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Park, E-Y,Kim, W-Y,Kim, Y-M,Lee, J-H,Han, K-H,Weiner, I D,Kim, J Gutenberg 2012 HISTOLOGY AND HISTOPATHOLOGY Vol.27 No.12
<P>Potassium depletion (K?-D) induces hypertrophy and hyperplasia of collecting duct cells, and potassium repletion (K?-R) induces regression of these changes. The purpose of this study was to examine the time courses of the changes in cellular composition, the origin of intercalated cells (ICs) and the mechanism responsible for these changes. SD rats received K?-depleted diets for 1, 7, or 14 days. After K?-D for 14 days some of the rats received normal diets for 1, 3, 5, or 7 days. In the inner stripe of the outer medulla, K?-D increased significantly the number and proportion of H?-ATPase-positive ICs, but decreased the proportion of H?-ATPase-negative principal cells (PCs). However, proliferation was limited to H?-ATPase-negative PCs. During K?-R, the cellular composition was recovered to control level. Apoptosis increased during K?-R and exclusively limited in H?-ATPase-negative PCs. Double immunolabeling with antibodies to PC and IC markers identified both cells negative or positive for all markers during both K?-D and K?-R. Electron microscopic observation showed that ultrastructure of AE1-positive some cells were similar to AE1-negative some cells during K?-R. LC3 protein expression increased significantly and autophagic vacuoles appeared particularly in PCs on days 14 of K?-D and in ICs on days 3 of K?-R. These results suggest that PCs and ICs may interconvert in response to changes in dietary K+ availability and that autophagic pathways may be involved in the interconversion.</P>
Chang, S-H,Kim, J-E,Lee, J-H,Minai-Tehrani, A,Han, K,Chae, C,Cho, Y-H,Yun, J-H,Park, K,Kim, Y-S,Cho, M-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.6
Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-ras<SUP>LA1</SUP> lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-ras<SUP>LA1</SUP> mice. Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-ras<SUP>LA1</SUP> mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment.
Novel signaling axis for ROS generation during K-Ras-induced cellular transformation
Park, M-T,Kim, M-J,Suh, Y,Kim, R-K,Kim, H,Lim, E-J,Yoo, K-C,Lee, G-H,Kim, Y-H,Hwang, S-G,Yi, J-M,Lee, S-J Macmillan Publishers Limited 2014 CELL DEATH AND DIFFERENTIATION Vol.21 No.8
Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47<SUP>phox</SUP>, a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47<SUP>phox</SUP> and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47<SUP>phox</SUP> C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47<SUP>phox</SUP>-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47<SUP>phox</SUP> and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47<SUP>phox</SUP> or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47<SUP>phox</SUP>/NOX1 for ROS generation and consequent malignant cellular transformation.
Park, M.K.,Park, S.,Kim, H.J.,Kim, E.J.,Kim, S.Y.,Kang, G.J.,Byun, H.J.,Kim, S.H.,Lee, H.,Lee, C.H. North-Holland ; Elsevier Science Ltd 2016 european journal of pharmacology Vol.775 No.-
<P>Sphingosylphosphorylcholine (SPC) evokes perinuclear reorganization of keratin 8 (K8) filaments and regulates the viscoelasticity of metastatic cancer cells leading to enhanced migration. Few studies have addressed the compounds modulating the viscoelasticity of metastatic cancer cells. We studied the effects of sphingosine (SPH), sphingosine 1-phosphate (S1P), FTY720 and FTY720-phosphate (FTY720P) on SPC-induced K8 phosphorylation and reorganization using Western blot and confocal microscopy, and also evaluated the elasticity of PANC-1 cells by atomic force microscopy. FTY720, FTY720P, SPH, and SIP concentration-dependently inhibited SPC-evoked phosphorylation and reorganization of K8, and migration of PANC-1 cells. SPC triggered reduction and narrow distribution of elastic constant K and conversely, FTY720 blocked them. A common upstream regulator of JNK and ERK, protein phosphatase 2A (PP2A) expression was reduced by SPC, but was restored by FTY720 and FTY72P. Butyryl forskolin, a PP2A activator, suppressed SPC-induced K8 phosphorylation and okadaic acid, a PP2A inhibitor, induced K8 phosphorylation. Gene silencing of PP2A also led to K8 phosphorylation, reorganization and migration. We also investigated the involvement of GPR12, a high-affinity SPC receptor, in SPC-evoked keratin phosphorylation and reorganization. GPR12 siRNA suppressed the SPC-triggered phosphorylation and reorganization of K8. GPR12 overexpression stimulated keratin phosphorylation and reorganization even without SPC. FTY720 and FTY720P suppressed the GPR12-induced phosphorylation and reorganization of K8. The collective data indicates that FTY720 and FTY720P suppress SPC-induced phosphorylation and reorganization of K8 in PANC-1 cells by restoring the expression of PP2A via GPR12. These findings might be helpful in the development of compounds that modulate the viscoelasticity of metastatic cancer cells and various SPC actions. (C) 2016 Elsevier B.V. All rights reserved.</P>
Kim, Y.-K.,Park, H.-W.,Yang, J.-S.,Oh, S.-Y.,Chang, Y.-S.,Shin, E.-S.,Lee, J.-E.,Kim, S.,Gho, Y. S.,Cho, S.-H.,Min, K.-U.,Kim, Y.-Y. Blackwell Scientific Publications 2007 Clinical and experimental allergy Vol.37 No.4
<P>Summary</P><P>Background</P><P>The hyper-sensitivity reaction of IgE, with its high-affinity receptors (FcϵRI), is central to the phenomenon of atopic diseases.</P><P>Objective</P><P>To evaluate the genetic effects of non-synonymous single-nucleotide polymorphisms (SNPs) of FcϵRI on intermediate phenotypes of asthma, i.e. atopy and airway hyper-responsiveness (AHR), in the Korean general population.</P><P>Subjects and methods</P><P>Atopy and AHR were evaluated in a cohort of 2055 subjects, aged 10–18 years, using skin prick tests (SPTs) for common aeroallergens and total serum IgE and methacholine bronchial provocation tests. All FcϵRI-α, FcϵRI-β, and FcϵRI-γ gene exons of 24 healthy subjects were sequenced to locate informative non-synonymous SNPs (minor allele frequency >2%). Informative SNPs were then scored, using the high-throughput single base extension method. Relative risk (RR) was determined by multiple logistic regression analysis, after adjusting for confounding factors. The functional relevance of non-synonymous SNPs was analysed using the sorting intolerant from tolerant (SIFT) program.</P><P>Results</P><P>The SNP search found only one informative non-synonymous SNP in FcϵRI-β: E237G (minor allele frequency=0.21). The positive rate of AHR was lower among subjects with the 237<SUP>*</SUP>E allele than among those with 237<SUP>*</SUP>G [RR (95% confidence interval)=0.41 (0.19–0.89); <I>P</I>=0.01]. However, the E237G substitution was not associated with either a positive SPT response or total serum IgE levels. Sequence evolution analysis predicted that the E237G variation is an intolerant amino acid substitution, with functional importance.</P><P>Conclusion</P><P>In the Korean general population, AHR is significantly associated with the E237G polymorphism of FcϵRI-β, which results in an intolerant amino acid substitution.</P>
Sohn, H.,Lee, K.-S.,Kim, S.-Y.,Shin, D.-M.,Shin, S.-J.,Jo, E.-K.,Park, J.-K.,Kim, H.-J. Blackwell Publishing Ltd 2009 Scandinavian journal of immunology Vol.69 No.1
<P>Abstract</P><P>Recent studies have suggested that virulent strains of <I>Mycobacterium tuberculosis</I> induce apoptosis in macrophages less often than do attenuated strains. K-strain, which belongs to the Beijing family, is the most frequently isolated clinical strain of <I>M. tuberculosis</I> in Korea. In this study, we investigated the differential induction of cell death in human monocytic THP-1 cells by K-strain and H37Rv, a virulent but laboratory-adapted strain of <I>M. tuberculosis</I>. Although no significant difference in growth rate was observed between the cells exposed to K-strain and those exposed to H37Rv, the levels of protective cytokines such as tumour necrosis factor (TNF)-&agr;, interleukin (IL)-6 and IL-12p40 were lower in K-strain-infected cells than in H37Rv-infected cells. Cell viability assays showed that both K-strain and H37Rv, but not heat- or streptomycin-killed bacteria, induced THP-1 cell death in a TNF-independent manner. In contrast, double staining with fluorochrome-labelled inhibitors of caspase and propidium iodide and lactate dehydrogenase release assays revealed that K-strain induced significantly higher levels of necrotic cell death, rather than apoptosis, in THP-1 cells than did H37Rv. Anti-apoptotic <I>Bcl-2</I>, <I>Mcl-1</I>, <I>Bfl-1</I> and <I>Bcl-xL</I> in the cells were significantly upregulated following infection with K-strain compared with H37Rv, whereas <I>Bax</I> was slightly upregulated in response to infection with both H37Rv and K-strain. These results suggest that the highly virulent K-strain keeps cellular apoptosis as a host defense mechanism to a minimum and induces necrosis in macrophages.</P>