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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor Ambros Mar 2016

Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor Ambros

Victor R. Ambros

The double-stranded RNA-binding protein Staufen has been implicated in various post-transcriptional gene regulatory processes. Here we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3' untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs, or other ...


Effects Of Cyclopropenoid Fatty Acids On Fungal Growth And Lipid Composition, Katherine Schmid, Glenn Patterson Feb 2016

Effects Of Cyclopropenoid Fatty Acids On Fungal Growth And Lipid Composition, Katherine Schmid, Glenn Patterson

Katherine Schmid

Cyclopropenoid fatty acids (CPE) isolated fromSterculia foetida oil by urea clathration and reverse phase high performance liquid chromatography (HPLC) were introduced into fungal cultures. Stearate levels in phospholipids and triacylglycerols fromUstilago maydis sporidia rose considerably in response to 30 μM CPE. In addition, CPE themselves were incorporated into glycerolipid fractions. Sterol composition was unaffected. Changes in lipid composition were accompanied by inhibition of dry weight accumulation and sporidial number. Treated sporidia showed irregular wall deposition and a branched morphology. Oleate alleviated CPE effects on growth and morphology. Hyphal extension byRhizoctonia solani was inhibited somewhat by 30 μM sterculate, whileFusarium oxysporum ...


Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco Jan 2016

Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco

Celia A. Schiffer

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the ...


Neutron Radiography With Combined Computed Tomography: A Novel Tool For Cancer Diagnosis And Imaging (Abstract), Maria Cekanova, H Bilheux, Kusum Rathore, J Bilheux, L Walker, Robert Donnell, Alfred Legendre May 2013

Neutron Radiography With Combined Computed Tomography: A Novel Tool For Cancer Diagnosis And Imaging (Abstract), Maria Cekanova, H Bilheux, Kusum Rathore, J Bilheux, L Walker, Robert Donnell, Alfred Legendre

Alfred M Legendre DVM, MS, DACVIM

No abstract provided.


Preclinical Single-Dose Safety And Pharmacokinetic Evaluation Of Fluorocoxib A: Pilot Study Of Novel Cyclooxygenase-2-Targeted Optical Imaging Agent In A Canine Model, Maria Cekanova, M Uddin, Alfred Legendre, Gina Gaylon, Joseph Bartges, Amanda Callens, L Marnett May 2013

Preclinical Single-Dose Safety And Pharmacokinetic Evaluation Of Fluorocoxib A: Pilot Study Of Novel Cyclooxygenase-2-Targeted Optical Imaging Agent In A Canine Model, Maria Cekanova, M Uddin, Alfred Legendre, Gina Gaylon, Joseph Bartges, Amanda Callens, L Marnett

Alfred M Legendre DVM, MS, DACVIM

We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1  mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs ...


Molecular Imaging Of Cyclooxygenase-2 In Canine Transitional Cell Carcinomas In Vitro And In Vivo, Maria Cekanova, M Uddin, Joseph Bartges, Amanda Callens, Kusum Rathore, Alfred Legendre, L Wright, L Marnett Apr 2013

Molecular Imaging Of Cyclooxygenase-2 In Canine Transitional Cell Carcinomas In Vitro And In Vivo, Maria Cekanova, M Uddin, Joseph Bartges, Amanda Callens, Kusum Rathore, Alfred Legendre, L Wright, L Marnett

Maria Cekanova MS, RNDr, PhD

The enzyme COX-2 is induced at high levels in tumors but not in surrounding normal tissues, which makes it an attractive target for molecular imaging of cancer. We evaluated the ability of novel optical imaging agent, fluorocoxib A to detect urinary bladder canine transitional cell carcinomas (K9TCC). Here, we show that fluorocoxib A uptake overlapped with COX-2 expression in primary K9TCC cells in vitro. Using subcutaneously implanted primary K9TCC in athymic mice, we show specific uptake of fluorocoxib A by COX-2-expressing K9TCC xenograft tumors in vivo. Fluorocoxib A uptake by COX-2-expressing xenograft tumors was blocked by 70% (P < 0.005) when pretreated with the COX-2 selective inhibitor, celecoxib (10 mg/kg), 4 hours before intravenous administration of fluorocoxib A (1 mg/kg). Fluorocoxib A was taken up by COX-2-expressing tumors but not by COX-2-negative human UMUC-3 xenograft tumors. UMUC-3 xenograft tumors with no expression of COX-2 showed no uptake of fluorocoxib A. In addition, fluorocoxib A uptake was evaluated in five dogs diagnosed with TCC. Fluorocoxib A specifically detected COX-2-expressing K9TCC during cystoscopy in vivo but was not detected in normal urothelium. Taken together, our findings show that fluorocoxib A selectively bound to COX-2-expressing primary K9TCC cells in vitro, COX-2-expressing K9TCC xenografts tumors in nude mice, and heterogeneous canine TCC during cystoscopy in vivo. Spontaneous cancers in companion animals offer a unique translational model for evaluation of novel imaging and therapeutic agents using primary cancer cells in vitro and in heterogeneous cancers in vivo.


Modulation Of Adipose Tissue Inflammation By Bioactive Food Compounds, N. Siriwardhana, N. Kalupahana, Maria Cekanova, M. Lemieux, B. Greer, N, Moustaid-Moussa Mar 2013

Modulation Of Adipose Tissue Inflammation By Bioactive Food Compounds, N. Siriwardhana, N. Kalupahana, Maria Cekanova, M. Lemieux, B. Greer, N, Moustaid-Moussa

Maria Cekanova MS, RNDr, PhD

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating ...


Neutron Radiography With Combined Computed Tomography: A Novel Tool For Cancer Diagnosis And Imaging (Abstract), Maria Cekanova, H Bilheux, Kusum Rathore, J Bilheux, L Walker, Robert Donnell, Alfred Legendre Jan 2013

Neutron Radiography With Combined Computed Tomography: A Novel Tool For Cancer Diagnosis And Imaging (Abstract), Maria Cekanova, H Bilheux, Kusum Rathore, J Bilheux, L Walker, Robert Donnell, Alfred Legendre

Maria Cekanova MS, RNDr, PhD

No abstract provided.


Preclinical Single-Dose Safety And Pharmacokinetic Evaluation Of Fluorocoxib A: Pilot Study Of Novel Cyclooxygenase-2-Targeted Optical Imaging Agent In A Canine Model, Maria Cekanova, M Uddin, Alfred Legendre, Gina Gaylon, Joseph Bartges, Amanda Callens, L Marnett Oct 2012

Preclinical Single-Dose Safety And Pharmacokinetic Evaluation Of Fluorocoxib A: Pilot Study Of Novel Cyclooxygenase-2-Targeted Optical Imaging Agent In A Canine Model, Maria Cekanova, M Uddin, Alfred Legendre, Gina Gaylon, Joseph Bartges, Amanda Callens, L Marnett

Maria Cekanova MS, RNDr, PhD

We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1  mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs ...


Breast Cancer Cell Proliferation Is Inhibited By Bad: Regulation Of Cyclin D1, R Fernando, Js Foster, A Bible, A Ström, Rg Pestell, M Rao, Arnold Saxton, Seung Baek, K Yamaguchi, Robert Donnell, Maria Cekanova, J Wimalasena Jul 2012

Breast Cancer Cell Proliferation Is Inhibited By Bad: Regulation Of Cyclin D1, R Fernando, Js Foster, A Bible, A Ström, Rg Pestell, M Rao, Arnold Saxton, Seung Baek, K Yamaguchi, Robert Donnell, Maria Cekanova, J Wimalasena

Seung J Baek

Recent investigations suggest that functions of the proapoptotic BCL2 family members, including BAD, are not limited to regulation of apoptosis. Here we demonstrate that BAD inhibits G(1) to S phase transition in MCF7 breast cancer cells independent of apoptosis. BAD overexpression inhibited G(1) transit and cell growth as well as cyclin D1 expression. Inhibition of cyclin D1 expression was mediated through inhibition of transcription activated by AP1. Chromatin immunoprecipitation assays indicated that BAD is localized at the 12-O-tetradecanoylphorbol-13-acetate-response element (TRE) and cAMP-response element (CRE) in the cyclin D1 promoter. This was shown to reflect direct binding interactions of ...


Pulmonary Fibroblasts Stimulate The Proliferation Of Cell Lines From Human Lung Adenocarcinomas, Maria Cekanova, T Masi, Howard Plummer, M Majidi, P Fedorocko, Hildegard Schuller Aug 2011

Pulmonary Fibroblasts Stimulate The Proliferation Of Cell Lines From Human Lung Adenocarcinomas, Maria Cekanova, T Masi, Howard Plummer, M Majidi, P Fedorocko, Hildegard Schuller

Howard K. Plummer III

Human lung cancer cell lines are widely used to test anticancer drugs. These in-vitro tests, however, preclude the detection of responses to paracrine factors from surrounding stroma. We have cocultured pulmonary fibroblasts CCD-19Lu, from a healthy donor, or HLF-A, from a patient with epidermoid carcinoma of the lung, with two human pulmonary adenocarcinoma cell lines to test the hypothesis that the fibroblasts stimulate the growth of the tumor cells. Both fibroblast cell lines significantly increased the proliferation of the pulmonary adenocarcinoma cell lines in 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assays, with HLF-A fibroblasts yielding the most pronounced responses ...


Resveratrol-Induced Apoptosis Is Mediated By Early Growth Response-1, Krüppel-Like Factor 4, And Activating Transcription Factor 3, N Whitlock, J Bahn, S Lee, T Eling, Seung Baek Dec 2010

Resveratrol-Induced Apoptosis Is Mediated By Early Growth Response-1, Krüppel-Like Factor 4, And Activating Transcription Factor 3, N Whitlock, J Bahn, S Lee, T Eling, Seung Baek

Seung J Baek

Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol upregulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located ...


Molecular Characterisation Of Canine Nonsteroidal Anti-Inflammatory Drug-Activated Gene (Nag-1), K Yamaguchi, Nichelle Whitlock, Jason Liggett, Alfred Legendre, Michael Fry, Seung Baek Dec 2010

Molecular Characterisation Of Canine Nonsteroidal Anti-Inflammatory Drug-Activated Gene (Nag-1), K Yamaguchi, Nichelle Whitlock, Jason Liggett, Alfred Legendre, Michael Fry, Seung Baek

Alfred M Legendre DVM, MS, DACVIM

Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1), a divergent member of the transforming growth factor beta superfamily, was previously identified as a gene induced by several anti-tumorigenic compounds, including NSAIDs and peroxisome proliferator-activated receptor gamma (PPARgamma) ligands in humans. In this study, canine NAG-1 was characterised from a canine genomic database. Gene induction by some NSAIDs and PPARgamma ligands was demonstrated in canine osteosarcoma cell lines. Phylogenetic analysis indicates that canine NAG-1 is more homologous with the corresponding mouse and rat genes than with human NAG-1. Expression of canine NAG-1 was increased by treatment with piroxicam and SC-560 (NSAIDs) and ...


Multiple Mechanisms Are Involved In 6-Gingerol-Induced Cell Growth Arrest And Apoptosis In Human Colorectal Cancer Cells, Seong Lee, Maria Cekanova, Seung Baek Oct 2010

Multiple Mechanisms Are Involved In 6-Gingerol-Induced Cell Growth Arrest And Apoptosis In Human Colorectal Cancer Cells, Seong Lee, Maria Cekanova, Seung Baek

Maria Cekanova MS, RNDr, PhD

6-Gingerol, a natural product of ginger, has been known to possess anti-tumorigenic and pro-apoptotic activities. However, the mechanisms by which it prevents cancer are not well understood in human colorectal cancer. Cyclin D1 is a proto-oncogene that is overexpressed in many cancers and plays a role in cell proliferation through activation by beta-catenin signaling. Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and anti-tumorigenic properties. In the present study, we examined whether 6-gingerol influences cyclin D1 and NAG-1 expression and determined the mechanisms by which 6-gingerol affects the growth of human colorectal cancer cells in ...


Peroxisome Proliferator-Activated Receptor Ligand Mcc-555 Suppresses Intestinal Polyps In Apcmin/+ Mice Via Extracellular Signal-Regulated Kinase And Peroxisome Proliferator-Activated Receptor-Dependent Pathways, K Yamaguchi, Maria Cekanova, Michael Mcentee, J Yoon, S Fischer, I Renes, I Van Seungnigen, Seung Baek Oct 2010

Peroxisome Proliferator-Activated Receptor Ligand Mcc-555 Suppresses Intestinal Polyps In Apcmin/+ Mice Via Extracellular Signal-Regulated Kinase And Peroxisome Proliferator-Activated Receptor-Dependent Pathways, K Yamaguchi, Maria Cekanova, Michael Mcentee, J Yoon, S Fischer, I Renes, I Van Seungnigen, Seung Baek

Maria Cekanova MS, RNDr, PhD

A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARgamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARgamma antagonist GW9662 revealed that MUC2 ...


Autonomous Bioluminescent Expression Of The Bacterial Luciferase Gene Cassette (Lux) In A Mammalian Cell Line, Dan Close, Patterson, Ripp, Seung Baek, Sanseverino, Gary Sayler Jul 2010

Autonomous Bioluminescent Expression Of The Bacterial Luciferase Gene Cassette (Lux) In A Mammalian Cell Line, Dan Close, Patterson, Ripp, Seung Baek, Sanseverino, Gary Sayler

Seung J Baek

No abstract provided.


Cell Adhesion Property Affected By Cyclooxygenase And Lipoxygenase: Opto-Electric Approach (With Chang Kyoung Choi, Mugdha Sukhthankar, Chul-Ho Kim, Seong-Ho Lee, Anthony English, Kenneth D. Kihm., Seung Baek Dec 2009

Cell Adhesion Property Affected By Cyclooxygenase And Lipoxygenase: Opto-Electric Approach (With Chang Kyoung Choi, Mugdha Sukhthankar, Chul-Ho Kim, Seong-Ho Lee, Anthony English, Kenneth D. Kihm., Seung Baek

Seung J Baek

Expression of cyclooxygenases (COX) and lipoxygenases (LOX) has been linked to many pathophysiological phenotypes, including cell adhesion. However, many current approaches to measure cellular changes are performed only in a fixed-time point. Since cells dynamically move in conjunction with the cell matrix, there is a pressing need for dynamic or time-dependent methods for the investigation of cell properties. In the presented study, we used stable human colorectal cancer cell lines ectopically expressing COX-1, COX-2, and 15LOX-1, to investigate whether expression of COX-1, COX-2, or 15LOX-1 would affect cell adhesion using our opto-electric methodology. In a fixed-time point experiment, only COX-1- ...


A Potential Proliferative Gene, Nudt6, Is Down-Regulated By Green Tea Catechins At The Posttranscriptional Level, Seung Baek, Mugdha Sukthankar, Ck Choi, A English, Js Kim Dec 2009

A Potential Proliferative Gene, Nudt6, Is Down-Regulated By Green Tea Catechins At The Posttranscriptional Level, Seung Baek, Mugdha Sukthankar, Ck Choi, A English, Js Kim

Seung J Baek

The main aims of this study were to elucidate the effect of green tea catechins on Nudix-type motif 6 (NUDT6) suppression and to characterize NUDT6's biological activity. Our microarray data showed that the green tea component epicatechin-3-gallate suppressed NUDT6 expression, and this was confirmed by RT-PCR. Subsequently, the use of different catechins showed that the effect of epigallocatechin-3-gallate (EGCG) was stronger than that of other catechins. At the posttranscriptional level, EGCG decreased the RNA stability of NUDT6, indicating it as a potential mechanism of NUDT6 suppression. Further cloning of the 3' untranslated region of human NUDT6 mRNA resulted in ...


In Vitro Anti-Proliferative Activity Of Alcoholic Stem Extract Of Coscinium Fenestratum In Human Colorectal Cancer Cells, P Rojsanga, M Sukthankar, C Krisanapun, W Gritsanapan, D Lawson, Seung Baek Dec 2009

In Vitro Anti-Proliferative Activity Of Alcoholic Stem Extract Of Coscinium Fenestratum In Human Colorectal Cancer Cells, P Rojsanga, M Sukthankar, C Krisanapun, W Gritsanapan, D Lawson, Seung Baek

Seung J Baek

Coscinium fenestratum (Gaertn.) Colebr. is traditionally used for the treatment of cancer, arthritis and diabetes mellitus. The purpose of this study was to determine the molecular mechanisms by which this plant shows beneficial effects. An 80% ethanolic extract of C. fenestratum (80ET) was separated by its polarity into dichloromethane (DCM) and aqueous fractions (WF), and the anti-proliferative effects of 80ET, DCM and WF were investigated. Berberine, one of the major components of C. fenestratum, was used as a control. The 80ET, DCM, WF and berberine showed anti-proliferative activity as assessed by cell growth assay. Subsequently, the pro-apoptotic proteins NAG-1 and ...


Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Expression Inhibits Urethane-Induced Pulmonary Tumorigenesis In Transgenic Mice, Maria Cekanova, Seong-Ho Lee, Robert Donnell, M Sukhthankar, Te Eling, Sm Fischer, Seung Baek Apr 2009

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Expression Inhibits Urethane-Induced Pulmonary Tumorigenesis In Transgenic Mice, Maria Cekanova, Seong-Ho Lee, Robert Donnell, M Sukhthankar, Te Eling, Sm Fischer, Seung Baek

Maria Cekanova MS, RNDr, PhD

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inhibits gastrointestinal tumorigenesis in NAG-1 transgenic mice (C57/BL6 background). In the present study, we investigated whether the NAG-1 protein would alter urethane-induced pulmonary lesions in NAG-1 transgenic mice on an FVB background (NAG-1(Tg+/FVB)). NAG-1(Tg+/FVB) mice had both decreased number and size of urethane-induced tumors, compared with control littermates (NAG-1(Tg+/FVB) = 16 +/- 4 per mouse versus control = 20 +/- 7 per mouse, P < 0.05). Urethane-induced pulmonary adenomas and adenocarcinomas were observed in control mice; however, only pulmonary adenomas were observed in NAG-1(Tg+/FVB) mice. Urethane-induced tumors from control littermates and NAG-1(Tg+/FVB) mice highly expressed proteins in the arachidonic acid pathway (cyclooxygenases 1/2, prostaglandin E synthase, and prostaglandin E(2) receptor) and highly activated several kinases (phospho-Raf-1 and phosphorylated extracellular signal-regulated kinase 1/2). However, only urethane-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation was decreased in NAG-1(Tg+/FVB) mice. Furthermore, significantly increased apoptosis in tumors of NAG-1(Tg+/FVB) mice compared with control mice was observed as assessed by caspase-3/7 activity. In addition, fewer inflammatory cells were observed in the lung tissue isolated from urethane-treated NAG-1(Tg+/FVB) mice compared with control mice. These results paralleled in vitro assays using human A549 pulmonary carcinoma cells. Less phosphorylated p38 MAPK was observed in cells overexpressing NAG-1 compared with control cells. Overall, our study revealed for the first time that the NAG-1 protein inhibits urethane-induced tumor formation, probably mediated by the p38 MAPK pathway, and is a possible new target for lung cancer chemoprevention.


Signal Pathway Of 17Β-Estradiol–Induced Muc5b Expression In Human Airway Epithelial Cells, H Choi, Y Chung, H Kim, U Moon, Y Choi, I Van Seuringen, Seung Baek, H Yoon, J Yoon Dec 2008

Signal Pathway Of 17Β-Estradiol–Induced Muc5b Expression In Human Airway Epithelial Cells, H Choi, Y Chung, H Kim, U Moon, Y Choi, I Van Seuringen, Seung Baek, H Yoon, J Yoon

Seung J Baek

MUC5B is a major mucin of the human respiratory tract, and it is not clear how MUC5B expression is regulated in various airway diseases. The goal of this study was to determine the mechanisms by which 17β-estradiol induces MUC5B gene expression in airway epithelial cells. It was found that E2, a sex hormone, stimulates MUC5B gene overexpression by interaction with estrogen receptor {alpha} (ER{alpha}) and by acting through extracellular signal–regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK). Pretreatment with ER antagonist ICI 182,780 blocked both E2-induced ERK1/2-MAPK activation and MUC5B gene expression. It was ...


Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Expression Inhibits Urethane-Induced Pulmonary Tumorigenesis In Transgenic Mice, M Cekanova, S Lee, M Sukhthankar, R Donnell, T Eling, S Fischer, Seung Baek Dec 2008

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Expression Inhibits Urethane-Induced Pulmonary Tumorigenesis In Transgenic Mice, M Cekanova, S Lee, M Sukhthankar, R Donnell, T Eling, S Fischer, Seung Baek

Seung J Baek

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inhibits gastrointestinal tumorigenesis in NAG-1 transgenic mice (C57/BL6 background). In the present study, we investigated whether the NAG-1 protein would alter urethane-induced pulmonary lesions in NAG-1 transgenic mice on an FVB background (NAG-1(Tg+/FVB)). NAG-1(Tg+/FVB) mice had both decreased number and size of urethane-induced tumors, compared with control littermates (NAG-1(Tg+/FVB) = 16 +/- 4 per mouse versus control = 20 +/- 7 per mouse, P < 0.05). Urethane-induced pulmonary adenomas and adenocarcinomas were observed in control mice; however, only pulmonary adenomas were observed in NAG-1(Tg+/FVB) mice. Urethane-induced tumors from control littermates and NAG-1(Tg+/FVB) mice highly expressed proteins in the arachidonic acid pathway (cyclooxygenases 1/2, prostaglandin E synthase, and prostaglandin E(2) receptor) and highly activated several kinases (phospho-Raf-1 and phosphorylated extracellular signal-regulated kinase 1/2). However, only urethane-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation was decreased in NAG-1(Tg+/FVB) mice. Furthermore, significantly increased apoptosis in tumors of NAG-1(Tg+/FVB) mice compared with control mice was observed as assessed by caspase-3/7 activity. In addition, fewer inflammatory cells were observed in the lung tissue isolated from urethane-treated NAG-1(Tg+/FVB) mice compared with control mice. These results paralleled in vitro assays using human A549 pulmonary carcinoma cells. Less phosphorylated p38 MAPK was observed in cells overexpressing NAG-1 compared with control cells. Overall, our study revealed for the first time that the NAG-1 protein inhibits urethane-induced tumor formation, probably mediated by the p38 MAPK pathway, and is a possible new target for lung cancer chemoprevention


Changes In Hepatic Gene Expression In Dogs With Experimentally Induced Nutritional Iron Deficiency, M Fry, C Kirk, J Liggett, G Daniel, Seung Baek, J Gouffon, P Chimakurthy, B Rekapalli Dec 2008

Changes In Hepatic Gene Expression In Dogs With Experimentally Induced Nutritional Iron Deficiency, M Fry, C Kirk, J Liggett, G Daniel, Seung Baek, J Gouffon, P Chimakurthy, B Rekapalli

Seung J Baek

BACKGROUND AND OBJECTIVE: We investigated hepatic gene expression in dogs with experimentally induced nutritional iron deficiency (ID). Our hypothesis was that ID would result in decreased hepcidin gene expression, and possibly in altered expression of other genes associated with iron metabolism. METHODS: Liver biopsies were collected from each of 3 dogs before induction of ID, at the point of maximal ID, and after resolution of ID. Using Affymetrix microarray technology and analytical tools specifically designed for microarray data, we identified genes that had at least a 2-fold change in expression in response to ID. Four genes were selected for further ...


The Cyclooxygenase Inhibitor Sulindac Sulfide Inhibits Ep4 Expression And Suppresses The Growth Of Glioblastoma Cells, A Kambe, H Yoshioka, H Kamitani, T Watanabe, Seung Baek, T Eling Dec 2008

The Cyclooxygenase Inhibitor Sulindac Sulfide Inhibits Ep4 Expression And Suppresses The Growth Of Glioblastoma Cells, A Kambe, H Yoshioka, H Kamitani, T Watanabe, Seung Baek, T Eling

Seung J Baek

EP4 expression in human glioblastoma cells correlates with growth on soft agar. The cyclooxygenase inhibitor sulindac sulfide first altered specificity protein-1 (Sp-1) and early growth response gene-1 expression, then increased the expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3, and then decreased EP4 expression. EP4 suppression was dependent on blocking the Sp-1 binding sites in the human EP4 promoter. Mutation in the Sp-1 sites in EP4 altered the promoter activity and abolished sulindac sulfide effects. The inhibitory effect of sulindac sulfide on EP4 expression was reversed by PD98059, a mitogen-activated protein/extracellular signal-regulated kinase kinase-1/extracellular ...


A Reciprocal Relationship Exists Between Non-Steroidal Anti-Inflammatory Drug-Activated Gene-1 (Nag-1) And Cyclooxygenase-2, G Iguchi, K Chrysovergis, S Lee, Seung Baek, R Langenbach, T Eling Dec 2008

A Reciprocal Relationship Exists Between Non-Steroidal Anti-Inflammatory Drug-Activated Gene-1 (Nag-1) And Cyclooxygenase-2, G Iguchi, K Chrysovergis, S Lee, Seung Baek, R Langenbach, T Eling

Seung J Baek

Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) and COX-2 are involved in cellular processes such as inflammation, apoptosis, and tumorigenesis. To address the relationship between COX-2 and NAG-1 expression, we investigated the expression of NAG-1 and COX-2 in normal and tumor tissue from human patients, Apc(Min/+) mice, and COX-2(-/-) mice. While COX-2 expression is highly induced in tumor tissue, NAG-1 expression is reduced. Furthermore, PGE(2) reduces NAG-1 while celebrex induces NAG-1 expression. The results suggest that a possible inverse relationship exists between the expression of NAG-1 and COX-2 in tumor formation of colon tissue.


Ese-1/Egr-1 Pathway Plays A Role In Tolfenamic Acid-Induced Apoptosis In Colorectal Cancer Cells, Seong Lee, J Bahn, C Choi, Nichelle Whitlock, A English, S Safe, Seung Baek Nov 2008

Ese-1/Egr-1 Pathway Plays A Role In Tolfenamic Acid-Induced Apoptosis In Colorectal Cancer Cells, Seong Lee, J Bahn, C Choi, Nichelle Whitlock, A English, S Safe, Seung Baek

Seung J Baek

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to prevent colorectal tumorigenesis. Although antitumor effects of NSAIDs are mainly due to inhibition of cyclooxygenase activity, there is increasing evidence that cyclooxygenase-independent mechanisms may also play an important role. The early growth response-1 (EGR-1) gene is a member of the immediate-early gene family and has been identified as a tumor suppressor gene. Tolfenamic acid is a NSAID that exhibits anticancer activity in a pancreatic cancer model. In the present study, we investigated the anticancer activity of tolfenamic acid in human colorectal cancer cells. Tolfenamic acid treatment inhibited cell growth and induced apoptosis as ...


Peroxisome Proliferator-Activated Receptor Ligand Mcc-555 Suppresses Intestinal Polyps In Apcmin/+ Mice Via Extracellular Signal-Regulated Kinase And Peroxisome Proliferator-Activated Receptor-Dependent Pathways, K Yamaguchi, Maria Cekanova, Michael Mcentee, J Yoon, S Fischer, I Renes, I Van Seungnigen, Seung Baek Aug 2008

Peroxisome Proliferator-Activated Receptor Ligand Mcc-555 Suppresses Intestinal Polyps In Apcmin/+ Mice Via Extracellular Signal-Regulated Kinase And Peroxisome Proliferator-Activated Receptor-Dependent Pathways, K Yamaguchi, Maria Cekanova, Michael Mcentee, J Yoon, S Fischer, I Renes, I Van Seungnigen, Seung Baek

Seung J Baek

A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARgamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARgamma antagonist GW9662 revealed that MUC2 ...


Epigallocatechin-3-Gallate Inhibits Interleukin-1beta-Induced Muc5ac Gene Expression And Muc5ac Secretion In Normal Human Nasal Epithelial Cells, H Kim, S Park, S Park, U Moon, B Lee, S Yoon, J Lee, Seung Baek, J Yoon Jul 2008

Epigallocatechin-3-Gallate Inhibits Interleukin-1beta-Induced Muc5ac Gene Expression And Muc5ac Secretion In Normal Human Nasal Epithelial Cells, H Kim, S Park, S Park, U Moon, B Lee, S Yoon, J Lee, Seung Baek, J Yoon

Seung J Baek

It has been reported that the proinflammatory cytokine interleukin-1beta (IL-1beta) induces mucus hypersecretion in normal human nasal epithelial (NHNE) cells and that the MAP kinase pathway may be an important signal pathway in IL-1beta-induced MUC5AC gene expression. Green tea (Camellia sinensis) polyphenols are potent anti-inflammatory agents and have been shown to inhibit inflammation in tumor cell lines and cultured respiratory epithelial cells. In this study, we examined the effect of (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on IL-1beta-induced MUC5AC gene expression and secretion in NHNE cells. After cells had been treated with IL-1beta (10 ng/ml) and pretreated with EGCG ...


A Green Tea Component Suppresses Posttranslational Expression Of Basic Fibroblast Growth Factor In Colorectal Cancer, M Sukthanka, K Yamaguchi, Sh Lee, Michael Mcentee, T Eling, Y Hara, Seung Baek May 2008

A Green Tea Component Suppresses Posttranslational Expression Of Basic Fibroblast Growth Factor In Colorectal Cancer, M Sukthanka, K Yamaguchi, Sh Lee, Michael Mcentee, T Eling, Y Hara, Seung Baek

Seung J Baek

BACKGROUND & AIMS: Green tea catechins are known to have anticarcinogenic effects. Epigallocatechin-3-gallate (EGCG) accounts for almost 50% of the total catechin content in green tea extract and has very potent antioxidant effects. EGCG also inhibits angiogenesis, possibly through the inhibition of proangiogenic factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn, inhibits tumor growth and metastasis. However, the exact molecular mechanism by which EGCG suppresses bFGF expression is not known. Our objective was to elucidate the molecular mechanisms by which EGCG inhibits bFGF expression in colorectal cancer. METHODS: We examined posttranslational regulation of ...


Gene Alterations By Peroxisome Proliferator-Activated Receptor Gamma Agonists In Human Colorectal Cancer Cells, Maria Cekanova, X Li, J Yuan, K Kim, Seung Baek Mar 2008

Gene Alterations By Peroxisome Proliferator-Activated Receptor Gamma Agonists In Human Colorectal Cancer Cells, Maria Cekanova, X Li, J Yuan, K Kim, Seung Baek

Seung J Baek

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear transcription factor that controls the genes involved in metabolism and carcinogenesis. In the present study, we examined the alteration of gene expression in HCT-116 human colorectal cancer cells by PPARgamma agonists: MCC-555 (5 microM), rosiglitazone (5 microM), and 15-deoxy-Delta12,14-prostaglandin J2 (1 microM). The long-oligo microarray data revealed a list of target genes commonly induced (307 genes) and repressed (32 genes) by tested PPARgamma agonists. These genes were analyzed by Onto-Express software and KEGG pathway analysis and revealed that PPARgamma agonists are involved in cell proliferation, focal adhesion, and several signaling ...