MicroRNA-130a–mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-β1 stimulation in granulocytic precursors

Abstract

Smad4 is important in the TGF-␤ pathway and required for transcriptional activation and inhibition of cell growth after TGF-␤1 stimulation. We demonstrate that miR-130a is differentially expressed during granulopoiesis and targets Smad4 mRNA. The transcript for Smad4 is present throughout neutrophil maturation, but Smad4 protein is undetectable in the most immature cells, where miR-130a is highly expressed. Two miR-130a binding sites were identified in the 3-untranslated region of the IntroductionMature neutrophils are generated in the bone marrow (BM) from myeloid precursor cells, the myeloblasts, which divide and mature along a tightly regulated path characterized by cessation of proliferation, nuclear condensation, and sequential acquisition of different types of granules, 1 collectively known as granulopoiesis. Granulopoiesis is controlled by intrinsic and extrinsic factors to ensure both a strict control of the stepwise maturation of the cells and to control the rate of production and release to meet the requirements for an adequate defense against microbial infections. 2 Under normal conditions, maturation of the neutrophil granulocyte precursors is accompanied by a progressive and differential expression of several transcription factors, 3 which regulate cell division 4,5 and formation of granules. 1 In case of an increased demand for neutrophils, the differentiation process can be adjusted by external stimuli such as G-CSF, 6 bacterial products, 7 or proinflammatory cytokines 8 that induce changes in the level and composition of the transcription factors that control cell proliferation and terminal differentiation.TGF-␤ is a potent cytokine that affects many biologic functions such as proliferation, differentiation, and apoptosis, depending on the developmental state and type of cell. 9 It has been shown that TGF-␤1 inhibits proliferation in quiescent HSCs. 10 Members of the TGF-␤ superfamily of growth factors, including TGF-␤s, bind to TGF-␤ receptor I (TGF␤RI) and TGF␤RII expressed on the cell surface. Binding of ligands to TGF␤RII induces formation of receptor complexes which phosphorylate and activate TGF␤RI. The active form of TGF␤RI then recruits and phosphorylates the receptor-activated Smads (R-Smad). Phosphorylated R-Smads assemble and form a hetero-oligomeric complex with a commonSmad (Co-Smad). This complex accumulates in the nucleus and binds to specific Smad-binding elements in the promoters of TGF-␤-responsive genes where it recruits coactivators and corepressors and thus exerts both a positive and a negative regulation of target gene expression. 11,12 Smad2 and Smad3 are R-Smads that transmit TGF-␤1/activin-induced signals, whereas Smad1, Smad5, and Smad8 are R-Smads that transmit bone morphogenetic proteininduced signals. Smad6 and Smad7 are inhibitory Smads that regulate TGF-␤1 signaling negatively by competitive binding to the TGF-␤ receptors or to the Smad4 is the only known Co-Smad in mammals and thus plays a central role in the TGF-␤-signaling pathway because all RSmads must form a...

miRNA-130a regulates C/EBP-ε expression during granulopoiesis

“…The functional importance of miRNAs has been demonstrated in granulopoiesis where miRNAs regulate expression of transcription factors and pathways important for correct neutrophil development. 12,13 A specific miRNA signature has been associated with some AMLs indicating that miRNAs contribute to the disease phenotype in these leukemias, thus underscoring the importance of correct expression of miRNAs during normal granulocytic development.…”

“…13,15 Using miRNA target-prediction software, we identified the transcription factor C/EBP-e as a putative target for miR-130a. The purpose of this study was to analyze the normal expression of miR-130a and C/EBP-e in human and murine granulocytic precursors, and to investigate whether miR-130a contributes to regulation of C/EBP-e protein levels during granulopoiesis.…”

A Novel Function of MicroRNA 130a-3p in Hepatic Insulin Sensitivity and Liver Steatosis

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“…A plazmaalkotó-részek soráról derült ki, hogy infl ammatio során jelentős koncentrációváltozást mutatnak. A mennyiségi meghatározás kissé önkényes, és az irányváltozás jelenthet megválaszolandó kérdéseket [11,12,13,14]. A valóságban alig van olyan plazmakomponens, amelynek mennyisége mozdulatlan maradna.…”

“…A specifi kus immunglobulinok kivétel nélkül GPszerkezetűek. Igen gazdag oligoszacharidokban az IgA (szekretoros) [13,14,15…”