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Iio A.,Gifu International Institute of Biotechnology | Nakagawa Y.,Aichi University | Hirata I.,Aichi University | Naoe T.,Nagoya University | And 2 more authors.
Molecular Cancer | Year: 2010

In a variety of cancers, altered patterns of microRNA (miRNA) expression are reported and may affect the cell cycle and cell survival. Recent studies suggest that the expression level of miRNAs that act as tumor suppressors is frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription and disturbances in miRNA processing. miR-143 and -145, which are located approximately 1.3 kb from each other at chromosome 5q33, are highly expressed in several tissues, but down-regulated in most cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that both miRNAs were expressed well under the same control program in human tissues, but were down-regulated equally in the most of the cancer cell lines tested. Then we identified the host gene encoding both miRNAs. The transcripts of this gene were approximately 11, 7.5, and 5.5 kb long; and the expression of these transcripts was coordinated with that of its resident miRNAs and down-regulated in the cancer cell lines tested as well as in colorectal cancer tissue samples. These data demonstrate that the host gene can function as a primary miRNA transcript and suggest that the down-regulation of host gene expression caused the low-expression of its encoded microRNAs-143 and -145 in human cancer cell lines and in cancer tissues.© 2010 Iio et al; licensee BioMed Central Ltd. Source


Naoi M.,Gifu International Institute of Biotechnology | Maruyama W.,National Research Center for Geriatrics and Gerontology | Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University
International Review of Neurobiology | Year: 2011

In Parkinson's disease, type B monoamine oxidase (MAO-B) is proposed to play an important role in the pathogenesis through production of reactive oxygen species and neurotoxins from protoxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In addition, inhibitors of MAO-B protect neurons in the cellular and animal models of Parkinson's and Alzheimer's diseases. However, the role of type A MAO (MAO-A) in neuronal death and neuroprotection by MAO-B inhibitors has been scarcely elucidated. This chapter presents our recent results on the involvement of MAO-A in the activation of mitochondrial death signal pathway and in the induction of prosurvival genes to prevent cell death with MAO-B inhibitors. The roles of MAO-A in the regulation of neuronal survival and death are discussed in concern to find a novel strategy to protect neurons in age-associated neurodegenerative disorders and depression. © 2011 Elsevier Inc. Source


Itoh T.,Gifu International Institute of Biotechnology | Takeda S.,Keio University | Akao Y.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University
Journal of Biological Chemistry | Year: 2010

MicroRNAs (miRs) represent a class of endogenous ∼18-25 nucleotide RNAs that regulate gene expression through translational repression by binding to a target mRNA. These miRs regulate several biological functions, such as cell growth, cell differentiation, carcinogenesis, and so on. In a previous report, we have indicated that miR-141 and -200a act as preosteoblast differentiation modulators. In the present study, using microRNA array and in silico analyses, we found that miR-208 is closely involved in preosteoblast differentiation by partially regulating the expression of Ets1 (V-ets erythroblastosis virus E26 oncogene homolog 1), which transactivates osteopontin, runt-related transcription factor 2, parathyroid hormone-related protein, and type I procollagen. Furthermore, the enforced expression of mature miR-208 in murine preosteoblast in MC3T3-E1 cells or primary osteoblast cells remarkably attenuated BMP-2-induced preosteoblast differentiation. In addition, we determined that Ets1 is a target gene of miR-208 by using a sensor luciferase reporter assay. Taken together, these results suggest that the down-regulation of miR-208 in BMP-2-stimulated osteoblast differentiation is an important part of the regulatory machinery involved in early osteogenesis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Naoi M.,Gifu International Institute of Biotechnology
Journal of Neural Transmission | Year: 2012

Rasagiline and (-)deprenyl (selegiline), irreversible type B monoamine oxidase (MAO-B) inhibitors, protect neuronal cells through gene induction of pro-survival Bcl-2 and neurotrophic factors in the cellular models of neurodegenerative disorders. In this paper, the role of MAO in the up-regulation of neuroprotective Bcl-2 gene by these inhibitors was studied using type A MAO (MAO-A) expressing wild SH-SY5Y cells and the transfectionenforced MAO-B overexpressed cells. Rasagiline and (-)deprenyl, and also befloxatone, a reversible MAO-A inhibitor, increased Bcl-2 mRNA and protein in SH-SY5Y cells. Silencing MAO-A expression with short interfering (si) RNA suppressed Bcl-2 induction by rasagiline, but not by (-)deprenyl. MAO-B overexpression inhibited Bcl-2 induction by rasagiline and befloxatone, but did not affect that by (-)deprenyl, suggesting the different mechanisms behind Bcl-2 gene induction by theseMAO-B inhibitors. The novel role of MAO-A in Bcl-2 induction by rasagiline is discussed with regard to the molecular mechanism underlying neuroprotection by the MAO inhibitors. © Springer-Verlag 2011. Source


Akao Y.,Gifu University | Iio A.,Gifu International Institute of Biotechnology | Itoh T.,Gifu International Institute of Biotechnology | Noguchi S.,Gifu University | And 3 more authors.
Molecular Therapy | Year: 2011

Microvesicles (MVs) and exosomes, which are shed from cells as a cell-to-cell communication tool, are possible vehicles for navigating RNA molecules to body tissues. It is considered that intravenous injection of such MVs or exosomes from patients would not cause severe not-self and toxic reactions. Previously, we found that macrophages take up liposome-entrapped RNA molecules, some of which remain undegraded in the cells. Here, we demonstrate that transfected RNA molecules in human monocytic leukemia THP-1 cells were shed from THP-1 macrophages as contents in MVs during incubation in serum-free medium, which shedding was shown by biochemical analyses such as quantitative reverse transcription (qRT)-PCR, expression of TSG101 (a membrane-associated exosomal protein), and immunoelectron microscopic study. More chemically modified RNA molecules (miR-143BPs) entrapped by MVs (MV-miR-143BPs) were secreted from THP-1 macrophages after miR-143BP transfection compared with the amount after transfection with nonmodified miR-143 transfection. Furthermore, we show that the THP-1 macrophages, which were transfected with the miR-143BP ex vivo, secreted MV-miR-143BPs in xenografted nude mice after intravenous injection, because miR-143 levels were significantly increased in the serum, tumor, and kidney of the host animals. These data suggest that some of the transfected miR-143BPs were secreted from THP-1 macrophages as MV-RNAs both in vitro and in vivo. © The American Society of Gene & Cell Therapy. Source

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