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Ara Koh,
Mi Nam Lee,
Yong Ryoul Yang,
Heeyoon Jeong, Jaewang Ghim,
Jeongeun Noh,
Jaeyoon Kim,
Dongryeol Ryu,
Sehoon Park,
Parkyong Song,
Seung-Hoi Koo,
Nick R Leslie,
Per-Olof Berggren,
Jang Hyun Choi,
Pann-Ghill Suh,
Sung Ho Ryu
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ABSTRACT: Muscle atrophy occurs with various catabolic conditions, including insulin deficiency, insulin resistance, or increased levels of glucocorticoids. This results from reduced levels of insulin receptor substrate (IRS)-1, leading to decreased phosphatidylinositol 3-kinase activity and thereby activation of FoxO transcription factors. However, the precise mechanism of reduced IRS-1 under a catabolic condition is unknown. Here, we report that C1-Ten is a novel protein tyrosine phosphatase (PTPase) of IRS-1 that acts as a mediator to reduce IRS-1 under a catabolic condition, resulting in muscle atrophy. C1-Ten preferentially dephosphorylated Y612 of IRS-1, which accelerated IRS-1 degradation. These findings suggest a novel type of IRS-1 degradation mechanism, which is dependent on C1-Ten and extends our understanding of the molecular mechanism of muscle atrophy under catabolic conditions. C1-Ten expression is increased by catabolic glucocorticoid and decreased by anabolic insulin. Reflecting these hormonal regulations, the muscle C1-Ten is upregulated in atrophy but downregulated in hypertrophy. This reveals a previously unidentified role of C1-Ten as a relevant PTPase, contributing to the skeletal muscle atrophy.
Molecular and cellular biology 02/2013; · 6.06 Impact Factor
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Parkyong Song,
Jong Hyun Kim, Jaewang Ghim,
Jong Hyuk Yoon,
Areum Lee,
Yonghoon Kwon,
Hyunjung Hyun,
Hyo-Youl Moon,
Hueng-Sik Choi,
Per-Olof Berggren,
Pann-Ghill Suh,
Sung Ho Ryu
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ABSTRACT: AMP-activated protein kinase has been described as a key signaling protein that can regulate energy homeostasis. Here, we aimed to characterize novel AMPK activating compounds that have a much lower effective concentration than metformin. As a result, Emodin, a natural anthraquinone derivative was shown to stimulate AMPK activity in skeletal muscle and liver cell. Emodin enhanced GLUT4 translocation and [14C] glucose uptake into myotube in an AMPK dependent manner. Also, emodin inhibited glucose production by suppressing the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in hepatocytes. Furthermore, we found that emodin can activate AMPK by inhibiting mitochondrial respiratory complex I activity, leading to increased reactive oxygen species (ROS) and Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) activity. Finally, we confirmed that a single-dose administration of emodin significantly decreased the fasting plasma glucose levels and improved glucose tolerance in C57Bl/6J mice. Increased insulin sensitivity was also confirmed after daily injection of emodin for eight days using an insulin tolerance test and insulin stimulated PI-3K phosphorylation in wild type and HFD induced diabetic mouse models. Our study suggests that emodin regulates glucose homeostasis in vivo by AMPK activation and that this may represent a novel therapeutic principle in the treatment of Type 2 diabetic models.
Journal of Biological Chemistry 01/2013; · 4.77 Impact Factor
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ABSTRACT: Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydrolysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically.
Nature Reviews Cancer 10/2012; 12(11):782-92. · 29.54 Impact Factor
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Yong Ryoul Yang,
Minseok Song,
Ho Lee,
Yoon Jeon,
Eun-Jeong Choi,
Hyun-Jun Jang,
Hyo Youl Moon,
Ha-Young Byun,
Eung-Kyun Kim,
Dae Hyun Kim,
Mi Nam Lee,
Ara Koh, Jaewang Ghim,
Jang Hyun Choi,
Whaseon Lee-Kwon,
Kyong Tai Kim,
Sung Ho Ryu,
Pann-Ghill Suh
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ABSTRACT: Dysregulation of O-GlcNAc modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer's disease. Here we found that natural aging in wild-type mice was marked by a decrease in OGA and OGT protein levels and an increase in O-GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O-GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum-stimulated cell cycle entry induced increased O-GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O-GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O-GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O-GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.
Aging cell 02/2012; 11(3):439-48. · 7.55 Impact Factor
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Jong Hyuk Yoon,
Parkyong Song,
Jin-Hyeok Jang,
Dae-Kyum Kim,
Sunkyu Choi,
Jaeyoon Kim, Jaewang Ghim,
Dayea Kim,
Sehoon Park,
Hyeongji Lee,
Dongoh Kwak,
Kyungmoo Yea,
Daehee Hwang,
Pann-Ghill Suh,
Sung Ho Ryu
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ABSTRACT: There is a strong possibility that skeletal muscle can respond to irregular metabolic states by secreting specific cytokines. Obesity-related chronic inflammation, mediated by pro-inflammatory cytokines, is believed to be one of the causes of insulin resistance that results in type 2 diabetes. Here, we attempted to identify and characterize the members of the skeletal muscle secretome in response to tumor necrosis factor-alpha (TNF-α)-induced insulin resistance. To conduct this study, we comparatively analyzed the media levels of proteins released from L6 skeletal muscle cells. We found 28 TNF-α modulated secretory proteins by using separate filtering methods: Gene Ontology, SignalP, and SecretomeP, as well as the normalized Spectral Index for label-free quantification. Ten of these secretory proteins were increased and 18 secretory proteins were decreased by TNF-α treatment. Using microarray analysis of Zuker diabetic rat skeletal muscle combined with bioinformatics and Q-PCR, we found a correlation between TNF-α-mediated insulin resistance and type 2 diabetes. This novel approach combining analysis of the conditioned secretome and transcriptome has identified several previously unknown, TNF-α-dependent secretory proteins, which establish a foothold for research on the different causes of insulin resistance and their relationships with each other.
Journal of Proteome Research 12/2011; 10(12):5315-25. · 5.11 Impact Factor
