miR-200b and Cancer/Testis Antigen CAGE Form a Feedback Loop to Regulate the Invasion and Tumorigenic and Angiogenic Responses of a Cancer Cell Line to Microtubule-targeting Drugs

Kim, Youngmi,Park, Deokbum,Kim, Hyuna,Choi, Munseon,Lee, Hansoo,Lee, Yun Sil,Choe, Jongseon,Kim, Young Myeong,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.51

<P>Cancer/testis antigen <U>ca</U>ncer-associated <U>ge</U>ne (CAGE) is known to be involved in various cellular processes, such as proliferation, cell motility, and anti-cancer drug resistance. However, the mechanism of the expression regulation of CAGE remains unknown. Target scan analysis predicted the binding of microRNA-200b (miR-200b) to CAGE promoter sequences. The expression of CAGE showed an inverse relationship with miR-200b in various cancer cell lines. miR-200b was shown to bind to the 3′-UTR of CAGE and to regulate the expression of CAGE at the transcriptional level. miR-200b also enhanced the sensitivities to microtubule-targeting drugs <I>in vitro</I>. miR-200b and CAGE showed opposite regulations on invasion potential and responses to microtubule-targeting drugs. Xenograft experiments showed that miR-200b had negative effects on the tumorigenic and metastatic potential of cancer cells. The effect of miR-200b on metastatic potential involved the expression regulation of CAGE by miR-200b. miR-200b decreased the tumorigenic potential of a cancer cell line resistant to microtubule-targeting drugs in a manner associated with the down-regulation of CAGE. ChIP assays showed the direct regulation of miR-200b by CAGE. CAGE enhanced the invasion potential of a cancer cell line stably expressing miR-200b. miR-200b exerted a negative regulation on tumor-induced angiogenesis. The down-regulation of CAGE led to the decreased expression of plasminogen activator inhibitor-1, a TGFβ-responsive protein involved in angiogenesis, and VEGF. CAGE mediated tumor-induced angiogenesis and was necessary for VEGF-promoted angiogenesis. Human recombinant CAGE protein displayed angiogenic potential. Thus, miR-200b and CAGE form a feedback regulatory loop and regulate the response to microtubule-targeting drugs, as well as the invasion, tumorigenic potential, and angiogenic potential.</P>

Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates <i>in vitro</i> and <i>in vivo</i> allergic inflammation

Kim, Youngmi,Eom, Sangkyung,Kim, Kyungjong,Lee, Yun-Sil,Choe, Jongseon,Hahn, Jang Hee,Lee, Hansoo,Kim, Young-Myeong,Ha, Kwon Soo,Ro, Jai Youl,Jeoung, Dooil Elsevier 2010 Molecular immunology Vol.47 No.5

<P><B>Abstract</B></P><P>Transglutaminase II (TGase II) is a protein cross-linking enzyme with diverse biological functions. Here we report the role of TGase II in allergic inflammation. Antigen stimulation induced expression and activity of TGase II by activation of NF-κB in rat basophilic leukemia (RBL2H3) cells. This induction of TGase II was dependent on FcϵRI and EGFR. Interaction between TGase II and rac1 was induced following antigen stimulation. TGase II was responsible for the increased production of reactive oxygen species, expression of prostaglandin E2 synthase (PGE2 synthase) and was responsible for increased secretion of prostaglandin E2. ChIP assay showed that TGase II, through interaction with NF-κB, was responsible for the induction of histone deacetylase-3 (HDAC3) and snail by direct binding to promoter sequences. HDAC3 and snail induced by TGase II, exerted transcriptional repression on E-cadherin. Snail exerted negative effect on expression of MMP-2, and secretion of Th2 cytokines. Inhibition of matrix metalloproteinase-2 (MMP-2) inhibited secretion of Th2 cytokines. <I>In vivo</I> induction of TGase II was observed in Balb/c mouse model of IgE antibody-induced passive cutaneous anaphylaxis. Chemical inhibition of TGase II exerted negative effect on IgE-dependent passive cutaneous anaphylaxis. Chemical inhibition of TGase II by cystamine exerted negative effect on Balb/c mouse model of phorbol myristate acetate (PMA)-induced atopic dermatitis. These results suggest novel role of TGase II in allergic inflammation and TGase II can be developed as target for the development of allergy therapeutics.</P>

Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis

Kim, Min-Seon,Pak, Youngmi K,Jang, Pil-Geum,Namkoong, Cherl,Choi, Yon-Sik,Won, Jong-Chul,Kim, Kyung-Sup,Kim, Seung-Whan,Kim, Hyo-Soo,Park, Joong-Yeol,Kim, Young-Bum,Lee, Ki-Up Nature Publishing Group 2006 NATURE NEUROSCIENCE Vol.9 No.7

Insulin signaling in the hypothalamus plays a role in maintaining body weight. Studies suggest that the forkhead transcription factor Foxo1 is an important mediator of insulin signaling in peripheral tissues. Here we demonstrate that in normal mice, hypothalamic Foxo1 expression is reduced by the anorexigenic hormones insulin and leptin. These hormones' effects on feeding are inhibited when hypothalamic Foxo1 is activated, establishing a new signaling pathway through which insulin and leptin regulate food intake in hypothalamic neurons. Moreover, activation of Foxo1 in the hypothalamus increases food intake and body weight, whereas inhibition of Foxo1 decreases both. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, but suppresses the transcription of anorexigenic proopiomelanocortin by antagonizing the activity of signal transducer–activated transcript-3 (STAT3). Our data suggest that hypothalamic Foxo1 is an important regulator of food intake and energy balance.

miR-326-Histone Deacetylase-3 Feedback Loop Regulates the Invasion and Tumorigenic and Angiogenic Response to Anti-cancer Drugs

Kim, Youngmi,Kim, Hyuna,Park, Hyunmi,Park, Deokbum,Lee, Hansoo,Lee, Yun Sil,Choe, Jongseon,Kim, Young Myeong,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.40

<P>Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs <I>in vitro</I> and <I>in vivo</I>. TargetScan analysis predicted <I>miR-326</I> as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and <I>miR-326. miR-326</I> decreased the apoptotic effect of anti-cancer drugs, and the <I>miR-326</I> inhibitor increased the apoptotic effect of anti-cancer drugs. <I>miR-326</I> enhanced the invasion and migration potential of cancer cells. The <I>miR-326</I> inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as <I>miR-200b</I>, <I>miR-217</I>, and <I>miR-335. miR-200b</I>, <I>miR-217</I>, and <I>miR-335</I> negatively regulated the expression of <I>miR-326</I> and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted <I>miR-200b</I> and <I>miR-217</I> as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and <I>miR-326</I> acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.</P>

Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect

Kim, Youngmi,Kim, Kyungjong,Lee, Hansoo,Han, Sanghwa,Lee, Yun-Sil,Choe, Jongseon,Kim, Young-Myeong,Hahn, Jang-Hee,Ro, Jai Youl,Jeoung, Dooil Elsevier 2009 european journal of pharmacology Vol.612 No.1

<P><B>Abstract</B></P><P>The role of celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial–mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on <I>in vivo</I> atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.</P>

Evaluation of Antigen-Specific Immunoglobulin G Responses in Pulmonary Tuberculosis Patients and Contacts

Hur, Yun-Gyoung,Kim, Ahreum,Kang, Young Ae,Kim, An Sik,Kim, Dae Yeon,Kim, Yeun,Kim, Youngmi,Lee, Hyeyoung,Cho, Sang-Nae American Society for Microbiology 2015 Journal of clinical microbiology Vol.53 No.3

<P>This study aimed to evaluate the serodiagnostic potential of immunoglobulin G (IgG) responses to <I>Mycobacterium tuberculosis</I> antigens in pulmonary tuberculosis (TB) patients, recent TB contacts with latent TB infection (LTBI), and healthy subjects. Infections were assessed using tuberculin skin tests, QuantiFERON-TB Gold In-Tube tests, drug susceptibility testing, and molecular genotyping of clinical isolates. Serum IgG responses to selective <I>M. tuberculosis</I> antigens, including the 38-kDa and 16-kDa antigens, lipoarabinomannan (LAM), and recombinant early secreted antigen target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10), were determined. We found that the serum IgG responses to all antigens might differentiate between active TB and LTBI, with LAM having the highest diagnostic value (area under the curve [AUC] of 0.7756, <I>P</I> < 0.001). Recurrent TB cases showed significantly higher IgG responses to 38 kDa, CFP-10 (<I>P</I> < 0.01), and LAM (<I>P</I> < 0.05) than new cases, and male patients had higher levels of antigen-specific IgG than females (<I>P</I> < 0.05). Conversely, drug resistance and patient body mass index did not affect IgG responses (<I>P</I> > 0.05). LAM-specific IgG responses differentiated between acid-fast bacillus (AFB) smear-positive and -negative patients (<I>P</I> < 0.01), whereas antigen-specific IgG responses did not vary with the <I>M. tuberculosis</I> genotype (<I>P</I> > 0.05). Significantly higher IgG responses to 38 kDa and 16 kDa were observed in AFB smear-negative patients than in controls. These results suggest that assessment of serum IgG responses to selective purified <I>M. tuberculosis</I> antigens may help improve the diagnosis of active TB, particularly for sputum smear-negative patients or recurrent cases, and these may also help to differentiate between active TB and LTBI.</P>

A boronate-based fluorescent probe for the selective detection of cellular peroxynitrite

Kim, Jiyoung,Park, Jeesook,Lee, Hawon,Choi, Yongdoo,Kim, Youngmi The Royal Society of Chemistry 2014 Chemical communications Vol.50 No.66

<P>A boronate-based fluorescent probe <B>1</B> for the selective monitoring of intracellular peroxynitrite has been developed. The probe takes advantage of the fast reaction of an arylboronate group with peroxynitrite, yielding a corresponding phenol that undergoes spontaneous subsequent reactions to produce a strongly fluorescent product associated with a large turn-on signal.</P> <P>Graphic Abstract</P><P>A boronate-based fluorescent probe <B>1</B> for the selective monitoring of intracellular peroxynitrite has been developed. The probe takes advantage of the fast reaction of an arylboronate group with peroxynitrite, yielding a corresponding phenol that undergoes spontaneous subsequent reactions to produce a strongly fluorescent product associated with a large turn-on signal. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4cc02943g'> </P>

Restriction of television food advertising in South Korea: impact on advertising of food companies.

Kim, Soyoung,Lee, Youngmi,Yoon, Jihyun,Chung, Sang-Jin,Lee, Soo-Kyung,Kim, Hyogyoo Oxford University Press 2013 Health promotion international Vol.28 No.1

<P>The association between exposure to television (TV) food advertising and children's dietary habits has been well established in previous studies. However, the efficacy of restrictions on TV food advertising in the prevention of childhood obesity remains controversial. The South Korean government has recently enforced a regulation, termed the Special Act on Safety Management of Children's Dietary Life, which restricts TV advertising of energy-dense and nutrient-poor (EDNP) foods targeting children. This study aimed to determine the impact of this regulation by examining changes in the TV advertising practices of South Korean food companies since the scheduled enforcement date of January 2010. The total advertising budget, number of advertisement placements and gross rating points (GRPs) for advertisements on EDNP foods aired on the five representative TV channels in South Korea were compared and analyzed for the year before and after January 2010. After January 2010, the total adverting budget, number of advertisement placements and GRPs decreased during regulated hours. Even during non-regulated hours, a significant decline was noticed in the number of advertisement placements and GRPs. The total advertising budget for non-EDNP foods increased, whereas that for EDNP foods decreased at a higher rate in addition to a drop in its percentage share. These results suggest positive changes in TV advertising practices of food companies because of the regulation, thereby lowering children's exposure to TV advertising of EDNP foods and promoting a safer environment that may facilitate child health improvement in South Korea.</P>

Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy

Kim, Jin Taek,Kim, Sang Soo,Jun, Dae Won,Hwang, Young Hwan,Park, Wook‐,Ha,Pak, Youngmi Kim,Lee, Hong Kyu Wiley-Blackwell 2013 Journal of diabetes investigation Vol.4 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>Evidence is emerging that exposure to persistent organic pollutants (POPs) is a risk factor for obesity‐related diseases and for diabetes mellitus (DM). We found that POPs could be measured by a cell‐based arylhydrocarbon receptor (AhR)‐dependent reporter assay. We tested if serum AhR transactivating (AHRT) activities are a risk factor for diabetic nephropathy in people with type 2 diabetes.</P><P><B>Materials and Methods</B></P><P>We enrolled diabetic patients with normoalbuminuria (<I>n </I>= 36), microalbuminuria (<I>n </I>= 29), macroalbuminuria (<I>n </I>= 8) and end‐stage renal disease (<I>n </I>= 31). Sera were tested for their AHRT activities, which were standardized by an AhR ligand, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and expressed as TCDD equivalents (TCDDeq pmol/L).</P><P><B>Results</B></P><P>Mean serum AHRT activities were higher in patients with microalbuminuria (40.1 ± 7.1 pmol/L), macroalbuminuria (37.4 ± 5.5 pmol/L) and end‐stage renal disease (59.1 ± 20.0 pmol/L) than in subjects with normoalbuminuria (12.7 ± 5.4 pmol/L; <I>P </I>< 0.05 for all comparisons). Serum AhR ligands showed a correlation with estimated glomerular filtration rate (eGFR;<I> r </I>= −0.663, <I>P </I>< 0.001), serum creatinine level (<I>r </I>= 0.635, <I>P </I>< 0.001), systolic blood pressure (<I>r </I>= 0.223, <I>P </I>= 0.026), glycated hemoglobim (<I>r </I>= 0.339, <I>P </I>< 0.001) and diabetic duration (<I>r </I>= 0.394, <I>P </I>< 0.001). In a multiple regression analysis, diabetic nephropathy was found to be an independent risk factor for higher AHRT activity after controlling for the confounding factors.</P><P><B>Conclusions</B></P><P>The present findings suggest serum AHRT activity, thus serum AhR ligands, is a risk factor for diabetic nephropathy. Further studies are required to clarify if an accumulation of POPs in the body is causally related to diabetic nephropathy.</P>

Rapid and accurate generation of various concentration gradients using polydimethylsiloxane-sealed hydrogel device

Kim, Minseok,Jia, Mingjie,Kim, Youngmi,Kim, Taesung Springer-Verlag 2014 MICROFLUIDICS AND NANOFLUIDICS Vol.16 No.4