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

Starczynowski, Daniel T.; Kuchenbauer, Florian; Argiropoulos, Bob; Sung, Sandy; Morin, Ryan D.; Muranyi, Andrew; Hirst, Martin; Hogge, Donna E.; Marra, Marco A.; Wells, Richard A.; Buckstein, Rena; Lam, Wan L.; Humphries, R. Keith; Karsan, Aly

doi:10.1038/nm.2054

Cited by 589 publications

(624 citation statements)

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“…70 Other key TLR signaling pathway components have also been demonstrated as miRNA targets. MyD88 adaptor-like protein, which functions as a bridge for the TLR2 and TLR4-mediated MyD88-dependent pathway, has emerged as a miR-145 target, 80 although the miR-145 expression profile following TLR agonist stimulation remains undetermined. Bruton's tyrosine kinase is a critical tyrosine kinase in TLR4, TLR7 and TLR9 signaling for activating NF-kB.…”

Section: Mirnas In Regulation Of Tlr and Rig-i Pathways Yk LI And Xy mentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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Section: Mirnas In Regulation Of Tlr and Rig-i Pathways Yk LI And Xy mentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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“…In conditional Dicer knockout mice which provide a model to determine miRNA function, miRNAs have been shown to be involved in various physiological processes, including development (Murchison et al, 2007), immunity (Belver et al, 2010), differentiation and homeostasis (Zhou et al, 2008). Moreover, recent studies have provided compelling evidence that deregulation of miRNAs has resulted in human diseases, such as autoimmune diseases and cancer (Starczynowski et al, 2010;Kasinski and Slack, 2011;Luo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

MiR-122 in hepatic function and liver diseases

et al. 2012

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“…33 For example, haploinsufficiency for miR-145 and miR-146a may contribute to thrombocytosis, and haploinsufficiency for EGR1 may contribute to the clonal advantage of the del(5q) clone. [36][37][38][39] Nevertheless, in vitro and in vivo studies indicate that the erythroid defect, the aspect of the 5qϪ syndrome phenotype most analogous to DBA, is caused by RPS14 haploinsufficiency. 3,35 Schwachman-Diamond syndrome SDS was first reported in 1964 by Schwachman et al in a group of 5 children being followed in a cystic fibrosis clinic at Harvard University.…”

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Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

679

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. 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. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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

Cited by 589 publications

References 45 publications

MicroRNAs in the regulation of TLR and RIG-I pathways

MicroRNAs in the regulation of TLR and RIG-I pathways

MiR-122 in hepatic function and liver diseases

Ribosomopathies: human disorders of ribosome dysfunction

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