Abstract: Toll-like receptors (TLRs) are central to the induction of pro-inflammatory responses, but their signalling pathways must be tightly regulated. As discussed in this article, an emerging level of fine-tuning is mediated by microRNAs, several of which are induced by TLR signalling. Toll-like receptor (TLR) signalling must be tightly regulated to avoid excessive inflammation and to allow for tissue repair and the return to homeostasis after infection and tissue injury. MicroRNAs (miRNAs) have emerged as important controllers of TLR signalling. Several miRNAs are induced by TLR activation in innate immune cells and these and other miRNAs target the 3′ untranslated regions of mRNAs encoding components of the TLR signalling system. miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases.

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820 citations

Cites background from "Identification of miR-145 and miR-1..."

...Another Toll/IL-1R domain-containing adaptor protein, MYD88 adaptor-like protein (MAL; also known as TIRAP), which functions as a bridging adaptor for TLR2- and TLR4-mediated MYD88-dependent signalling, has emerged as a target of miR-145 (Ref...
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Journal Article•DOI•

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

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Mark Boldin¹, Konstantin Taganov², Konstantin Taganov¹, Dinesh S. Rao³, Dinesh S. Rao¹, Lili Yang¹, Jimmy L. Zhao¹, Manorama Kalwani¹, Yvette Garcia-Flores¹, Mui Luong¹, Asli Devrekanli¹, Jessica Xu², Guizhen Sun², Jia Tay², Peter S. Linsley², David Baltimore¹ - Show less +12 more•Institutions (3)

California Institute of Technology¹, Regulus Therapeutics², University of California, Los Angeles³

06 Jun 2011-Journal of Experimental Medicine

TL;DR: Mice lacking miR-146a exhibit exaggerated inflammatory responses, autoimmunity, and increased rate of tumorigenesis.

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Abstract: Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

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805 citations

Cites background from "Identification of miR-145 and miR-1..."

...Moreover, chimeric mice overexpressing TRAF6 in the hematopoietic compartment were shown to develop either BM failure or AML starting at 5 mo after BM transplantation (Starczynowski et al., 2010)....
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...S5 C), which are abnormalities frequently associated with BM failure, myelodysplastic syndrome (MDS), and myeloproliferative conditions....
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...Recently, abrogation of miR-146a expression with consequent up-regulation of TRAF6 expression was strongly implicated in the pathogenesis of MDS (Starczynowski et al., 2010)....
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...Mark P. Boldin: mboldin@coh.org OR David Baltimore: baltimo@caltech.edu Abbreviations used: AML, acute myeloid leukemia; BMDM, BM-derived macrophage; MDS, myelodysplastic syndrome; miRNA, microRNA; mRNA, messenger RNA; qRT-PCR, quantitative RT-PCR; snRNA, small nuclear RNA; TLR, Tolllike receptor; UTR, untranslated region....
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...It is worth noting that the loss of human chromosome 5 or deletion of the 5q region, which harbors the miR-146a gene, is associated with MDS and AML (Thirman and Larson, 1996)....
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Journal Article•DOI•

microRNA Regulation of Inflammatory Responses

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Ryan M. O'Connell¹, Dinesh S. Rao², Dinesh S. Rao³, David Baltimore²•Institutions (3)

University of Utah¹, California Institute of Technology², University of California, Los Angeles³

26 Mar 2012-Annual Review of Immunology

TL;DR: Recent advances in the understanding of miRNAs and their connection to inflammatory responses are discussed, and the link between perturbations in miRNA levels and the onset of human inflammatory diseases is considered.

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Abstract: The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.

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802 citations

Cites methods from "Identification of miR-145 and miR-1..."

...In contrast, repression of the miR-146a targets IRAK1 and TRAF6, both signaling proteins in the TLR/IL-1R pathways, reduces the magnitude of this reaction (39)....
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...A similar phenotype was independently observed when miR-146a was repressed using a sponge strategy, and in that case the phenotype seemed largely dependent on a target of miR-146a, TRAF6 (96)....
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...MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2....
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...It will be of interest to delineate how precisely miR-146a activity regulates the expression levels of TRAF6 and whether different levels of TRAF6 can lead to distinct differentiation patterns during inflammatory hematopoiesis....
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...However, TRAF6 and IRAK1 proteins already synthesized will continue to transduce signals, producing a built-in delay to the action of miR-146a that would be predicted to cause a gradual downregulation of the inflammatory signaling cascades in innate immune cells....
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Journal Article•DOI•

Ribosomopathies: human disorders of ribosome dysfunction.

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Anupama Narla¹, Benjamin L. Ebert¹, Benjamin L. Ebert²•Institutions (2)

Harvard University¹, Brigham and Women's Hospital²

22 Apr 2010-Blood

TL;DR: The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies.

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703 citations

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References

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Journal Article•DOI•

MicroRNAs: Genomics, Biogenesis, Mechanism, and Function

[...]

David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

23 Jan 2004-Cell

TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

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32,946 citations

Journal Article•DOI•

Prediction of Mammalian MicroRNA Targets

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Benjamin P. Lewis¹, I-hung Shih¹, Matthew W. Jones-Rhoades¹, David P. Bartel¹, Christopher B. Burge¹ - Show less +1 more•Institutions (1)

Massachusetts Institute of Technology¹

26 Dec 2003-Cell

TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.

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5,246 citations

Additional excerpts

...miR-145 and miR-146a target TIRAP and TRAF6, respectively According to published online algorithm...
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Journal Article•DOI•

NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

[...]

Konstantin Taganov¹, Mark Boldin, Kuang Jung Chang, David Baltimore•Institutions (1)

California Institute of Technology¹

15 Aug 2006-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: A role is proposed for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor- associated factor 6 protein levels.

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Abstract: Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-κB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3′ UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.

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3,947 citations

"Identification of miR-145 and miR-1..." refers methods in this paper

...To test whether miR-145 and miR-146a directly target the 3′ UTRs of TIRAP and TRAF6, respectively, we performed luciferase assays using 3′ UTR sequence fragments containing the predicted targets of each of the two miRNAs inserted separately downstream of a luciferase reporter, as previously describe...
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Journal Article•DOI•

TAK1 is a ubiquitin-dependent kinase of MKK and IKK

[...]

Chen Wang¹, Li Deng², Mei Hong², Giridhar R. Akkaraju², Jun-ichiro Inoue³, Zhijian J. Chen¹ - Show less +2 more•Institutions (3)

University of Texas Southwestern Medical Center¹, University of Texas at Dallas², Keio University³

19 Jul 2001-Nature

TL;DR: The purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism, indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

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Abstract: TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

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2,075 citations

"Identification of miR-145 and miR-1..." refers methods in this paper

..., we transfected TIRAP into HEK293 cells, immunoprecipitated TRAF6 and directly showed TRAF6 activation by TIRAP, as indicated by increased polyubiquitination of TRAF6 (ref...
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Journal Article•DOI•

MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells

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Margaret S. Ebert¹, Joel R. Neilson¹, Phillip A. Sharp¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Sep 2007-Nature Methods

TL;DR: These competitive inhibitors are transcripts expressed from strong promoters, containing multiple, tandem binding sites to a microRNA of interest that specifically inhibit microRNAs with a complementary heptameric seed, such that a single sponge can be used to block an entire microRNA seed family.

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Abstract: MicroRNAs are predicted to regulate thousands of mammalian genes, but relatively few targets have been experimentally validated and few microRNA loss-of-function phenotypes have been assigned. As an alternative to chemically modified antisense oligonucleotides, we developed microRNA inhibitors that can be expressed in cells, as RNAs produced from transgenes. Termed 'microRNA sponges', these competitive inhibitors are transcripts expressed from strong promoters, containing multiple, tandem binding sites to a microRNA of interest. When vectors encoding these sponges are transiently transfected into cultured cells, sponges derepress microRNA targets at least as strongly as chemically modified antisense oligonucleotides. They specifically inhibit microRNAs with a complementary heptameric seed, such that a single sponge can be used to block an entire microRNA seed family. RNA polymerase II promoter (Pol II)-driven sponges contain a fluorescence reporter gene for identification and sorting of sponge-treated cells. We envision the use of stably expressed sponges in animal models of disease and development.

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2,054 citations