Journal ArticleDOI
Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype
Daniel T. Starczynowski,Florian Kuchenbauer,Bob Argiropoulos,Sandy Sung,Ryan D. Morin,Andrew L Muranyi,Martin Hirst,Donna E. Hogge,Marco A. Marra,Richard A. Wells,Rena Buckstein,Wan L. Lam,R. Keith Humphries,Aly Karsan +13 more
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TLDR
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.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.read more
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Journal ArticleDOI
MicroRNA expression in maturing murine megakaryocytes.
Joanna B. Opalinska,Alexey Bersenev,Zhe Zhang,Alec A. Schmaier,John K. Choi,Yu Yao,Janine D'Souza,Wei Tong,Mitchell J. Weiss +8 more
TL;DR: The results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibitsmegakaryopoiesis cell-autonomously.
Journal ArticleDOI
Guarding the 'translation apparatus': defective ribosome biogenesis and the p53 signaling pathway.
TL;DR: It is now clear that disruption of ribosome biogenesis causes nucleolar stress that triggers a p53 signaling pathway, thus providing cells with a surveillance mechanism for monitoring ribosomal integrity.
Journal ArticleDOI
TRAF6 Upregulates Expression of HIF-1α and Promotes Tumor Angiogenesis
TL;DR: It is shown that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)-1α and promotes tumor angiogenesis and growth.
Journal ArticleDOI
Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside.
Varda Deutsch,Aaron Tomer +1 more
TL;DR: The regulation of megakaryocytopoiesis and platelet production in normal and disease states, and the innovative drugs and therapeutic modalities to stimulate or decrease thrombopoiedis are reviewed.
Journal ArticleDOI
miRNAs link metabolic reprogramming to oncogenesis
TL;DR: In this review, the regulatory role of miRNAs on enzymes, signaling pathways, and transcription factors involved in glucose and lipid metabolism are discussed and the therapeutic potential of metabolism-relatedmiRNAs in cancer is considered.
References
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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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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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TAK1 is a ubiquitin-dependent kinase of MKK and IKK
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MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells
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