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Lee S.,Seoul National University | Yu K.-R.,Seoul National University | Ryu Y.-S.,Seoul National University | Oh Y.S.,Seoul National University | And 9 more authors.

Previously, AIMP3 (aminoacyl-tRNAsynthetase-interacting multifunctional protein-3) was shown to be involved in the macromolecular tRNA synthetase complex or to act as a tumor suppressor. In this study, we report a novel role of AIMP3/p18 in the cellular aging of human mesenchymal stem cells (hMSCs). We found that AIMP3/p18 expression significantly increased in senescent hMSCs and in aged mouse bone marrow-derived MSCs (mBM-MSCs). AIMP3/p18 overexpression is sufficient to induce the cellular senescence phenotypes with compromised clonogenicity and adipogenic differentiation potential. To identify the upstream regulators of AIMP3/p18 during senescence, we screened for potential epigenetic regulators and for miRNAs. We found that the levels of miR-543 and miR-590-3p significantly decreased under senescence-inducing conditions, whereas the AIMP3/p18 protein levels increased. We demonstrate for the first time that miR-543 and miR-590-3p are able to decrease AIMP3/p18 expression levels through direct binding to the AIMP/p18 transcripts, which further compromised the induction of the senescence phenotype. Taken together, our data demonstrate that AIMP3/p18 regulates cellular aging in hMSCs possibly through miR-543 and miR-590-3p. © 2014, American Aging Association. Source

Jang S.-Y.,University of Seoul | Kang H.T.,University of Seoul | Kang H.T.,Lee Gil Ya Cancer and Diabetes Institute | Kang H.T.,Seoul National University | Hwang E.S.,University of Seoul
Journal of Biological Chemistry

Active autophagy coupled with rapid mitochondrial fusion and fission constitutes an important mitochondrial quality control mechanism and is critical to cellular health. In our previous studies, we found that exposure of cells to nicotinamide causes a decrease in mitochondrial content and an increase in mitochondrial membrane potential (MMP) by activating autophagy and inducing mitochondrial fragmentation. Here, we present evidence to show that the effect of nicotinamide is mediated through an increase of the [NAD+]/[NADH] ratio and the activation of SIRT1, an NAD+-dependent deacetylase that plays a role in autophagy flux. The [NAD+]/[NADH] ratio was inversely correlated with the mitochondrial content, and an increase in the ratio by the mobilization of the malate-aspartate shuttle resulted in autophagy activation and mitochondrial transformation from lengthy filaments to short dots. Furthermore, treatment of cells with SIRT1 activators, fisetin or SRT1720, induced similar changes in the mitochondrial content. Importantly, the activators induced mitochondrial fragmentation only when SIRT1 expression was intact. Meanwhile, MMP did not increase when the cells were treated with the activators, suggesting that the change in MMP is not induced by the mitochondrial turnover per se and that elevation of the [NAD+]/[NADH] ratio may activate additional mechanisms that cause MMP augmentation. Together, our results indicate that a metabolic state resulting in an elevated [NAD +]/[NADH] ratio can modulate mitochondrial quantity and quality via pathways that may include SIRT1-mediated mitochondrial autophagy. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Lee K.M.,Gwangju Institute of Science and Technology | Yang S.-J.,Gwangju Institute of Science and Technology | Kim Y.D.,Chonnam National University | Choi Y.D.,Chonnam National University | And 5 more authors.

A nonsense mutation in cereblon (CRBN ) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the a1-subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. For elucidation of the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyperphosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high-fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver. © 2013 by the American Diabetes Association. Source

Yu H.-J.,Chonbuk National University | Shin J.-A.,Chonbuk National University | Jung J.-Y.,Kongju National University | Nam J.-S.,Lee Gil Ya Cancer and Diabetes Institute | And 3 more authors.
Head and Neck

Background The purpose of our study was to investigate the anticancer effect of sorafenib on mucoepidermoid carcinoma (MEC) and find its new molecular mechanism. Methods The apoptotic effects of sorafenib were performed using MTS assay, diamidino-phenylindole (DAPI) staining, Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), siRNA, and xenograft. Results Sorafenib had apoptotic effects on MC-3 and YD15 cells and decreased myeloid cell leukemia-1 (Mcl-1) through proteasome-dependent protein degradation and the inhibition of protein synthesis. Sorafenib significantly affected truncated bid (t-Bid) and siMcl-1 resulting in the upregulation of t-Bid to induce apoptosis. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was also blocked by sorafenib and a potent STAT3 inhibitor, cryptotanshinone clearly induced poly ADP-ribose polymerase (PARP) cleavage by inhibiting Mcl-1 and increasing t-Bid. Finally, administration of sorafenib significantly suppressed tumor growth and induced apoptosis in tumor xenograft model in association with downregulation of Mcl-1 without any side effects. Conclusion Taken together, these findings suggest that sorafenib can be a good anticancer drug candidate for the treatment of MEC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1326-1335, 2015 © 2014 Wiley Periodicals, Inc. Source

Yi J.-S.,Korea University | Park J.S.,Korea University | Ham Y.-M.,Korea University | Nguyen N.,Korea University | And 25 more authors.
Nature Communications

Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/-mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/-mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance. © 2013 Macmillan Publishers Limited. Source

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