Age-dependent gait abnormalities in mice lacking the <i>Rnf170</i> gene linked to human autosomal-dominant sensory ataxia

Kim, Youngsoo,Kim, Seong Hun,Kim, Kook Hwan,Chae, Sujin,Kim, Chanki,Kim, Jeongjin,Shin, Hee-Sup,Lee, Myung-Shik,Kim, Daesoo IRL Press 2015 Human molecular genetics Vol.24 No.25

<P>Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of <I>RNF170</I> gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking <I>Rnf170</I> (<I>Rnf170<SUP>−/−</SUP></I>) to evaluate the effect of its loss of function <I>in vivo</I>. Remarkably, <I>Rnf170<SUP>−/−</SUP></I> mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in <I>Rnf170<SUP>−/−</SUP></I> mice. These results suggest that the loss of <I>Rnf170</I> gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities.</P>

Citicoline Reduces Upregulated Clusterin Following Kainic Acid Injection in the Rat Retina

Park, Chang Hwan,Kim, Yoon Sook,Lee, Ho Kyung,Kim, Young Hee,Choi, Mee Young,Jung, Dhong Eun,Yoo, Ji Myong,Kang, Sang Soo,Choi, Wan Sung,Cho, Gyeong Jae IRL Press 2007 Current eye research Vol.32 No.12

<P> Purpose: To investigate the effects of citicoline on upregulated clusterin and retinal damage induced by kainic acid (KA). Methods: KA was injected into the vitreous of rats. Effects of systemic citicoline treatments were estimated by measuring the thickness of the various retinal layers, immunoblotting, and immunohistochemical techniques. Results: One day after KA injection, the immunoreactivity of clusterin increased significantly. In rats treated with KA plus citicoline, clusterin immunoreactivity was markedly reduced compared to KA-treated rats. Western blot analysis showed that clusterin protein levels were increased in KA-treated rats, but decreased in KA plus citicoline-treated rats. Apoptotic cell death was determined by TUNEL method. Citicoline reduced the expression of clusterin, as well as the expression of TUNEL after KA injection in the rat retina. Conclusion: The increased expression of clusterin following KA injection in the rat retina suggests the presence of neurodegenerative events; citicoline may provide neuroprotection against neuronal cell damage.</P>

Cold plasma treatments for improvement of the applicability of defatted soybean meal-based edible film in food packaging

Oh, Y.A.,Roh, S.H.,Min, S.C. IRL Press ; Elsevier Science Ltd 2016 Food hydrocolloids Vol.58 No.-

<P>This study investigated the effects of cold plasma treatment (CPT) using various plasma-forming gases on the physical properties of defatted soybean meal (DSM)-based edible film (DSM film). The effect of packaging smoked salmon using a cold plasma (CP)-treated DSM film on the storage stability of salmon was also evaluated. DSM film was formed by casting film-forming solutions (DSM/glycerol at a ratio of 10: 3) prepared by high-pressure (172 MPa) homogenization. Among the O-2-, N-2-, air-, He- and Ar-CPTs, Ar-CPT, which increased elongation and lightness of the DSM film, was optimized against tensile strength, elongation, and water vapor permeability using a response surface analysis. Optimal plasma generation time and power were predicted as 15 min and 400 W, respectively. The tensile strength, elongation, and moisture barrier property of DSM film increased by 6.8%, 13.4%, and 24.4%, respectively, after CPT at optimal conditions. The CPT formed DSM film that decomposed easily and retarded lipid oxidation and hardness reduction of smoked salmon during storage at 4 degrees C. The results from this study suggest the use of CPT for improving the applicability of DSM film in food packaging. (C) 2016 Elsevier Ltd. All rights reserved.</P>

Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β.

Park, Hyejin,Kam, Tae-In,Kim, Youngdoo,Choi, Hyunwoo,Gwon, Youngdae,Kim, Changsoo,Koh, Jae-Young,Jung, Yong-Keun IRL Press ; Oxford University Press 2012 Human Molecular Genetics Vol.21 No.12

<P>Abnormally hyperphosphorylated tau is often caused by tau kinases, such as GSK3β and Cdk5. Such occurrence leads to neurofibrillary tangle formation and neuronal degeneration in tauopathy, including Alzheimer's disease (AD). However, little is known about the signaling cascade underlying the pathologic phosphorylation of tau by Aβ(42). In this study, we show that adenylate kinase 1 (AK1) is a novel regulator of abnormal tau phosphorylation. AK1 expression is markedly increased in the brains of AD patients and AD model mice and is significantly induced by Aβ(42) in the primary neurons. Ectopic expression of AK1 alone augments the pathologic phosphorylation of tau at PHF1, CP13 and AT180 epitopes and enhances the formation of tau aggregates. Inversely, downregulation of AK1 alleviates Aβ(42)-induced hyperphosphorylation of tau. AK1 plays a role in Aβ(42)-induced impairment of AMPK activity and GSK3β activation in the primary neurons. Pharmacologic studies show that treatment with an AMPK inhibitor activates GSK3β, and a GSK3β inhibitor attenuates AK1-mediated tau phosphorylation. In a Drosophila model of human tauopathy, the retinal expression of human AK1 severely exacerbates rough eye phenotype and increases abnormal tau phosphorylation. Further, neural expression of AK1 reduces the lifespan of tau transgenic files. Taken together, these observations indicate that the neuronal expression of AK1 is induced by Aβ(42) to increase abnormal tau phosphorylation via AMPK-GSK3β and contributes to tau-mediated neurodegeneration, providing a new upstream modulator of GSK3β in the pathologic phosphorylation of tau.</P>

Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.

Yoon, Mi Jin,Park, Seok Soon,Kang, You Jung,Kim, In Young,Lee, Ju Ahn,Lee, Jong Soo,Kim, Eu-Gene,Lee, Chang-Woo,Choi, Kyeong Sook IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.3

<P>Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. In this study, we examined whether Aurora B, which is frequently overexpressed in cancer cells, is associated with TRAIL resistance. The protein levels of Aurora B were higher in TRAIL-resistant cancer cell lines than in TRAIL-sensitive cancer cell lines. Exogenously expressed Aurora B attenuated TRAIL-induced apoptosis in the tested TRAIL-sensitive cancer cell lines, whereas the small interfering RNA-mediated suppression of Aurora B expression stimulated TRAIL-mediated apoptosis in the tested TRAIL-resistant cancer cell lines. Furthermore, combined treatment with TRAIL and ZM447439, a specific inhibitor of Aurora B, synergistically induced apoptosis in various TRAIL-resistant cancer cells, suggesting that this combined regimen may represent an attractive strategy for effectively treating TRAIL-resistant malignant cancers. Mechanistically, the inhibition of Aurora B activity in various cancer cells commonly downregulated survivin protein levels and potentiated the activation of caspase-3. In addition, Aurora B inhibition induced mitotic catastrophe, which also contributed to the sensitization of cells to TRAIL-mediated apoptosis. Interestingly, forced overexpression of Aurora B increased the protein levels of survivin, but not those of a non-phosphorylatable survivin mutant in which threonine 117 was replaced by alanine, indicating that phosphorylation of survivin is required for this effect. Furthermore, TRAIL-induced apoptosis in MDA-MB-435S cells was attenuated by wild-type survivin but not by the non-phosphorylatable survivin mutant. Collectively, our results demonstrate that Aurora B confers TRAIL resistance to cancer cells via phosphorylation of survivin.</P>

Maspin genetically and functionally associates with gastric cancer by regulating cell cycle progression.

Kim, Minjin,Ju, Hyoungseok,Lim, Byungho,Kang, Changwon IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.12

<P>Human SERPINB5, commonly known as maspin, has diverse functions as a tumor suppressor. In this study, we discovered that maspin has a novel role in cell cycle control, and common variants were discovered to be associated with gastric cancer. The genotypes of 836 unrelated Korean participants (including 430 with gastric cancer) were examined for 12 tag single-nucleotide polymorphisms (SNPs) and imputed for 178 SNPs in the maspin gene. Susceptibility to diffuse-type gastric cancer was strongly and significantly associated with several SNPs including rs3744941 (C>T) in the promoter (TT versus CC+CT, odds ratio = 0.56 [0.37-0.83], P = 0.0038) and rs8089104 (C>T) in intron 1 (TT+CT versus CC, odds ratio = 1.7 [1.2-2.5], P = 0.0021). No SNPs were associated with susceptibility to intestinal-type gastric cancer. A haplotype of three highly correlated promoter SNPs associated with higher cancer risk showed 40% of the activity of a non-risk-associated haplotype promoter in the diffuse-type gastric cancer cell line MKN45. Maspin downregulation achieved either by a short hairpin RNA targeting maspin or overexpression of the E2F1-DP1 complex in MKN45 cells dramatically accelerated cell cycle progression and caused an increase of active CDC25C levels and a decrease of inactive CDK1 levels. In contrast, maspin upregulation had the opposite effect, substantially retarding cell proliferation. Therefore, our results suggest that a maspin promoter haplotype that reduces maspin gene expression accelerates cell cycle progression and, consequently, is associated with increased susceptibility to diffuse-type gastric cancer. Furthermore, a novel maspin-related pathway is demonstrated to underlie gastric carcinogenesis.</P>

NDRG2 correlated with favorable recurrence-free survival inhibits metastasis of mouse breast cancer cells via attenuation of active TGF-β production.

Oh, Sang-seok,Kim, Donghyeok,Kim, Dong-Hee,Chang, Hong Hee,Sohn, Kyung-Cheol,Kim, Kyo Hyun,Jung, Sung Hoo,Lee, Byoung Kil,Kim, Joo Heon,Kim, Kwang Dong IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.10

<P>N-myc downstream-regulated gene 2 (NDRG2) has been studied for its inhibitory effects against growth and metastasis of many tumor cell types. In this study, we showed NDRG2 expression was correlated with favorable recurrence-free survival of patients with breast cancer and inhibited metastasis of breast cancer cells (4T1). NDRG2 expression was examined in 189 breast carcinoma tissues and paired normal breast tissues using immunohistochemistry. Histological and clinicopathological data were correlated using Pearson's chi-square test of independence. NDRG2 expression in human breast cancer tissues was inversely associated with lymph node metastasis and pTNM stage. Furthermore, patients with breast cancer with a high level of NDRG2 expression showed favorable recurrence-free survival (P = 0.038). To study the effect of NDRG2 on metastasis in vivo, we established an NDRG2-overexpressing mouse breast cancer cell line (4T1-NDRG2) and measured the metastasis and survival of 4T1-NDRG2 tumor-bearing mice. To test whether transforming growth factor β (TGF-β)- mediated metastasis of 4T1 was inhibited by NDRG2 expression, TGF-Smad-binding element (SBE)-luciferase activity and/or measurement of active TGF-β were performed in cell or tumor tissue level. 4T1-NDRG2 cells grew gradually and showed less metastatic activity in vivo and low invasiveness in vitro. 4T1-NDRG2 cells showed lower SBE-luciferase activity and lower level of active autocrine TGF-β than 4T1-Mock did. Correctly, our data show that NDRG2 significantly suppress tumor metastasis by attenuating active autocrine TGF-β production, and the attenuation might be typically associated with the favorable recurrence-free survival of patients clinically.</P>

The TFG-TEC fusion gene created by the t(3;9) translocation in human extraskeletal myxoid chondrosarcomas encodes a more potent transcriptional activator than TEC.

Lim, Bobae,Jun, Hee Jung,Kim, Ah-young,Kim, Sol,Choi, JeeHyun,Kim, Jungho IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.8

<P>The t(3;9)(q11-q12;q22) translocation associated with human extraskeletal myxoid chondrosarcomas results in a chimeric molecule in which the N-terminal domain (NTD) of the TFG (TRK-fused gene) is fused to the TEC (Translocated in Extraskeletal Chondrosarcoma) gene. Little is known about the biological function of TFG-TEC. Because the NTDs of TFG-TEC and TEC are structurally different, and the TFG itself is a cytoplasmic protein, the functional consequences of this fusion in extraskeletal myxoid chondrosarcomas were examined. The results showed that the chimeric gene encoded a nuclear protein that bound DNA with the same sequence specificity as the parental TEC protein. Comparison of the transactivation properties of TFG-TEC and TEC indicated that the former has higher transactivation activity for a known target reporter containing TEC-binding sites. Additional reporter assays for TFG (NTD) showed that the TGF (NTD) of TFG-TEC induced a 12-fold increase in the activation of luciferase from a reporter plasmid containing GAL4 binding sites when fused to the DNA-binding domain of GAL4, indicating that the TFG (NTD) of the TFG-TEC protein has intrinsic transcriptional activation properties. Finally, deletion analysis of the functional domains of TFG (NTD) indicated that the PB1 (Phox and Bem1p) and SPYGQ-rich region of TFG (NTD) were capable of activating transcription and that full integrity of TFG (NTD) was necessary for full transactivation. These results suggest that the oncogenic effect of the t(3;9) translocation may be due to the TFG-TEC chimeric protein and that fusion of the TFG (NTD) to the TEC protein produces a gain-of-function chimeric product.</P>

Tectorigenin sensitizes paclitaxel-resistant human ovarian cancer cells through downregulation of the Akt and NFκB pathway.

Yang, Yeong-In,Lee, Kyung-Tae,Park, Hee-Juhn,Kim, Tae Jin,Choi, Youn Seok,Shih, Ie-Ming,Choi, Jung-Hye IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.12

<P>Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic agent for several cancers including ovarian carcinoma; however, the drug frequently induces drug resistance through multiple mechanisms. The new strategy of using natural compounds in combination therapies is highly attractive because those compounds may enhance the efficacy of chemotherapy. In this study, we found that tectorigenin, an isoflavonoid isolated from flower of Pueraria thunbergiana, enhanced the growth-inhibitory effect of paclitaxel in paclitaxel-resistant ovarian cancer cells (MPSC1(TR), A2780(TR) and SKOV3(TR)) as well as their naive counterparts. The combination of tectorigenin with paclitaxel resulted in a synergistic apoptosis compared with either agent alone through activation of caspases-3, -8 and -9. Treatment with tectorigenin inhibited the nuclear translocation of NFκB and the expression of NFκB-dependent genes such as FLIP, XIAP, Bcl-2, Bcl-xL and COX-2, which are known to be associated with chemoresistance. In addition, the tectorigenin-paclitaxel combination inhibited the phosphorylation of IκB and IKK and the activation of Akt in paclitaxel-resistant cancer cells. Moreover, tectorigenin-paclitaxel-induced cell growth inhibition was enhanced by pretreatment with the Akt inhibitor LY294002 or overexpression of the dominant negative Akt (Akt-DN), but reduced by overexpression of constitutively activated Akt (Akt-Myr). Furthermore, we found that Akt-Myr, at least in part, reversed tectorigenin-paclitaxel-induced nuclear translocation of NFκB and the phosphorylation of IκB and IKK. These data suggest that tectorigenin could sensitize paclitaxel-resistant human ovarian cancer cells through inactivation of the Akt/IKK/IκB/NFκB signaling pathway, and promise a new intervention to chemosensitize paclitaxel-induced cytotoxicity in ovarian cancer.</P>

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Lin, Wei-Yu,Camp, Nicola J,Ghoussaini, Maya,Beesley, Jonathan,Michailidou, Kyriaki,Hopper, John L,Apicella, Carmel,Southey, Melissa C,Stone, Jennifer,Schmidt, Marjanka K,Broeks, Annegien,Van't Veer, L IRL Press 2015 Human molecular genetics Vol.24 No.1

<P>Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 ?? 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 ?? 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 ?? 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.</P>