Kato M, Putta S, Wang M et al.TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol 11:881-889

Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Nature Cell Biology (Impact Factor: 19.68). 07/2009; 11(7):881-9. DOI: 10.1038/ncb1897
Source: PubMed


Akt kinase is activated by transforming growth factor-beta1 (TGF-beta) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells. However, the mechanisms of Akt activation by TGF-beta are not fully understood. Here we show that TGF-beta activates Akt in glomerular mesangial cells by inducing the microRNAs (miRNAs) miR-216a and miR-217, both of which target PTEN (phosphatase and tensin homologue), an inhibitor of Akt activation. These miRNAs are located within the second intron of a non-coding RNA (RP23-298H6.1-001). The RP23 promoter was activated by TGF-beta and miR-192 through E-box-regulated mechanisms, as shown previously. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-beta. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-beta. Due to the diversity of PTEN function, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.

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Available from: Mitsuo Kato
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    • "TGF-β regulates its miRNA targets mainly through Smad signaling pathway. For example, TGF-β induces both miR-216a and miR-217inglomerularmesangialcellsviaSmadbindingelements (SBEs) in the miR-216 promoter[10]. TGF-β increases miR-143 and miR-145 through activation of myocardin and myocardinrelated transcription factors (MRTFs) that associates with the pro- moters[31], suggesting that TGF-β/Smads can also indirectly modulate miRNA levels through other transcription factors. In addition, TGF-β/Smad signaling also regulates miRNA by nontranscriptionalmechanisms .TGF-βup-regulatesmiR-21through Smad binding to CAGA sequences in the pre-miR-21 thereby promoting miR-21 maturation[32]. "
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    ABSTRACT: The microRNA-30 family plays important roles in maintaining kidney homeostasis. Patients with focal segmental glomerulosclerosis (FSGS) have reduced miR-30 levels in glomerulus. TGF-β represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-β represses miR-30d in vitro. The human miR-30d promoter contains multiple copies of Smad binding element-like sequences. A fragment of 150 base pairs close to the transcription start site was negatively regulated by TGF-β to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-β specifically enhanced HDAC3 expression. Knockdown of HDAC3 by shRNA or a selective inhibitor RGFP966 significantly relieved the repression of miR-30d mRNA and the promoter transcription. TGF-β promoted HDAC3 association with Smad2/3 and NCoR and caused their accumulation at the putative Smad binding site on the miR-30d promoter, which was prohibited by TSA or RGFP966. Furthermore, TSA or RGFP966 treatment reversed TGF-β-induced up-regulation of miR-30d targets Notch1 and p53 and alleviated the podocyte cytoskeleton damage and apoptosis. Taken together, these findings pinpoint that TGF-β represses miR-30d through a Smad2/3-HDAC3-NCoR repression complex and provide novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies. Key message MiR-30d promoter is negatively regulated by TGF-β. TGF-β down-regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-β. HDAC3 acts as a critical player in TGF-β-induced miR-30d repression and podocyte injuries.
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    • "The pre-miRNA is exported into the cytoplasm where it is further cleaved by Dicer-TRBP complex to release the mature miRNA [Yates et al., 2013]. Most of miRNAs are located to chromosome 14q32 [Seitz et al., 2004] that is enriched with SMAD binding sites and may be coordinately regulated by TGF-b1 suggesting that this pluripotent growth factor exerts global effects on cellular phenotypes [Milosevic et al., 2012; Kato et al., 2009]. "
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    ABSTRACT: Preclinical Research Idiopathic Pulmonary Fibrosis (IPF) is the most severe fibrotic lung disease and characterized by the accumulation of (myo)fibroblasts and collagen within the alveolar wall resulting in obliteration of the gas-exchange surface. Although the detailed pathogenesis is not understood, recent studies have found that several microRNAs (miRNAs) are associated with the progression of lung diseases including IPF. IPF is a fibrotic disease and, most frequently found in an aged population. In this review, the functional roles of miRNAs that are deregulated in IPF progression are discussed together with how aging affects the miRNA signature, altering the fibroblast phenotype and promoting lung fibrosis. Finally, the possibility of targeting miRNAs as a therapeutic approach for the treatment of IPF is discussed. Drug Dev Res, 2015. © 2015 Wiley Periodicals, Inc. © 2015 The Authors Drug Development Research Published by Wiley Periodicals, Inc.
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    • "Results in this study support the conclusion that miR-217 targets the KRAS in osteosarcoma. Interestingly, miR-217 plays contrasting roles in cancer depending on cancer type (Kato et al., 2009; Zhao et al., 2010). Herein, miR-217 is a tumor suppressor which inhibits cell proliferation and metastasis in osteosarcoma. "
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    ABSTRACT: Quercetin can suppress osteosarcoma cell growth and metastasis. However, other effects of quercetin on osteosarcoma remain largely unknown. This research aims to evaluate the effects of quercetin in combination with cisplatin as treatment for osteosarcoma and investigate its regulatory mechanism. Cell viability and apoptosis in 143B cell line were determined after treatment with quercetin and/or cisplatin. RT-PCR and Western blot analysis were performed to determine the RNA or protein expression levels. Moreover, transwell assay was used to evaluate metastasis. Furthermore, rescue experiments were performed to investigate the potential regulatory mechanism of the treatment. Results showed that quercetin with concentration that was equal to or greater than 10 μM inhibited 143B proliferation, while 5 μM quercetin enhanced the cisplatin sensitivity of 143B cells. Expression of miR-217 was upregulated after quercetin and/or cisplatin treatment, while its target KRAS was downregulated both at mRNA and protein levels. MiR-217 knockdown led to the loss of enhanced cisplatin sensitivity while miR-217 overexpression showed the opposite effects, indicating that quercetin regulated cisplatin sensitivity by modulating the miR-217-KRAS axis. In conclusion, 5 μM quercetin enhanced the cisplatin sensitivity by modulating the miR-217-KRAS axis. This finding suggests that quercetin may be administered with cisplatin to improve the treatment for osteosarcoma.
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