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Articles by H. J. Han
Total Records ( 8 ) for H. J. Han
  Y. J Lee , H. N Suh and H. J. Han

Recent studies demonstrated that endoplasmic reticulum (ER) stress regulates glucose homeostasis and that ER stress preconditioning which induces an adaptive, protective unfolded protein response (UPR) offers cytoprotection against nephrotoxins. Thus the aim of the present study was to use renal proximal tubule cells (PTCs) to further elucidate the link between the BSA-induced ER stress and -methyl-d-glucopyranoside (-MG) uptake and to identify related signaling pathways. Among ER stress inducers such as high glucose, BSA, H2O2, or tumicamycin, BSA pretreatment ameliorated the reduction of Na+-glucose cotransporter (SGLT) expression and -MG uptake by gentamicin or cyclosporine A. Immunofluorescence studies revealed that BSA (10 mg/ml) stimulated the expression of glucose-regulated protein 78 (GRP78), an ER stress biomarker. In addition, BSA increased levels of GRP78 protein expression and eukaryotic initiation factor 2 (eIF2) phosphorylation in a time-dependent manner. Furthermore, transfection with a GRP78-specific small interfering RNA (siRNA) inhibited BSA-stimulated SGLT expression and -MG uptake. In experiments designed to unravel the mechanisms underlying BSA-induced ER stress, BSA stimulated the production of cellular reactive oxygen species (ROS), and antioxidants such as ascorbic acid or N-acetylcysteine (NAC) blocked BSA-induced increases in GRP78 activation, eIF2 phosphorylation, SGLT expression, and -MG uptake. Moreover, the cells upregulated peroxisome proliferator-activated receptor- (PPAR) mRNA levels in response to BSA or troglitazone (a PPAR agonist), but BSA was ineffective in the presence of GW9662 (a PPAR antagonist). In addition, both BSA and troglitazone stimulated GRP78 and eIF2 activation, SGLT expression, and -MG uptake, whereas GW9662 inhibited the effects of BSA. BSA also stimulated phosphorylation of JNK and NF-B, and GW9662 or GRP78 siRNA attenuated this response. Moreover, SP600125 or SN50 effectively blocked SGLT expression and -MG uptake in BSA- or PPAR agonists (troglitazone or PGJ2)-treated PTCs. We conclude that BSA induces ER stress through ROS production and PPAR activation, which subsequently activates JNK/NF-B signaling to enhance glucose uptake in renal PTCs.

  S. H Lee , M. H Kim and H. J. Han

Recent investigations suggest that hypoxia increases the release of fatty acids, which participate in the regulation of cytokine synthesis and cell growth. Therefore, in this study, we examined the effect of arachidonic acid (AA) on hypoxia-induced vascular endothelial growth factor (VEGF) expression and its related signaling pathways in mouse embryonic stem (ES) cells. Hypoxia increased the level of [3H]AA release and VEGF expression. AA treatment concurrent with hypoxia further increased the PGE2 production and VEGF expression level, which was inhibited by the suppression of cPLA2 and cyclooxygenase 2 (COX-2) pathways. Hypoxia increased the level of Notch-1 and Wnt-1/β-catenin expression, which was blocked by the inhibition of COX-2, and inhibition of Notch-1 by -secretase inhibitor blocked Wnt-1 activation. Moreover, the hypoxia-induced increase of hypoxia-inducible factor 1 (HIF-1) expression induced Notch-1 activation and was regulated by Wnt-1 activation. The expression of each signaling molecule induced an increase in VEGF expression that was greater in hypoxia with AA than in hypoxia alone. The inhibition of VEGF expression using VEGF-targeted small interfering RNA decreased the hypoxia-induced increase in cell cycle regulatory protein expression, DNA synthesis, and cell number, suggesting that hypoxia-induced VEGF expression stimulates proliferation of mouse ES cells. In conclusion, AA potentiates hypoxia-induced VEGF expression in mouse ES cells through the Notch-1, Wnt-1, and HIF-1 pathways.

  J. H Park and H. J. Han

The involvement of caveolin-1 in the regulation of embryonic stem (ES) cell growth by epidermal growth factor (EGF) is by no means clear cut. Thus we examined the relationship between EGF and caveolin-1 in mouse ES cell migration and proliferation. The results revealed that EGF increased Src, caveolin-1, focal adhesion kinase (FAK), Akt, and extracellular signal-regulated kinase-1/2 (ERK) phosphorylation levels. Especially, phosphorylation of caveolin-1 is attenuated by AG1478, herbimycin A (tyrosine kinase inhibitors), and pyrazolopyrimidine 2 (PP2, Src inhibitor) and EGF-induced ERK activation was blocked by PP2, methyl-β-cyclodextrin (MβCD), caveolin-1 small interfering RNA (siRNA), LY-294002 [phosphoinositol-3 kinase inhibitor (PI3K)], and Akt inhibitor. In addition, EGF promoted the cell migration, which was attenuated by PP2, caveolin-1 siRNA, FAK siRNA, LY-294002, Akt inhibitor, and PD-98059. EGF also increased matrix metalloproteinase (MMP-2) expression levels and EGF-induced MMP2 expression was inhibited by caveolin-1 siRNA, FAK siRNA, LY-294002, Akt inhibitor, and PD-98059. Furthermore, EGF-induced increase of cell cycle proteins expression level and [3H]thymidine incorporation was blocked by MMP inhibitor. EGF also significantly increases [3H]thymidine incorporation and cell number, which were significantly blocked by AG 1478, PP2, MβCD, caveolin-1 siRNA, FAK siRNA, LY-294002, and PD-98059 (ERK inhibitor). EGF-induced increase of protooncogenes (c-fos, c-myc, and c-Jun) and cell cycle regulatory proteins (cyclin D1, CDK4, cyclin E, and CDK2) expression levels were also attenuated by caveolin-1 siRNA and FAK siRNA. In conclusion, these results demonstrated that EGF-induced DNA synthesis and cell migration are mediated by caveolin-1, which is activated by Src, FAK, PI3K/Akt, ERK, and MMP-2 signals in mouse ES cells.

  S. H Lee , Y. J Lee , C. H Song , Y. K Ahn and H. J. Han

Here we show that the effect of hypoxia on human umbilical cord blood mesenchymal stem cell (hMSC) migration is via the modulation of focal adhesion kinase (FAK) and its related signaling pathways. Hypoxia increased hMSC migration and cell viability, whereas lactate dehydrogenase (LDH) release was not affected for up to 48 h (data not shown). In addition, hypoxia increased the level of reactive oxygen species (ROS) generation in a time-dependent manner. Hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) were inhibited by the antioxidant (N-acetylcysteine, NAC, 10–6 M) and (taurine, 4x10–6 M). Hypoxia-induced endothelial nitric oxide synthase (eNOS) phosphorylation was regulated by p38 MAPK and SAPK/JNK activation. In addition, hypoxia increased the level of hypoxia inducible factor (HIF)-1 expression, which was blocked by inhibition of eNOS. Also, hypoxia-induced expression of Flk-1, vascular endothelial growth factor (VEGF), and its secreted form were inhibited by HIF-1 small interfering RNA (siRNA). In this hypoxic condition, FAK and Src phosphorylation were increased in a time-dependent manner. Inhibition of Src with specific inhibitor (PP2, 10–8 M) blocked hypoxia-induced FAK activation. Subsequently, hypoxia-induced FAK phosphorylation was blocked by VEGF siRNA. Finally, hypoxia-induced increase of hMSC migration was inhibited by FAK siRNA. The results indicate that hypoxia increases migration of hMSCs via VEGF-mediated FAK phospholylation and involves the cooperative activity of the ROS, MAPK, eNOS and HIF-1 pathways.

  H. N Suh and H. J. Han

Laminin is the first extracellular matrix (ECM) component to be expressed in the developing mammalian embryo. However, the roles of laminin or the related signal pathways are not well known in mouse embryonic stem cells (mESCs). Presently, we examined the effect of laminin on mESC migration. Laminin (10 µg/ml) decreased cell aggregation, whereas migration was increased. Laminin bound 6β1 integrin and laminin receptor 1 (LR1), decreasing their mRNA levels. Laminin increased focal adhesion kinase (FAK) and paxillin phosphorylation, cAMP intracellular concentration, and the protein levels of exchange factor directly activated by cAMP (Epac1) and Rap1. These increases were completely blocked by 6β1 integrin and LR1 neutralizing antibody, indicating that laminin-bound LR1 assists laminin-induced 6β1 integrin activity and initiates signal. As a downstream signal molecule, laminin activated small G protein such as Rac1/cdc42 and its effector protein p21-activated kinase (PAK). Subsequently, laminin stimulated E-cadherin complex disruption. Inhibition of each pathway such as those for 6β1 integrin and LR1, FAK, Rap1, and PAK1 blocked laminin-induced migration. We conclude that laminin binds both 6β1 integrin and LR1 and induces signaling FAK/paxillin and cAMP/Epac1/Rap1. These signaling merge at Rac1/cdc42 subsequently activate PAK1. Activated PAK1 enhances E-cadherin complex disruption and finally increases mESCs migration.

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