82 results on '"Ichiro Takada"'
Search Results
2. Peroxisome proliferator-activated receptor agonists and antagonists: a patent review (2014-present)
- Author
-
Ichiro Takada and Makoto Makishima
- Subjects
Mitochondrial disease ,Peroxisome proliferator-activated receptor ,Inflammation ,Type 2 diabetes ,Pharmacology ,Ligands ,01 natural sciences ,PPAR agonist ,Patents as Topic ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,Drug Discovery ,Animals ,Humans ,Medicine ,PPAR alpha ,PPAR delta ,Receptor ,chemistry.chemical_classification ,Autoimmune disease ,business.industry ,General Medicine ,medicine.disease ,0104 chemical sciences ,PPAR gamma ,010404 medicinal & biomolecular chemistry ,Nuclear receptor ,chemistry ,030220 oncology & carcinogenesis ,medicine.symptom ,business - Abstract
Introduction: Peroxisome proliferator-activated receptors (PPARs), PPARα, PPARδ, and PPARγ, play an important role in the regulation of various physiological processes, specifically lipid and energy metabolism and immunity. PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism but PPARδ-acting drugs are not yet available. Many synthetic ligands for PPARs have been developed to expand their therapeutic applications.Areas covered: The authors searched recent patent activity regarding PPAR ligands. Novel PPARα agonists, PPARδ agonists, PPARγ agonists, PPARα/γ dual agonists, and PPARγ antagonists have been claimed for the treatment of metabolic disease and inflammatory disease. Methods for the combination of PPAR ligands with other drugs and expanded application of PPAR agonists for bone and neurological disease have been also claimed.Expert opinion: Novel PPAR ligands and the combination of PPAR ligands with other drugs have been claimed for the treatment of mitochondrial disease, inflammatory/autoimmune disease, neurological disease, and cancer in addition to metabolic diseases including dyslipidemia and type 2 diabetes. Selective therapeutic actions of PPAR ligands should be exploited to avoid adverse effects. More basic studies are needed to elucidate the molecular mechanisms of selective actions.
- Published
- 2019
3. Transcriptional coregulator Ess2 controls survival of post-thymic CD4
- Author
-
Ichiro, Takada, Shinya, Hidano, Sayuri, Takahashi, Kaori, Yanaka, Hidesato, Ogawa, Megumi, Tsuchiya, Atsushi, Yokoyama, Shingo, Sato, Hiroki, Ochi, Tohru, Nakagawa, Takashi, Kobayashi, Shinichi, Nakagawa, and Makoto, Makishima
- Subjects
CD4-Positive T-Lymphocytes ,Mice, Knockout ,Transcription, Genetic ,Cell Survival ,Interleukin-7 ,Nuclear Proteins ,Cell Differentiation ,Thymus Gland ,CD8-Positive T-Lymphocytes ,Proto-Oncogene Proteins c-myc ,Mice ,Animals ,Humans ,Natural Killer T-Cells ,Signal Transduction - Abstract
Ess2, also known as Dgcr14, is a transcriptional co-regulator of CD4
- Published
- 2021
4. FGFR2 loss sensitizes MYCN-amplified neuroblastoma CHP134 cells to CHK1 inhibitor-induced apoptosis
- Author
-
Takehiko Kamijo, Tsugumichi Koshinaga, Miki Ohira, Ichiro Takada, Hiroki Nagase, Makoto Makishima, Yusuke Suenaga, Shinichi Kobayashi, Kiyohiro Ando, Satoshi Wada, and Verna Cázares-Ordoñez
- Subjects
MAPK/ERK pathway ,Cancer Research ,MAP Kinase Signaling System ,Pyridones ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Apoptosis ,Pyrimidinones ,Neuroblastoma ,Cell Line, Tumor ,medicine ,Humans ,CHEK1 ,RNA, Messenger ,Receptor, Fibroblast Growth Factor, Type 2 ,Protein Kinase Inhibitors ,Trametinib ,N-Myc Proto-Oncogene Protein ,Fibroblast growth factor receptor 2 ,Chemistry ,Cell growth ,MEK inhibitor ,Gene Amplification ,Drug Synergism ,General Medicine ,Cell cycle ,medicine.disease ,Prognosis ,Oncology ,Drug Resistance, Neoplasm ,Checkpoint Kinase 1 ,Cancer research - Abstract
Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. In this study, one CHK1i-sensitive neuroblastoma cell line, CHP134, was investigated, which characteristically carries MYCN amplification and a chromosome deletion within the 10q region. Among several cancer-related genes in the chromosome 10q region, mRNA expression of fibroblast growth factor receptor 2 (FGFR2) was altered in CHP134 cells and associated with an unfavorable prognosis of patients with neuroblastoma. Induced expression of FGFR2 in CHP134 cells reactivated downstream MEK/ERK signaling and resulted in cells resistant to CHK1i-mediated cell growth inhibition. Consistently, the MEK1/2 inhibitor, trametinib, potentiated CHK1 inhibitor-mediated cell death in these cells. These results suggested that FGFR2 loss might be prone to highly effective CHK1i treatment. In conclusion, extreme cellular dependency of ERK activation may imply a possible application for the MEK1/2 inhibitor, either as a single inhibitor or in combination with CHK1i in MYCN-amplified neuroblastomas.
- Published
- 2021
5. Transcriptional coregulator Ess2 controls survival of post-thymic CD4+ T cells through the Myc and IL-7 signaling pathways
- Author
-
Ichiro Takada, Shinya Hidano, Sayuri Takahashi, Kaori Yanaka, Hidesato Ogawa, Megumi Tsuchiya, Atsushi Yokoyama, Shingo Sato, Hiroki Ochi, Tohru Nakagawa, Takashi Kobayashi, Shinichi Nakagawa, and Makoto Makishima
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2022
6. The ribosomal S6 kinase inhibitor BI-D1870 ameliorated experimental autoimmune encephalomyelitis in mice
- Author
-
Makoto Makishima, Ichiro Takada, and Yoshiko Yogiashi
- Subjects
Central Nervous System ,Receptors, CCR6 ,0301 basic medicine ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Immunology ,Central nervous system ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 6 ,Biology ,Ribosomal Protein S6 Kinases, 90-kDa ,Ribosomal s6 kinase ,Mice ,03 medical and health sciences ,Cell Movement ,RAR-related orphan receptor gamma ,In vivo ,medicine ,Demyelinating disease ,Animals ,Immunology and Allergy ,RNA, Messenger ,Protein Kinase Inhibitors ,Pteridines ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,hemic and immune systems ,Hematology ,Th1 Cells ,medicine.disease ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer research ,biology.protein ,Th17 Cells ,Myelin-Oligodendrocyte Glycoprotein ,Signal Transduction - Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) caused by the infiltration of TH1 and TH17 cells into the CNS. Ribosomal S6 kinase 2 (RSK2; RPS6KA3) regulates TH17 differentiation by attenuating RORγt transcriptional activities and IL-17A production. The pan-RSK inhibitor BI-D1870 also inhibits TH17 differentiation, but the effect of BI-D1870 in vivo remains unclear. Here, we generated mice with experimental autoimmune encephalomyelitis (EAE) and treated them with BI-D1870. BI-D1870 administration protected mice from EAE by reducing the infiltration of TH1 and TH17 cells into the CNS and decreasing mRNA levels of Ccr6 in TH17 cells. These results suggest that RSK inhibition is a promising strategy for the treatment of MS.
- Published
- 2016
7. Farnesoid X Receptor Activation Enhances Transforming Growth Factor β-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells
- Author
-
Makoto Makishima, Keiji Sano, Masahiko Kainuma, and Ichiro Takada
- Subjects
0301 basic medicine ,Receptors, Cytoplasmic and Nuclear ,epithelial–mesenchymal transition ,lcsh:Chemistry ,chemistry.chemical_compound ,Chenodeoxycholic acid ,Receptor ,transforming growth factor β ,lcsh:QH301-705.5 ,Spectroscopy ,Bile acid ,Liver Neoplasms ,Obeticholic acid ,General Medicine ,hepatocellular carcinoma ,Cadherins ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Liver ,Carcinoma, Hepatocellular ,Epithelial-Mesenchymal Transition ,medicine.drug_class ,guggulsterone ,Chenodeoxycholic Acid ,Catalysis ,Article ,Inorganic Chemistry ,Bile Acids and Salts ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,bile acid ,Epithelial–mesenchymal transition ,Physical and Theoretical Chemistry ,Molecular Biology ,N-cadherin ,Organic Chemistry ,focal adhesion kinase ,Isoxazoles ,digestive system diseases ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Cancer research ,Farnesoid X receptor ,Guggulsterone ,farnesoid X receptor ,Transforming growth factor - Abstract
Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial&ndash, mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)&mdash, but not an antagonist (guggulsterone)&mdash, induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor &beta, (TGF-&beta, ). FXR agonist treatment enhanced TGF-&beta, induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-&beta, Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.
- Published
- 2018
8. Ess2 bridges transcriptional regulators and spliceosomal complexes via distinct interacting domains
- Author
-
Sayuri Takahashi, Makoto Makishima, Kaori Yanaka, Megumi Tsuchiya, Sinichi Nakagawa, Takashi Kobayashi, Shinya Hidano, Ichiro Takada, and Hidesato Ogawa
- Subjects
0301 basic medicine ,Transcriptional Activation ,Spliceosome ,RNA Splicing ,Biophysics ,Biochemistry ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Transcription (biology) ,RNA, Small Nuclear ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Nuclear protein ,Molecular Biology ,Transcription factor ,Orphan receptor ,Gene knockdown ,urogenital system ,Chemistry ,Nuclear Proteins ,Cell Biology ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Cell biology ,030104 developmental biology ,HEK293 Cells ,Gene Knockdown Techniques ,RNA splicing ,Mutation ,Spliceosomes ,030217 neurology & neurosurgery ,Small nuclear RNA - Abstract
Transcription and pre-mRNA splicing are complex, coupled processes that involve transcriptional co-regulators. Ess2 (also termed Dgcr14) is a nuclear protein that enhances the transcriptional activity of retinoic acid receptor-related orphan receptor gamma/gamma-t (Rorγ/γt). Ess2 is also a component of the spliceosomal C complex (containing U2, U5 and U6 snRNAs). However, the domains in Ess2 that function in splicing and transcription have not been identified. To elucidate the roles of Ess2 in splicing and transcription, we performed RNA immunoprecipitation (RIP) assays to detect Ess2-interacting snRNAs. We found that Ess2 associated with U6 snRNA as well as U1 and U4 snRNAs. Experiments using Ess2 deletion mutants showed that a C-terminus deletion mutant of Ess2 (1-399 a. a.) lost its ability to associate with snRNAs, whereas the N-terminus domain of Ess2 (1-200 a. a.) associated with Rorγ/γt, but not with snRNAs. Interestingly, experiments using anti-ROR common antibody showed that Rors also associated with U4 and U6 snRNAs. Ess2 knockdown in a T cell hybridoma (68-41 cells) abrogated the interaction between spliceosomes and Rors. An Ess2-dependent association was also found between an lncRNA (Rmrp) and Rors. We thus propose that Ess2 associates with both transcriptional factors and spliceosomal complexes and modulates splicing reactions coupled with transcription factors.
- Published
- 2018
9. Therapeutic application of vitamin D receptor ligands: an updated patent review
- Author
-
Ichiro Takada and Makoto Makishima
- Subjects
Inflammation ,Pharmacology ,Ligands ,Calcitriol receptor ,Patents as Topic ,In vivo ,Drug Discovery ,Vitamin D and neurology ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Vitamin D ,Autoimmune disease ,business.industry ,Cancer ,Vitamins ,General Medicine ,medicine.disease ,Nuclear receptor ,Drug Design ,Hypercalcemia ,Receptors, Calcitriol ,medicine.symptom ,business ,Hepatic fibrosis - Abstract
The vitamin D receptor (VDR) is a promising drug target in the treatment of cancer, autoimmune disease, inflammation, infection and cardiovascular disease, as well as bone and mineral disorders. Although many VDR ligands have been developed and shown to activate VDR in vitro and in vivo, including vitamin D derivatives and non-secosteroidal compounds, a principal adverse effect of hypercalcemia has limited their clinical application.We summarize recent patent activity regarding VDR ligands, including vitamin D derivatives, non-secosteroidal compounds and tissue-selective prodrugs, alongside their therapeutic applications. The potential for use of VDR ligands in the treatment of hepatic fibrosis, pancreatic fibrosis and neuronal disease is also reviewed.Several VDR ligands have been shown to have increased therapeutic efficiency in experimental models of cancer, inflammation and cardiovascular disease, and to exhibit function-selective and/or tissue-selective activity. The underlying molecular and pharmacological mechanisms remain to be elucidated. Further studies, both basic and applied, should make successful VDR-targeting therapy possible.
- Published
- 2015
10. Structural Features and Transcriptional Activity of Chicken PPARs (α,β, andγ)
- Author
-
Mime Kobayashi and Ichiro Takada
- Subjects
chemistry.chemical_classification ,Gene isoform ,biology ,Peroxisome proliferator-activated receptor ,Lipid metabolism ,Carbohydrate metabolism ,Bioinformatics ,Transactivation ,Biochemistry ,chemistry ,Drug Discovery ,biology.protein ,Pharmacology (medical) ,Bovine serum albumin ,Gene ,Function (biology) - Abstract
While an understanding of lipid metabolism in chickens is critical for a further improvement of food production, there are few studies concerning differences in lipid metabolism mechanisms between chickens and other species at a molecular level. Chickens have three PPAR gene subtypes (α,β, andγ) that function differently from those present in humans and mice. The chicken PPAR-gamma (cPPARγ) gene is shorter than that in humans and lacks aγ2 isoform. Moreover, in serum-free media, cPPARγshows high transcriptional activity without exogenous ligands. Luciferase reporter assays were used to examine the effect of sera on cPPAR transcriptional activities and showed that adult bovine serum and chicken serum highly activate cPPARαandβfunctions. Moreover, we found that bezafibrate induces the transactivation function of cPPARβ, but not human PPARδ(human PPARβortholog). This ligand selectivity relies on one amino acid residue (chicken: Val419, human: Met444). These results show the possibilities for unique functions of cPPARs on chicken-specific lipid glucose metabolism. As such, a better understanding of the molecular mechanisms of lipid metabolism in chickens could result in higher productivity for the poultry industry.
- Published
- 2013
11. Control of Inflammatory Bowel Disease and Colorectal Cancer by Synthetic Vitamin D Receptor Ligands
- Author
-
Makoto Makishima and Ichiro Takada
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Lithocholic acid ,Colorectal cancer ,Biology ,Ligands ,Biochemistry ,Inflammatory bowel disease ,Calcitriol receptor ,vitamin D deficiency ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Internal medicine ,Drug Discovery ,medicine ,Vitamin D and neurology ,Animals ,Humans ,Pharmacology ,Organic Chemistry ,Cancer ,medicine.disease ,Inflammatory Bowel Diseases ,030104 developmental biology ,Endocrinology ,chemistry ,Molecular Medicine ,Receptors, Calcitriol ,Colorectal Neoplasms - Abstract
Vitamin D deficiency and insufficiency are associated with an increased risk of cancer, autoimmune disease, inflammation, infection, cardiovascular disease and metabolic disease, as well as bone and mineral disorders. The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, is a receptor for the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and mediates vitamin D regulation of specific target gene expression. The secondary bile acid lithocholic acid, which is produced by intestinal bacteria, is another natural VDR ligand. VDR signaling has been suggested to be involved in reciprocal communication between intestinal cells, including immune and epithelial cells, and intestinal microflora. In addition to epidemiological studies on vitamin D status, genome-wide analyses and cellular and animal experiments have shown that VDR is involved in the prevention of inflammatory bowel disease (IBD) and colorectal cancer (CRC). VDR deletion in mice exaggerates colitis and colon tumorigenesis in experimental models, and treatment of mice with synthetic vitamin D analogues ameliorates pathological changes in these diseases. Several VDR ligands are less active in increasing serum calcium levels, showing higher therapeutic efficiency than the natural hormone 1,25(OH)2D3. VDR plays a role in intestinal homeostasis and in protection against IBD and CRC. The development of VDR ligands with reduced or no calcemic activity will be necessary to expand clinical application of VDRtargeting therapy.
- Published
- 2016
12. Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway
- Author
-
Yuki Sugiyama, Masatoshi Nomura, Ikko Kashiwagi, Tomohito Takimoto, Akihiro Kimura, Akihiko Yoshimura, Tomohiro Fukaya, Rimpei Morita, Ichiro Takada, Taiga Tamiya, Yu Wakabayashi, and Naoko Inoue
- Subjects
CD4-Positive T-Lymphocytes ,Methyltransferase ,Transcription, Genetic ,T cell ,Immunology ,Smad2 Protein ,Biology ,Methylation ,Biochemistry ,Histones ,Mice ,Histone H3 ,Transforming Growth Factor beta ,Histone methylation ,medicine ,Animals ,Gene Silencing ,Smad3 Protein ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,Cells, Cultured ,Mice, Knockout ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,Cell Biology ,Transforming growth factor beta ,biochemical phenomena, metabolism, and nutrition ,Molecular biology ,Repressor Proteins ,medicine.anatomical_structure ,Histone methyltransferase ,Histone Methyltransferases ,biology.protein ,Interleukin-2 - Abstract
Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4(+) T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2(-/-)Smad3(+/-) T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.
- Published
- 2011
13. Transcriptionally active nuclei are selective in mature multinucleated osteoclasts
- Author
-
Min Young Youn, Hisataka Yasuda, Ichiro Takada, Yuuki Imai, and Shigeaki Kato
- Subjects
Cell type ,biology ,Cell ,Cell Biology ,Molecular biology ,Cell biology ,Histone ,Multinucleate ,medicine.anatomical_structure ,Nuclear receptor ,Cytoplasm ,Genetics ,biology.protein ,medicine ,Nuclear protein ,Nucleus - Abstract
Multinucleation is indispensable for the bone-resorbing activity of mature osteoclasts. Although multinucleation is evident in mature osteoclasts and certain other cell types, putative regulatory networks among nuclei remain poorly characterized. To address this issue, transcriptional activity of each nucleus in a multinucleated osteoclast was assessed by detecting the distributions of nuclear proteins by immunocytochemistry and primary transcripts by RNA FISH. Patterns of epigenetic histone markers governing transcription as well as localization of tested nuclear receptor proteins appeared indistinguishable among nuclei in differentiated Raw264 cells and mouse mature osteoclasts. However, RNAPII-Ser5P/2P and NFATc1 proteins were selectively distributed in certain nuclei in the same cell. Similarly, the distributions of primary transcripts for osteoclast-specific genes (Nfatc1, Ctsk and Acp5) as well as a housekeeping gene (beta-tubulin) were limited in certain nuclei within individual cells. By fusing two Raw264 cell lines that stably expressed ZsGreen-NLS and DsRed-NLS proteins, transmission of nuclear proteins across all of the nuclei in a cell could be observed, presumably through the shared cytoplasm. Taken together, we conclude that although nuclear proteins are diffusible among nuclei, only certain nuclei within a multinucleated osteoclast are transcriptionally active.
- Published
- 2010
14. Purification and identification of estrogen receptor alpha co-regulators in osteoclasts
- Author
-
Yuuki Imai, Naoya Tsuji, Sally Fujiyama, Maiko Okada, Hisataka Yasuda, Shigeaki Kato, Shino Kondo, Hirochika Kitakawa, Min-Young Youn, and Ichiro Takada
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,General Neuroscience ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Fas ligand ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,Multinucleate ,Endocrinology ,History and Philosophy of Science ,Osteoclast ,Internal medicine ,medicine ,Transcriptional regulation ,Stem cell ,Estrogen receptor alpha ,Transcription factor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Mature osteoclasts are multinuclear, macrophage-like cells derived from hematopoietic stem cells in the bone marrow. Several transcription factors regulating osteoclast differentiation have been identified. However, the molecular basis of transcriptional regulation in osteoclasts at epigenetic levels is largely unknown. In fact, no osteoclast-specific transcriptional co-regulators have been characterized. Recently, selective ablation of estrogen receptor alpha (ERalpha) in mature osteoclasts derived from female mice (ERalpha(Deltaoc/Deltaoc)) exhibited trabecular bone loss due to induced apoptosis via upregulated expression of Fas ligand mRNA. In general, the component composition of the ERalpha-associated co-activator complex and its expression levels are distinct among tissues. However, ERalpha transcriptional co-regulators in mature osteoclasts remain unclear. In the present study, we achieved large-scale cultivation of mature, multinucleated osteoclasts and established a purification system for ERalpha-associated proteins. In addition to co-regulators previously found in other ERalpha target cells, several unexpected factors were found such as CAP-H. The mRNA expression level of CAP-H was high during osteoclast differentiation. These results demonstrate the existence of osteoclast-specific transcriptional co-regulators supporting ERalpha function.
- Published
- 2010
15. DNA demethylation in hormone-induced transcriptional derepression
- Author
-
Ikuko Yamaoka, Hiroshi Shibuya, Takahiro Matsumoto, Sayuri Takahashi, Shigeaki Kato, Ichiro Takada, Yuko Shirode, Sally Fujiyama, Ken-ichi Takeyama, Yoko Yamamoto, Min Young Youn, Takeshi Kondo, Fumiaki Ohtake, Hirochika Kitagawa, and Mi Sun Kim
- Subjects
DNA (Cytosine-5-)-Methyltransferase 1 ,Transcription, Genetic ,Epigenetics in learning and memory ,Down-Regulation ,Biology ,Response Elements ,Cell Line ,DNA Glycosylases ,MBD4 ,Mice ,Epigenetics of physical exercise ,Animals ,DNA (Cytosine-5-)-Methyltransferases ,Cancer epigenetics ,Phosphorylation ,Vitamin D ,RNA-Directed DNA Methylation ,Protein Kinase C ,Epigenomics ,25-Hydroxyvitamin D3 1-alpha-Hydroxylase ,Endodeoxyribonucleases ,Multidisciplinary ,DNA Methylation ,Molecular biology ,DNA demethylation ,Parathyroid Hormone ,DNA methylation ,CpG Islands - Abstract
Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.
- Published
- 2009
16. Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF)
- Author
-
Rumiko Matsuoka, Yoko Yamamoto, Hisato Yagi, Masahiko Tanabe, Jun K. Takeuchi, Takeyoshi Masuda, Hirochika Kitagawa, Dean Y. Li, Yoshiyuki Furutani, Shin Yoshinaga, Ryoji Fujiki, Shigeaki Kato, Toru Fukuda, Kanae Ebihara, Masayoshi Yonezawa, Ichiro Takada, Shinichiro Takezawa, Kimihiro Yoshimura, Takahiro Matsumoto, Ikuko Yamaoka, and Takeshi Kondo
- Subjects
Multidisciplinary ,Histone ,biology ,biology.protein ,Transcriptional regulation ,WICH complex ,Biological Sciences ,Molecular biology ,Transcription factor ,SWI/SNF ,Chromatin remodeling ,Chromatin ,Proliferating cell nuclear antigen - Abstract
A number of nuclear complexes modify chromatin structure and operate as functional units. However, the in vivo role of each component within the complexes is not known. ATP-dependent chromatin remodeling complexes form several types of protein complexes, which reorganize chromatin structure cooperatively with histone modifiers. Williams syndrome transcription factor (WSTF) was biochemically identified as a major subunit, along with 2 distinct complexes: WINAC, a SWI/SNF-type complex, and WICH, an ISWI-type complex. Here, WSTF −/− mice were generated to investigate its function in chromatin remodeling in vivo. Loss of WSTF expression resulted in neonatal lethality, and all WSTF −/− neonates and ≈10% of WSTF +/− neonates suffered cardiovascular abnormalities resembling those found in autosomal-dominant Williams syndrome patients. Developmental analysis of WSTF −/− embryos revealed that Gja5 gene regulation is aberrant from E9.5, conceivably because of inappropriate chromatin reorganization around the promoter regions where essential cardiac transcription factors are recruited. In vitro analysis in WSTF −/− mouse embryonic fibroblast (MEF) cells also showed impaired transactivation functions of cardiac transcription activators on the Gja5 promoter, but the effects were reversed by overexpression of WINAC components. Likewise in WSTF −/− MEF cells, recruitment of Snf2h, an ISWI ATPase, to PCNA and cell survival after DNA damage were both defective, but were ameliorated by overexpression of WICH components. Thus, the present study provides evidence that WSTF is shared and is a functionally indispensable subunit of the WICH complex for DNA repair and the WINAC complex for transcriptional control.
- Published
- 2009
17. Molecular switching of osteoblastogenesis versus adipogenesis: implications for targeted therapies
- Author
-
Alexander Kouzmenko, Shigeaki Kato, and Ichiro Takada
- Subjects
medicine.medical_specialty ,Cellular differentiation ,Clinical Biochemistry ,Bone Marrow Cells ,Epigenesis, Genetic ,Transactivation ,Drug Delivery Systems ,Osteogenesis ,Neoplasms ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Transcription factor ,beta Catenin ,Transrepression ,Pharmacology ,Adipogenesis ,Osteoblasts ,Guided Tissue Regeneration ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Wnt signaling pathway ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell biology ,PPAR gamma ,Wnt Proteins ,Endocrinology ,Adipose Tissue ,Gene Expression Regulation ,Histone methyltransferase ,Cytokines ,Molecular Medicine ,Signal transduction ,Signal Transduction - Abstract
Osteoblasts and adipocytes differentiate from a common precursor, the pluripotent mesenchymal stem cell (MSC) found in bone marrow (BMSC) and adipose tissue (AD-MSC). Numerous transcription factors and multiple extracellular and intracellular signals regulating adipogenesis and osteoblastogenesis have been identified and analyzed. Significantly, inducers of differentiation towards one lineage may inhibit cell differentiation into an alternative lineage. For example, the canonical Wnt/beta-catenin pathway induces osteoblastogenesis and inhibits adipogenesis, whereas the peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a prime inducer of adipogenesis and, as shown in recent studies, inhibits osteoblastogenesis. We have identified two signaling pathways that switch the cell fate decision from adipocytes to osteoblasts by suppressing the transactivation function of PPAR-gamma. In the first pathway, the TNF-alpha- or IL-1-induced TAK1/TAB1/NIK signaling cascade attenuates PPAR-gamma-mediated adipogenesis by inhibiting the binding of PPAR-gamma to the DNA response element. The second is the noncanonical Wnt pathway through the CaMKII-TAK1/TAB2-NLK (nemo-like kinase) signaling cascade. Specifically, Wnt-5a-induced phosphorylation of NLK triggers formation of a complex with the histone methyltransferase SETDB1 (SET domain, bifurcated 1) that represses PPAR-gamma transactivation through histone H3-K9 methylation at the target genes. Thus, two signaling cascades promote osteoblastic differentiation from MSC through two distinct modes of PPAR-gamma transrepression.
- Published
- 2009
18. A new PPAR-γ function in bone
- Author
-
Shigeaki Kato and Ichiro Takada
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,medicine ,Peroxisome proliferator-activated receptor ,Function (biology) - Published
- 2008
19. Retracted: Switching of chromatin‐remodelling complexes for oestrogen receptor‐α
- Author
-
Hirochika Kitagawa, Ichiro Takada, Shinichiro Takezawa, Maiko Okada, Shigeaki Kato, Ikuko Yamaoka, and Yoshihiro Mezaki
- Subjects
Cell growth ,medicine.medical_treatment ,Cellular differentiation ,Cell cycle ,Biology ,Biochemistry ,Chromatin ,Cell biology ,Transactivation ,Steroid hormone ,Genetics ,medicine ,Receptor ,Molecular Biology ,Estrogen receptor alpha - Abstract
The female sex steroid hormone oestrogen stimulates both cell proliferation and cell differentiation in target tissues. These biological actions are mediated primarily through nuclear oestrogen receptors (ERs). The ligand-dependent transactivation of ERs requires several nuclear co-regulator complexes; however, the cell-cycle-dependent associations of these complexes are poorly understood. By using a synchronization system, we found that the transactivation function of ERalpha at G2/M was lowered. Biochemical approaches showed that ERalpha associated with two discrete classes of ATP-dependent chromatin-remodelling complex in a cell-cycle-dependent manner. The components of the NuRD-type complex were identified as G2/M-phase-specific ERalpha co-repressors. Thus, our results indicate that the transactivation function of ERalpha is cell-cycle dependent and is coupled with a cell-cycle-dependent association of chromatin-remodelling complexes.
- Published
- 2008
20. Suppression of PPAR Transactivation Switches Cell Fate of Bone Marrow Stem Cells from Adipocytes into Osteoblasts
- Author
-
Ichiro Takada, Shigeaki Kato, Miyuki Suzawa, and Kunihiro Matsumoto
- Subjects
Transcriptional Activation ,Cell signaling ,Osteoblasts ,General Neuroscience ,Cellular differentiation ,Peroxisome Proliferator-Activated Receptors ,Mesenchymal stem cell ,Wnt signaling pathway ,Cell Differentiation ,Histone-Lysine N-Methyltransferase ,Biology ,Hematopoietic Stem Cells ,General Biochemistry, Genetics and Molecular Biology ,Transactivation ,History and Philosophy of Science ,Adipogenesis ,Adipocytes ,Histone Methyltransferases ,Cancer research ,Animals ,Cell Lineage ,Protein Methyltransferases ,Stem cell ,Transrepression - Abstract
Osteoblasts and adipocytes differentiate from common pleiotropic mesenchymal stem cells under transcriptional controls by numerous factors and multiple intracellular signalings. However, cellular signaling factors that determine cell fates of mensenchymal stem cells in bone marrow remain to be largely uncovered, though peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is well established as a prime inducer of adipogenesis. Here, we describe two signaling pathways that induce the cell fate decision into osteoblasts from adipocytes. One signaling is a TAK1/TAB1/NIK cascade activated by TNF-alpha and IL-1, and the activated NF-kappaB blocked the DNA binding of PPAR-gamma, attenuating the activated PPAR-mediated adipogenesis. The second signaling is the noncanonical Wnt pathway through CaMKII-TAK1/TAB2-NLK. Activated NLK by a noncanonical Wnt ligand (Wnt-5a) transrepresses PPAR transactivation through a histone methyltransferase, SETDB1. Wnt-5a induces phosphorylation of NLK, leading to the formation of a corepressor complex that inactivates PPAR function through histone H3-K9 methylation. Thus, two signaling pathways lead to an osteoblastic cell lineage decision from mesenchymal stem cells through two distinct modes of PPAR transrepression.
- Published
- 2007
21. Vitamin K Induces Osteoblast Differentiation through Pregnane X Receptor-Mediated Transcriptional Control of the Msx2 Gene
- Author
-
Hirochika Kitagawa, Ichiro Takada, Mamoru Igarashi, Shigeaki Kato, Masatomo Mihara, and Yoshiko Yogiashi
- Subjects
Regulation of gene expression ,Pregnane X receptor ,Retinoid X receptor alpha ,Vitamin K2 ,Osteoblast ,Promoter ,Articles ,Cell Biology ,Vitamin k ,Biology ,Bioinformatics ,digestive system ,Molecular biology ,digestive system diseases ,Cell biology ,medicine.anatomical_structure ,Coactivator ,medicine ,Transcriptional regulation ,Gene ,Molecular Biology ,Transcription factor ,Estrogen receptor alpha - Abstract
Vitamin K is a fat-soluble vitamin that serves as a coenzyme for vitamin K-dependent carboxylase. Besides its canonical action, vitamin K binds to the steroid and xenobiotic receptor (SXR)/pregnane X receptor (PXR) and modulates gene transcription. To determine if the osteoprotective action of vitamin K is the result of the PXR/SXR pathway, we screened by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis the PXR/SXR target genes in an osteoblastic cell line (MC3T3-E1) treated with a vitamin K2 (menaquinone 4 [MK4]). Osteoblastic differentiation of MC3T3-E1 cells was induced by MK4. Msx2, an osteoblastogenic transcription factor, was identified as an MK4-induced gene. Functional analysis of the Msx2 gene promoter mapped a vitamin K-responsive element (PXR-responsive element [PXRE]) that was directly bound by a PXR/retinoid X receptor alpha heterodimer. In a chromatin immunoprecipitation analysis, PXR was recruited together with a coactivator, p300, to the PXRE in the Msx2 promoter. MK4-bound PXR cooperated with estrogen-bound estrogen receptor alpha to control transcription at the Msx2 promoter. Knockdown of either PXR or Msx2 attenuated the effect of MK4 on osteoblastic differentiation. Thus, the present study suggests that Msx2 is a target gene for PXR activated by vitamin K and suggests that the osteoprotective action of MK4 in the human mediates, at least in part, a genomic pathway of vitamin K signaling.
- Published
- 2007
22. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation
- Author
-
Yasuhiro Minami, Shinichiro Takezawa, Shinji Takada, Fumiaki Ohtake, Mamoru Igarashi, Ken-ichi Takeyama, Min Young Youn, Gen Yamada, Takashi Nakamura, Shigeaki Kato, Hirochika Kitagawa, Yoshiko Yogiashi, Yoshihiro Mezaki, Kobayashi Shinji, Miyuki Suzawa, Hiroshi Shibuya, Ichiro Takada, Masatomo Mihara, and Kunihiro Matsumoto
- Subjects
Transcriptional Activation ,Genetic Vectors ,Down-Regulation ,Core Binding Factor Alpha 1 Subunit ,Mice, Transgenic ,Wnt-5a Protein ,Mice ,Transactivation ,Osteogenesis ,Transcriptional regulation ,Animals ,Phosphorylation ,Cells, Cultured ,Adipogenesis ,biology ,Wnt signaling pathway ,Histone-Lysine N-Methyltransferase ,Cell Biology ,Chromatin ,Cell biology ,PPAR gamma ,Wnt Proteins ,RUNX2 ,Histone ,Histone methyltransferase ,Mutation ,biology.protein ,Cancer research ,Plasmids ,Signal Transduction - Abstract
Histone modifications induced by activated signalling cascades are crucial to cell-lineage decisions. Osteoblast and adipocyte differentiation from common mesenchymal stem cells is under transcriptional control by numerous factors. Although PPAR-gamma (peroxisome proliferator activated receptor-gamma) has been established as a prime inducer of adipogenesis, cellular signalling factors that determine cell lineage in bone marrow remain generally unknown. Here, we show that the non-canonical Wnt pathway through CaMKII-TAK1-TAB2-NLK transcriptionally represses PPAR-gamma transactivation and induces Runx2 expression, promoting osteoblastogenesis in preference to adipogenesis in bone marrow mesenchymal progenitors. Wnt-5a activates NLK (Nemo-like kinase), which in turn phosphorylates a histone methyltransferase, SETDB1 (SET domain bifurcated 1), leading to the formation of a co-repressor complex that inactivates PPAR-gamma function through histone H3-K9 methylation. These findings suggest that the non-canonical Wnt signalling pathway suppresses PPAR-gamma function through chromatin inactivation triggered by recruitment of a repressing histone methyltransferase, thus leading to an osteoblastic cell lineage from mesenchymal stem cells.
- Published
- 2007
23. Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes
- Author
-
Ichiro Takada, Ken-ichi Takeyama, Saya Ito, Setsuya Aiba, Mamoru Igarashi, Shigeaki Kato, A Memezawa, and Alexander Kouzmenko
- Subjects
Keratinocytes ,Cancer Research ,Small interfering RNA ,Down-Regulation ,Tretinoin ,Biology ,Response Elements ,Cell Line ,Histones ,Proto-Oncogene Proteins c-myc ,Retinoids ,Histone H3 ,Cyclin D1 ,Gene expression ,Genetics ,Humans ,RNA, Small Interfering ,Molecular Biology ,Transcription factor ,Cell Proliferation ,Inhibitor of Differentiation Protein 2 ,Histone Demethylases ,Wnt signaling pathway ,Acetylation ,Oxidoreductases, N-Demethylating ,Wnt Proteins ,HaCaT ,Gene Expression Regulation ,Cancer research ,Signal transduction - Abstract
We investigated the effect of all-trans-retinoic acid (atRA) on proliferation in several human skin cell lines and found that antiproliferative potency of atRA correlated with the endogenous activity of canonical Wnt signaling. In HaCaT keratinocytes, we found that atRA significantly suppressed the expression of Id2, a member of the inhibitor of differentiation family of transcription factors that regulate cell growth and differentiation. However, no apparent change in the expression of other Wnt targets, like c-Myc or cyclin D1, was observed. Retinoid-induced Id2 gene suppression was associated with decreased levels of histone H3 and H4 acetylation and histone H3 Lys-4 methylation, and with recruitment of the LSD1 demethylase at the Wnt-response element (WRE) (TCF/LEF-binding site), in the Id2 gene promoter. None of such changes was detected at the WRE of c-Myc and cyclin D1 gene promoters. Inhibition of Id2 by short interfering RNA (siRNA) had a similar effect on the proliferation of HaCaT cells as exposure to atRA, whereas anti-beta-catenin siRNA significantly inhibited its antiproliferative effect. These data suggest that downregulation of Id2 gene expression through transcriptional convergence between Wnt and retinoid signaling pathways underlies the antiproliferative effect of retinoids in keratinocytes, and provide evidence of gene-targeted crosstalk between signaling pathways.
- Published
- 2007
24. MP37-04 ANDROGEN RECEPTOR POSITIVE STROMAL CELLS REGULATE PROSTATE CANCER PROLIFERATION THROUGH NON-CANONICAL WNT SIGNALING
- Author
-
Sayuri Takahashi, Ichiro Takada, Naoki Terada, Yukio Homma, and Robert H. Getzenberg
- Subjects
Urology - Published
- 2015
25. Expression patterns of the chicken peroxisome proliferator-activated receptors (PPARs) during the development of the digestive organs
- Author
-
Ichiro Takada, Motoki Hojo, Kimiko Fukuda, Wataru Kimura, and Sadao Yasugi
- Subjects
medicine.medical_specialty ,Cellular differentiation ,Peroxisome Proliferator-Activated Receptors ,Peroxisome proliferator-activated receptor ,Chick Embryo ,Biology ,Internal medicine ,Genetics ,medicine ,Animals ,Tissue Distribution ,RNA, Messenger ,Receptor ,Molecular Biology ,chemistry.chemical_classification ,Regulation of gene expression ,Stomach ,Gene Expression Regulation, Developmental ,Lipid metabolism ,Proventriculus ,Peroxisome ,Endocrinology ,medicine.anatomical_structure ,chemistry ,lipids (amino acids, peptides, and proteins) ,Chickens ,Digestive System ,Developmental Biology - Abstract
Peroxisome proliferator-activated receptors (PPARs) play very important roles in various biological phenomena such as regulation of lipid metabolism, homeostasis, cell differentiation and proliferation, in a variety of organs and tissues. However, their functions in the development of the digestive organs have not been studied yet, although it has been supposed that they are involved in the tumor development and regression of digestive organs. To provide fundamental data to analyze functions of PPARs in the developing digestive organs in the chicken embryos, we performed thorough analysis of expression of PPARalpha, beta (delta) and gamma in the esophagus, proventriculus (glandular stomach), gizzard (muscular stomach), small and large intestines from early developmental stages to post hatch stages. The results showed that each PPAR is expressed in spatio-temporally regulated manner. In general, PPARbeta is widely expressed among digestive organs whereas PPARalpha and gamma showed restricted expression. In the intestine, all PPARs are expressed after hatch, indicating that they play important roles in the physiology of the adult intestine.
- Published
- 2006
26. PPARγ ligands and their therapeutic applications: a patent review (2008 - 2014)
- Author
-
Makoto Makishima and Ichiro Takada
- Subjects
Inflammation ,Type 2 diabetes ,Pharmacology ,Ligands ,Patents as Topic ,Diabetes mellitus ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Adverse effect ,Cell growth ,business.industry ,Lipid metabolism ,General Medicine ,medicine.disease ,Lipid Metabolism ,PPAR gamma ,Nuclear receptor ,Diabetes Mellitus, Type 2 ,Drug Design ,Patent activity ,Thiazolidinediones ,medicine.symptom ,business - Abstract
PPARγ regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are synthetic PPARγ ligands that are used in the treatment of type 2 diabetes. However, TZDs can cause adverse effects, such as increased risks of heart failure, bone fractures and bladder cancer. PPARγ has a large ligand-binding pocket, which makes it possible to develop a variety of PPARγ ligands, leading to patents on their therapeutic applications.We summarize recent patent activity regarding PPARγ ligands and their therapeutic applications from 2008. Pharmacologic methods to increase PPARγ expression and to decrease PPARγ adverse effects by combining PPARγ ligands with other drugs are also reviewed.In addition to novel PPARγ ligands that exhibit selective therapeutic activity without adverse effects, such as bone loss, fluid retention or weight gain, methods for the combination of PPARγ ligands and other compounds have been claimed to decrease adverse effects and/or to enhance targeted effects. Combination therapy is useful but has the potential risk of unexpected adverse effects. Patent applications for expanding clinical application of PPARγ ligands to non-metabolic diseases, such as neurological and inflammatory diseases, and to skin whitening have been filed, and future studies are needed to elucidate the underlying mechanisms.
- Published
- 2014
27. DGCR14 induces Il17a gene expression through the RORγ/BAZ1B/RSKS2 complex
- Author
-
Ichiro Takada
- Subjects
Cellular differentiation ,Biology ,Ribosomal Protein S6 Kinases, 90-kDa ,Histones ,Mice ,Gene expression ,Coactivator ,Transcriptional regulation ,Animals ,Humans ,RNA, Messenger ,Nuclear protein ,Molecular Biology ,Regulation of gene expression ,Gene knockdown ,Interleukin-17 ,Nuclear Proteins ,Cell Differentiation ,Cell Biology ,Articles ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Molecular biology ,Gene Expression Regulation ,Signal transduction ,Signal Transduction ,Transcription Factors - Abstract
The Dgcr14/Es2 gene is located in a chromosomal region the loss of which has been associated with DiGeorge syndrome, a cause of immunodeficiency, heart defects, and skeletal abnormalities. However, the role of DGCR14 protein remains to be elucidated. Here, I found that DGCR14 protein acts as a coactivator of RORγt in TH17 cells. Biochemical purification of the RORγ coregulator complex allowed me to identify the associated DGCR14 protein by matrix-assisted laser desorption ionization–time of flight mass spectrometry. Overexpression of Dgcr14 mRNA enhanced RORγt-mediated transcriptional activity and facilitated TH17 cell differentiation. Furthermore, knockdown of Dgcr14 reduced Il17a mRNA expression. I also found that DGCR14 associated with ribosomal S6 kinase 2 (RSK2, also called RpS6ka3) and BAZ1B, both of which were recruited to the Il17a promoter during TH17 cell differentiation. Knockdown of Baz1b or RpS6ka3 also reduced Il17a mRNA expression, and Baz1b knockdown increased transcriptional suppressive histone marks (histone H3K9me3) on the Il17a promoter. My findings showed the roles of DGCR14, RSK2, and BAZ1B in the transcriptional regulation of Il17a mRNA during TH17 cell differentiation.
- Published
- 2014
28. Resonant vibration and flashover phenomena of a water droplet located on a hydrophobic sheet under ac field
- Author
-
Take-ichiro Takada, Yoshio Higashiyama, and Toshiyuki Sugimoto
- Subjects
Materials science ,Analytical chemistry ,Natural frequency ,Deformation (meteorology) ,Condensed Matter Physics ,Silicone rubber ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Physics::Fluid Dynamics ,Vibration ,chemistry.chemical_compound ,chemistry ,Electric field ,Electrode ,Physics::Atomic and Molecular Clusters ,Arc flash ,Electrohydrodynamics ,Electrical and Electronic Engineering ,Composite material ,Biotechnology - Abstract
The electrohydrodynamic behavior of a single water droplet located on a hydrophobic silicone rubber sheet under an ac electric field was investigated. The water droplet under the ac electric field vibrates strongly at a particular frequency range. It corresponds to resonant vibration with natural frequency defined with the diameter of the droplet. To make the effect of resonant vibration on flashover via the water droplet clear, the time variation of the shape of a 30 μl droplet placed between the parallel electrodes was observed with a high-speed video camera. The flashover voltage via the droplet at the resonant frequency of 19 Hz was much lower than that at 50 Hz owing to larger deformation of the droplet.
- Published
- 2005
29. TRRAP as a hepatic coactivator of LXR and FXR function
- Author
-
Ichiro Takada, Atsushi Unno, Shigeaki Kato, Junn Yanagisawa, Shinichiro Takezawa, Takafumi Shimizu, Akifumi Tokita, Atsushi Baba, and Hajime Oishi
- Subjects
Transcriptional Activation ,Biophysics ,Receptors, Cytoplasmic and Nuclear ,Biology ,Ligands ,Biochemistry ,Bile Acids and Salts ,Transactivation ,Coactivator ,Liver X receptor ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Liver X Receptors ,Regulation of gene expression ,Nuclear Proteins ,Liver X receptor alpha ,Cell Biology ,Lipid Metabolism ,Orphan Nuclear Receptors ,G protein-coupled bile acid receptor ,DNA-Binding Proteins ,PPAR gamma ,Gene Expression Regulation ,Liver ,Nuclear receptor ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Farnesoid X receptor ,Transcription Factors - Abstract
TBP-free TAF II-containing-type HAT complex subclasses, which contain hGCN5 HAT and TRRAP, appear to act as common coactivator complexes for nuclear receptors. However, their physiological significance with respect to each nuclear receptor remains to be established. To address this issue, we used hepatic cell lines (HepG2) with reduced endogenous TRRAP expression through antisense RNA expression or with overexpressed TRRAP or other major coactivators. The ligand-induced transactivation function of liver X receptor alpha (LXRalpha) and farnesoid X receptor/bile acid receptor reflected TRRAP expression levels, while that of PPARgamma did not. A GST pull-down assay indicated that TRRAP contains two potential LXRalpha-interacting domains in the C-terminal and central domains. Expression of antisense TRRAP RNA in HepG2 cells abolished the ligand-induced expression of LXRalpha target genes. These results suggested that TRRAP plays an important role as a coactivator, presumably part of a complex, in lipid metabolism through regulation of the LXRalpha-mediated gene cascade in hepatic cells.
- Published
- 2005
30. BRCA1 function mediates a TRAP/DRIP complex through direct interaction with TRAP220
- Author
-
Hajime Oishi, Ichiro Takada, Tetsu Yano, Osamu Wada, Shigeaki Kato, and Junn Yanagisawa
- Subjects
Transcriptional Activation ,Cancer Research ,Tumor suppressor gene ,DNA damage ,DNA repair ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Mediator Complex Subunit 1 ,Transactivation ,Genetics ,medicine ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Regulation of gene expression ,Mediator Complex ,BRCA1 Protein ,Nuclear Proteins ,Cell cycle ,Cell biology ,BRCT domain ,Trans-Activators ,Female ,Carcinogenesis ,DNA Damage ,HeLa Cells ,Transcription Factors - Abstract
Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene mutated in a high percentage of hereditary breast and ovarian cancers. The multifunctional BRCA1 protein acts on cell cycle control, exerting several highly specialized DNA repair processes through diverse domains. Gene regulation through its C-terminal domain (BRCT) is indispensable for BRCA1-mediated tumor suppression, suggesting the possibility that the BRCT domain interacts with co-regulator complexes. Using a biochemical approach with HeLa S3 nuclear extracts, we isolated BRCT-associated complexes and identified one of the purified components as TRAP220. We then performed interaction studies in vivo (co-immunoprecipitation) and in vitro (glutathione S-transferase pull-down assays) and showed that BRCT directly interacted with TRAP220. This in vitro interaction was completely abolished by BRCT point mutations typical of those found in patients with BRCA1 that lack transactivation function. BRCA1 transactivation function was dependent on TRAP220 expression level in a transient expression assay. Moreover, a cell survival assay showed that antisense TRAP220 expression to disrupt endogenous TRAP220 expression significantly reduced the survival rate potentiated by BRCA1 after DNA damage. These results suggested that a TRAP220 complex play an important role as putative co-activator complexes in BRCA1-mediated tumor suppression.
- Published
- 2004
31. Both N- and C-terminal transactivation functions of DNA-bound ERα are blocked by a novel synthetic estrogen ligand
- Author
-
Kenji Kitazato, Ichiro Takada, Shigeaki Kato, Junn Yanagisawa, Yasuji Yamamoto, Yoshiko Yogiashi, Osamu Wada, and Jiro Shibata
- Subjects
Transcriptional Activation ,medicine.medical_specialty ,animal structures ,medicine.drug_class ,Biophysics ,Estrogen receptor ,Kidney ,Ligands ,Biochemistry ,Structure-Activity Relationship ,Transactivation ,Internal medicine ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Raloxifene ,Molecular Biology ,Estrogen receptor beta ,Receptors, Interferon ,Estradiol ,Chemistry ,Estrogen Antagonists ,Estrogen Receptor alpha ,Nuclear Proteins ,Cell Biology ,Cell biology ,DNA-Binding Proteins ,Endocrinology ,Receptors, Estrogen ,Selective estrogen receptor modulator ,Estrogen ,COS Cells ,Trans-Activators ,Estrogen receptor alpha ,Tamoxifen ,Protein Binding ,medicine.drug - Abstract
Estrogen receptors (ERs) play a central role in the diverse actions of estrogen. A number of synthetic ER ligands have been generated that can modulate various ER functions. Here we show that TAS-108, representing a novel class of synthetic ER ligands, blocked both ER transactivation functions without inhibiting DNA-binding activity. A transient expression assay showed that similar to ICI182,780, TAS-108 exhibited pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions. However, unlike ICI182,780, TAS-108 promoted the recruitment of the SMRT co-repressor that abolished ER transactivation function without inhibition of the ability of ERalpha to bind to its target DNA. Both TAS-108 and ICI182,780 acted as antagonists for the transactivation functions of the D351Y mutant, derived from tamoxifen-resistant breast cancer cells, while estrogen and known selective estrogen receptor modulators (SERMs), 4-OH tamoxifen and raloxifene, stimulated D351Y-mediated transcription. Thus, our findings indicated that TAS-108 acts as a novel estrogen antagonist that recruits co-repressors to ERs without AF-1 activation or prevention of DNA binding. Therefore, TAS-108 may be effective against tamoxifen-resistant breast cancer via a different mechanism than that for ICI182,780.
- Published
- 2003
32. The function of nuclear receptors in bone tissues
- Author
-
Hirochika Kitagawa, Ichiro Takada, Jun Yanagizawa, Miyuki Suzawa, Shigeaki Kato, Ken-ichi Takeyama, and Ryoji Fujiki
- Subjects
Endocrinology, Diabetes and Metabolism ,Cellular differentiation ,Receptors, Cytoplasmic and Nuclear ,Bone Marrow Cells ,Biology ,Bone and Bones ,Endocrinology ,Gene expression ,medicine ,Humans ,Orthopedics and Sports Medicine ,Promoter Regions, Genetic ,Messenger RNA ,Mediator Complex ,Osteoblasts ,Nuclear Proteins ,Mesenchymal Stem Cells ,Osteoblast ,General Medicine ,Chromatin Assembly and Disassembly ,Chromatin ,medicine.anatomical_structure ,Nuclear receptor ,Trans-Activators ,Cancer research ,Cytokines ,Receptors, Calcitriol ,Bone marrow ,Function (biology) ,Signal Transduction ,Transcription Factors - Published
- 2003
33. Involvement of Macrophage Chemotactic Protein-1 and Interleukin-1β During Inflammatory but Not Basic Fibroblast Growth Factor–Dependent Neovascularization in the Mouse Cornea
- Author
-
Ayako Yoshida, Hironori Matsui, Yu ichiro Takada, Shigeo Yoshida, and Tatsuro Ishibashi
- Subjects
Male ,Pathology ,medicine.medical_specialty ,genetic structures ,medicine.medical_treatment ,Basic fibroblast growth factor ,Biology ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,Cornea ,Rats, Sprague-Dawley ,Neovascularization ,Mice ,chemistry.chemical_compound ,Cell Movement ,medicine ,Animals ,Macrophage ,RNA, Messenger ,Antibodies, Blocking ,Chemokine CCL4 ,Molecular Biology ,In Situ Hybridization ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Macrophages ,Monocyte ,Epithelium, Corneal ,Drug Synergism ,Cell Biology ,Macrophage Inflammatory Proteins ,medicine.disease ,eye diseases ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Cytokine ,chemistry ,Corneal neovascularization ,Female ,Fibroblast Growth Factor 2 ,sense organs ,medicine.symptom ,Interleukin-1 - Abstract
Corneal neovascularization develops in several pathologic conditions, but its underlying mechanisms remain elusive. We used a mouse inflammatory corneal model (corneas cauterized with silver nitrate) and assessed the role of monocyte/macrophage-attracting factors, macrophage chemotactic protein-1 (MCP-1), and a proinflammatory cytokine, IL-1beta, on macrophage recruitment and neovascularization. Both MCP-1, IL-1beta protein, and mRNA levels increased markedly 12 hours after the chemical cauterization. In situ hybridization showed that MCP-1 was located in corneal epithelial cells, and IL-1beta was located in corneal epithelial cells and infiltrating inflammatory cells. In addition, double staining of corneas with antibodies specific for monocytes/macrophages and IL-1beta revealed that IL-1beta was found in infiltrating monocytes/macrophages at Day 2 after cauterization. Both IL-1beta and MCP-1 induced neovascularization in a rat cornea model, and the cauterization-induced corneal neovascularization was partially inhibited by subconjunctival injection of anti-IL-1beta or anti-MCP-1. Coadministration of two antibodies inhibited corneal neovascularization slightly more than that by the administration of each. In contrast, administration of the anti-MCP-1 or anti-IL-1beta showed minimal inhibition of basic fibroblast growth factor-driven corneal neovascularization by mouse cornea assay. Cauterized corneas treated with anti-MCP-1 antibody had significantly fewer monocytes/macrophages than control. These results indicate the existence of distinct monocyte/macrophage-involved angiogenic pathways in mouse cornea, in which MCP-1 released from corneal epithelial cells attracts monocytes/macrophages into the cornea, where they release IL-1beta leading to inflammatory neovascularization. In addition, the IL-1beta and MCP-1 released from the corneal epithelial cells may directly induce corneal neovascularization.
- Published
- 2003
34. Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade
- Author
-
Satoko Ogawa, Yukiko Gotoh, Yasuhiro Takeuchi, Kunihiro Matsumoto, Miyuki Suzawa, Takashi Kadowaki, Hiroshi Shibuya, Shigeaki Kato, Junn Yanagisawa, Toshimasa Yamauchi, Ichiro Takada, and Fumiaki Ohtake
- Subjects
Recombinant Fusion Proteins ,Cellular differentiation ,medicine.medical_treatment ,Blotting, Western ,Receptors, Cytoplasmic and Nuclear ,Electrophoretic Mobility Shift Assay ,HIV Envelope Protein gp120 ,Protein Serine-Threonine Kinases ,Biology ,Cell Line ,Mice ,Troglitazone ,Transactivation ,Adipocytes ,medicine ,Animals ,Chromans ,Adaptor Proteins, Signal Transducing ,Growth factor ,Mesenchymal stem cell ,Cell Biology ,Blotting, Northern ,MAP Kinase Kinase Kinases ,Precipitin Tests ,Cell biology ,Thiazoles ,medicine.anatomical_structure ,Cytokine ,Adipogenesis ,Cytokines ,Thiazolidinediones ,Bone marrow ,Stem cell ,Cell Division ,Plasmids ,Signal Transduction ,Transcription Factors - Abstract
Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.
- Published
- 2003
35. Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor- (PPAR ) Generates a PPAR Phenotype
- Author
-
H. Eric Xu, Steven A. Kliewer, Ronald M. Evans, Millard H. Lambert, Valerie G. Montana, Ruth T. Yu, Ichiro Takada, and Kazuhiko Umesono
- Subjects
chemistry.chemical_classification ,Peroxisome proliferator-activated receptor gamma ,Xenopus ,Peroxisome proliferator-activated receptor ,General Medicine ,Biology ,Peroxisome ,biology.organism_classification ,Amino acid ,Endocrinology ,Biochemistry ,chemistry ,Nuclear receptor ,Peroxisome proliferator-activated receptor alpha ,Receptor ,Molecular Biology - Abstract
Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs α,γ , and δ), mediate key transcriptional responses involved in lipid homeostasis. The PPARα and γ subtypes are well conserved from Xenopus to man, but the β/δ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) α and γ subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) β and mammalian δ, establishing that β and δ are orthologs. Like xPPARβ, cPPARβ responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with...
- Published
- 2000
36. On Rotations and Orthogonal Projections in n-Dimensional Euclidean Space
- Author
-
Ichiro Takada
- Subjects
Combinatorics ,Euclidean distance ,Euclidean space ,Orthogonal transformation ,Euclidean group ,Rotations in 4-dimensional Euclidean space ,Coordinate rotations and reflections ,Euclidean plane isometry ,Euclidean distance matrix ,Mathematics - Abstract
本研究では, n次元ユークリド空間Rnの立体の, 図形的な認識方法の整理と解析を, 系統的にしかも実用的に行うことを目標にした.Rnの立体を図形的に把握する過程の数理的側面は, Rnの回転 (運動) と投影の解析に集約されるが, 今回は特に前者の解析と実用的な表現について述べた.理論的には, 直交変換の標準形として, n次元空間の回転σはn/2個以下の適当な2次元平面上の回転たちの積で表されることが知られている.これは純数学的に有用かつ無駄のない表現だが, そこに現れる2次元平面上の各回転の軸は, σに依存し一定しないので, 特に高次元での図学的な実用性に乏しい.本論文では, 回転と投影を一緒に取扱う図学的な立場を踏まえ, 「Rn回転はn-1個を越えない固定された軸を持つ2次元平面上の回転たちと投影面 (超平面Rn-11) 上の回転との積で表される」という結果と, その具体的な表現を証明付きで得た.
- Published
- 1999
37. Nuclear receptors in bone physiology and diseases
- Author
-
Ichiro Takada, Shigeaki Kato, Yuuki Imai, Alexander Kouzmenko, Kazuki Inoue, and Min-Young Youn
- Subjects
medicine.medical_specialty ,Physiology ,medicine.drug_class ,Osteoporosis ,Receptors, Cytoplasmic and Nuclear ,Biology ,Ligands ,Bone and Bones ,Skeletal disorder ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Transcription factor ,Regulation of gene expression ,Bone Development ,General Medicine ,Articles ,medicine.disease ,Cell biology ,Endocrinology ,Nuclear receptor ,Gene Expression Regulation ,Estrogen ,Signal transduction ,Signal Transduction - Abstract
During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders.
- Published
- 2013
38. [Physiological functions of PPARs]
- Author
-
Ichiro, Takada and Shigeaki, Kato
- Subjects
Metabolic Diseases ,Drug Design ,Peroxisome Proliferator-Activated Receptors ,Animals ,Humans ,Molecular Targeted Therapy ,Ligands ,Bone and Bones - Published
- 2013
39. Structural Features and Transcriptional Activity of Chicken PPARs (α, β, and γ)
- Author
-
Ichiro Takada and Mime Kobayashi
- Subjects
animal structures ,lcsh:Biology (General) ,Review Article ,lcsh:QH301-705.5 - Abstract
While an understanding of lipid metabolism in chickens is critical for a further improvement of food production, there are few studies concerning differences in lipid metabolism mechanisms between chickens and other species at a molecular level. Chickens have three PPAR gene subtypes (α, β, and γ) that function differently from those present in humans and mice. The chicken PPAR-gamma (cPPARγ) gene is shorter than that in humans and lacks a γ2 isoform. Moreover, in serum-free media, cPPARγ shows high transcriptional activity without exogenous ligands. Luciferase reporter assays were used to examine the effect of sera on cPPAR transcriptional activities and showed that adult bovine serum and chicken serum highly activate cPPARα and β functions. Moreover, we found that bezafibrate induces the transactivation function of cPPARβ, but not human PPARδ (human PPARβ ortholog). This ligand selectivity relies on one amino acid residue (chicken: Val419, human: Met444). These results show the possibilities for unique functions of cPPARs on chicken-specific lipid glucose metabolism. As such, a better understanding of the molecular mechanisms of lipid metabolism in chickens could result in higher productivity for the poultry industry.
- Published
- 2012
40. Headspace gas chromatography analysis of uncombusted gasoline diluent in used gasoline engine oils
- Author
-
Ichiro Takada, Masatoshi Ichikawa, Naomi Nonaka, Shigeru Ishimori, and Nomura Masaya
- Subjects
business.product_category ,Chassis dynamometer ,Chromatography ,Chemistry ,Diluent ,Analytical Chemistry ,Fuel Technology ,Kovats retention index ,Gas chromatography ,Gasoline ,business ,Motor oil ,Pyrolysis ,Petrol engine - Abstract
A method for analyzing the uncombusted gasoline diluent in used gasoline engine oils using a combination of headspace gas chromatography (GC) and PONA ( P araffins, Q lefins, N aphthenes and A romatics) analysis was studied. The gasoline diluents in ten types of used gasoline engine oils, taken from engines submitted to road, bench, and chassis dynamometer tests, were determined using headspace gas chromatograms after their peak intensities had been corrected according to their retention indices. These results were compared with those from ASTM D3525 to assess the appropriateness of the headspace GC method. A further attempt was made to analyze corrected headspace gas chromatograms by PONA analysis in order to determine the diluting components in the used engine oils. The results of the study revealed that there was no reason to think that the sample would decompose when injected into GC apparatus, and that the information on the gasoline diluent and its diluting components should be readily obtainable. Analysis showed that the diluting components of uncombusted gasoline consisted mainly of less combustible gasoline components.
- Published
- 1995
41. [Switching of osteoblastogenesis versus adipogenesis]
- Author
-
Ichiro, Takada
- Subjects
PPAR gamma ,Osteoblasts ,Adipocytes ,Animals ,Humans ,Osteoclasts ,Cell Differentiation ,Signal Transduction - Abstract
To maintain a balance between the differentiation of adipocytes and osteoblasts is one of significant issues related to osteoporosis and metabolic syndrome. Both adipocytes and osteoblasts are derived from mesenchymal stem cells and recent studies have shown that osteoblast or adipocyte differentiation regulators reciprocally control each cell differentiations. In particular, PPAR-gamma plays a pivotal role for adipocyte differentiation and directly controls the differentiation of osteoblast and osteoclast. In this report, I summarize recent researches mainly focusing on the transcriptional co-regulators and extracellular signals regulating the transactivation function of PPAR-gamma.
- Published
- 2012
42. Smad2 and Smad3 are redundantly essential for the suppression of iNOS synthesis in macrophages by regulating IRF3 and STAT1 pathways
- Author
-
Ikko Kashiwagi, Yu Wakabayashi, Yuki Sugiyama, Masatoshi Nomura, Rimpei Morita, Ichiro Takada, Akihiko Yoshimura, Akihiro Kimura, and Kyosuke Kakoi
- Subjects
Transcription, Genetic ,medicine.medical_treatment ,Immunology ,Nitric Oxide Synthase Type II ,Bone Marrow Cells ,Smad2 Protein ,Biology ,Nitric oxide ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Interferon-gamma ,Mice ,medicine ,Immunology and Allergy ,Animals ,STAT1 ,Smad3 Protein ,Cells, Cultured ,Mice, Knockout ,Interleukin-6 ,Macrophages ,General Medicine ,Interferon-beta ,Macrophage Activation ,Cell biology ,Interleukin-10 ,Toll-Like Receptor 3 ,Toll-Like Receptor 4 ,Interleukin 10 ,Cytokine ,STAT1 Transcription Factor ,chemistry ,biology.protein ,Cancer research ,Macrophages, Peritoneal ,Tumor necrosis factor alpha ,Interferon Regulatory Factor-3 ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,IRF3 ,Transforming growth factor ,Signal Transduction - Abstract
Although transforming growth factor (TGF)-β1 is a well-known immunosuppressive cytokine, little is known about the role of its downstream transcription factors, Smad2 and Smad3, in the suppression of macrophage activation. Previous studies have demonstrated that Smad3 is critical for the suppression of LPS-mediated inducible nitric oxide (NO) synthase (iNOS) induction, although the role of Smad2 remains to be investigated. In this study, we found that iNOS induction was enhanced in Smad2-deficient bone marrow-derived macrophages (BMDMs) and peritoneal macrophages in vitro and tumor-associated macrophages in vivo, compared with wild-type (WT) macrophages. However, TGF-β1 still suppressed iNOS induction in Smad2-deficient macrophages. In Smad2/3 double knockout (KO) (Smad2/3 DKO) BMDMs, LPS-mediated NO/iNOS induction was more strongly elevated than in Smad2 or Smad3 single KO BMDMs, and its suppression by exogenous TGF-β1 was severely impaired. These data suggest that Smad2 and Smad3 redundantly regulate iNOS induction. Similarly, the production of IL-6 and TNFα, but not IL-10 was augmented in Smad2/3 DKO BMDMs, suggesting that Smad2 and Smad3 also redundantly suppressed some cytokines production. In Smad2/3 DKO macrophages, TLR3- as well as TLR4-mediated IRF3 activation and IFN-β production were strongly augmented, which resulted in hyper STAT1 phosphorylation. Furthermore, IFN-β- and IFN-γ-induced iNOS induction in the absence of TLR signaling and STAT1 transcriptional activity were augmented in Smad2/3 DKO BMDMs. These results suggest that Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway.
- Published
- 2012
43. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
- Author
-
Ichiro Takada, Kensuke Miyake, Shuji Mori, Akihiro Kimura, Eiichi Hasegawa, Takanari Kitazono, Kazumichi Kuroda, Shizuo Akira, Masahiro Nishibori, Tetsuro Ishii, Takashi Sekiya, Takashi Shichita, Toru Yanagawa, Hideo Takahashi, Rimpei Morita, Ryota Sakaguchi, Akihiko Yoshimura, and Hiroaki Ooboshi
- Subjects
Male ,Inflammation ,HMGB1 ,Neuroprotection ,Interleukin-23 ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Brain Ischemia ,Mice ,medicine ,Extracellular ,Animals ,RNA, Messenger ,HMGB1 Protein ,biology ,Brain ,General Medicine ,Peroxiredoxins ,Toll-Like Receptor 2 ,Cell biology ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Immunology ,biology.protein ,TLR4 ,Encephalitis ,Rabbits ,medicine.symptom ,Peroxiredoxin ,Intracellular - Abstract
Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.
- Published
- 2012
44. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis
- Author
-
Nobuyuki Udagawa, Yuichiro Kikuchi, Shigeaki Kato, T. John Martin, Toshihide Mizoguchi, Naoyuki Takahashi, Yasuhiro Kobayashi, Shuichi Kani, Ichiro Takada, Kazuhiro Maeda, Michiru Nishita, Akihiro Ishihara, Shunsuke Uehara, Yasuhiro Minami, and Keishi Marumo
- Subjects
medicine.medical_specialty ,MAP Kinase Kinase 4 ,Proto-Oncogene Proteins c-jun ,Osteoclasts ,Receptor Tyrosine Kinase-like Orphan Receptors ,General Biochemistry, Genetics and Molecular Biology ,Bone resorption ,Wnt-5a Protein ,Mice ,Osteoclast ,Internal medicine ,medicine ,Animals ,Cell Lineage ,Receptor ,Promoter Regions, Genetic ,Wnt Signaling Pathway ,Orphan receptor ,Osteoblasts ,biology ,Receptor Activator of Nuclear Factor-kappa B ,Chemistry ,Arthritis ,Skull ,Wnt signaling pathway ,RANK Ligand ,ROR2 ,General Medicine ,X-Ray Microtomography ,Cell biology ,body regions ,Wnt Proteins ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,RANKL ,embryonic structures ,biology.protein ,sense organs ,Bone Diseases - Abstract
The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.
- Published
- 2011
45. Mass Spectrometric Analysis for Distinction between Regular and Premium Motor Gasolines
- Author
-
Naomi Nonaka, Masatoshi Ichikawa, Sigeru Ishimori, and Ichiro Takada
- Subjects
Chemistry ,Mass spectrum ,Analytical chemistry ,Octane rating ,Gasoline ,Mass spectrometry ,Mass spectrometric ,Analytical Chemistry - Abstract
A method to estimate the octane number of motor gasoline by mass spectrometry (MS) has been studied, by first examining whether the octane number can be estimated from its mass spectrum (MS). The MS of 29 different regular gasolines and 32 premium gasolines, sampled in the market from spring to autumn, were measured. We studied whether it is possible to extract any available parameters for clearly distinguishing between regular and premium gasolines, by applying both feature-selection and pattern-recognition methods to MS. It was found that a clear distinction between regular and premium gasolines could be made using MS information.
- Published
- 1993
46. Transcriptionally active nuclei are selective in mature multinucleated osteoclasts
- Author
-
Min-Young, Youn, Ichiro, Takada, Yuuki, Imai, Hisataka, Yasuda, and Shigeaki, Kato
- Subjects
Cell Nucleus ,Epigenomics ,Mice ,Transcription, Genetic ,Animals ,Nuclear Proteins ,Osteoclasts ,Cell Differentiation ,RNA, Messenger ,Giant Cells ,In Situ Hybridization, Fluorescence ,Cell Line - Abstract
Multinucleation is indispensable for the bone-resorbing activity of mature osteoclasts. Although multinucleation is evident in mature osteoclasts and certain other cell types, putative regulatory networks among nuclei remain poorly characterized. To address this issue, transcriptional activity of each nucleus in a multinucleated osteoclast was assessed by detecting the distributions of nuclear proteins by immunocytochemistry and primary transcripts by RNA FISH. Patterns of epigenetic histone markers governing transcription as well as localization of tested nuclear receptor proteins appeared indistinguishable among nuclei in differentiated Raw264 cells and mouse mature osteoclasts. However, RNAPII-Ser5P/2P and NFATc1 proteins were selectively distributed in certain nuclei in the same cell. Similarly, the distributions of primary transcripts for osteoclast-specific genes (Nfatc1, Ctsk and Acp5) as well as a housekeeping gene (beta-tubulin) were limited in certain nuclei within individual cells. By fusing two Raw264 cell lines that stably expressed ZsGreen-NLS and DsRed-NLS proteins, transmission of nuclear proteins across all of the nuclei in a cell could be observed, presumably through the shared cytoplasm. Taken together, we conclude that although nuclear proteins are diffusible among nuclei, only certain nuclei within a multinucleated osteoclast are transcriptionally active.
- Published
- 2010
47. [Structural insights of PPARgamma]
- Author
-
Shigeaki, Kato and Ichiro, Takada
- Subjects
PPAR gamma ,Ligands - Published
- 2010
48. Proton NMR Analysis of Octane Number for Motor Gasoline: Part IV
- Author
-
H. Andoh, H. Amano, Ichiro Takada, Naomi Nonaka, K. Kumamoto, S. Ishimori, and Masatoshi Ichikawa
- Subjects
Chemistry ,business.industry ,010401 analytical chemistry ,Analytical chemistry ,01 natural sciences ,Proton magnetic resonance ,0104 chemical sciences ,010309 optics ,chemistry.chemical_compound ,Petroleum product ,Standard addition ,0103 physical sciences ,Linear regression ,Proton NMR ,Octane rating ,Gasoline ,business ,Instrumentation ,Spectroscopy ,Octane - Abstract
Software (a program) for predicting the octane number of motor gasoline by proton magnetic resonance (PMR) spectrometry has been formulated. At the same time, a method has been studied to predict the composition of gasoline (in terms of the contents of paraffin, olefin, and aromatic compounds). The formulated program was evaluated by using it to predict the octane numbers of 31 samples of marketed summer gasoline (including 16 regular and 15 premium products), whose octane numbers and compositions were identified according to the ASTM standards. Also, the relationship between the PMR spectrum and gasoline composition was subjected to linear regression analysis by using the 31 samples whose octane numbers were calculated, and the appropriateness of the resultant regression equations was assessed. This report concerns the results of the study in which the octane numbers of the 31 samples were satisfactorily predicted by the formulated program and useful linear regression equations were obtained for the prediction of the composition of gasoline.
- Published
- 1992
49. Estimation of the Octane Number of Automobile Gasoline by Fourier Transform Infrared Absorption Spectrometry
- Author
-
Ichiro Takada, Naomi Nonaka, S. Ishimori, and Masatoshi Ichikawa
- Subjects
Absorption spectroscopy ,010401 analytical chemistry ,Analytical chemistry ,Infrared spectroscopy ,01 natural sciences ,0104 chemical sciences ,010309 optics ,symbols.namesake ,chemistry.chemical_compound ,Fourier transform ,chemistry ,0103 physical sciences ,symbols ,Octane rating ,Fourier transform infrared spectroscopy ,Gasoline ,Dispersion (chemistry) ,Instrumentation ,Spectroscopy ,Octane - Abstract
A method to estimate the octane number of automobile gasoline by Fourier transform infrared absorption spectrometry has been studied. Thirty-six kinds of regular gasoline and 38 of unleaded premium gasoline, collected from the market from winter to summer, were used as samples, and the absorptions of the C-H stretching vibration in the 3150-2800 cm−1 range of their IR spectra were used to plot each sample in a two-dimensional space, followed by an attempt to graphically classify the two broad types. On the other hand, the IR spectra of other samples with known octane numbers (88.0 to 100.8 in octane number) and, on that basis, samples with known octane numbers, were mapped into the space in which the regular gasolines and the premium gasolines were classified to determine their dispersion in this space. A further attempt was made to formulate a linear regression equation for use in octane number estimation. As a result, it was found that regular and premium gasolines could be definitely distinguished from each other according to the C-H stretching vibration in the 3150-2800 cm−1 near-infrared range, and that the octane number could be visually estimated. The formulation of a satisfactory regression equation was also made possible. These results are reported.
- Published
- 1992
50. SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis
- Author
-
Takuma Ishizaki, Ryusuke Nakagawa, Yu Wakabayashi, Kyoko Komai, Ichiro Takada, Mako Nakaya, Akihiko Yoshimura, Hiroki Yoshida, and Masayuki Hashimoto
- Subjects
Transgene ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Blotting, Western ,chemical and pharmacologic phenomena ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Suppressor of Cytokine Signaling Proteins ,Biology ,Lymphocyte Activation ,Hepatitis ,Mice ,Conditional gene knockout ,medicine ,Concanavalin A ,Immunology and Allergy ,Animals ,SOCS3 ,Liver injury ,Reverse Transcriptase Polymerase Chain Reaction ,digestive, oral, and skin physiology ,hemic and immune systems ,medicine.disease ,Natural killer T cell ,Flow Cytometry ,Cytokine ,Cell culture ,Suppressor of Cytokine Signaling 3 Protein ,Cancer research ,Cytokines ,Natural Killer T-Cells ,Mitogens - Abstract
Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-γ and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-γ and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with α-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-γ and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis.
- Published
- 2009
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.