Yoshiaki Fujii-Kuriyama

Tokyo Medical and Dental University, Edo, Tōkyō, Japan

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Publications (279)1271.59 Total impact

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    ABSTRACT: Aryl hydrocarbon receptor (Ahr), a transcription factor, plays a critical role in autoimmune inflammation of the intestine. In addition, microRNAs (miRNAs), small non-coding oligonucleotides, mediate pathogenesis of inflammatory bowel diseases (IBD). However, the precise mechanism and interactions of these molecules in IBD pathogenesis have not yet been investigated. We analyzed the role of Ahr and Ahr-regulated miRNAs in colonic inflammation. Our results show that deficiency of Ahr in intestinal epithelial cells in mice exacerbated inflammation in dextran sodium sulfate (DSS)-induced colitis. Deletion of Ahr in T cells attenuated colitis, which was manifested by suppressed TH17 cell infiltration into the lamina propria. Candidate miRNA analysis showed that induction of colitis elevated expression of the miR-212/132 cluster in colon of wild-type mice, whereas in Ahr(-/-) mice, expression was clearly lower. Furthermore, miR-212/132(-/-) mice were highly resistant to colitis and had reduced levels of TH17 cells and elevated levels of IL-10-producing CD4(+) cells. In vitro analyses revealed that induction of Type 1 regulatory T (Tr1) cells was significantly elevated in miR-212/132(-/-) T cells with increased c-Maf expression. Our findings emphasize the vital role of Ahr in intestinal homeostasis, and suggest that inhibition of miR-212/132 represents a viable therapeutic strategy for treating colitis. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Full-text · Article · Apr 2015 · International Immunology
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    Tai-Yong Yu · Takeshi Kondo · Takahiro Matsumoto · Yoshiaki Fujii-Kuriyama · Yuuki Imai
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    ABSTRACT: Bone mass is regulated by various molecules including endogenous factors as well as exogenous factors, such as nutrients and pollutants. Aryl hydrocarbon receptor (AhR) is known as a dioxin receptor and is responsible for various pathological and physiological processes. However, the role of AhR in bone homeostasis remains elusive because the cell type specific direct function of AhR has never been explored in vivo. Here, we show the cell type specific function of AhR in vivo in bone homeostasis. Systemic AhR knockout (AhRKO) mice exhibit increased bone mass with decreased resorption and decreased formation. Meanwhile, osteoclast specific AhRKO (AhR(ΔOc/ΔOc)) mice have increased bone mass with reduced bone resorption, although the mice lacking AhR in osteoblasts have a normal bone phenotype. Even under pathological conditions, AhR(ΔOc/ΔOc) mice are resistant to sex hormone deficiency-induced bone loss resulting from increased bone resorption. Furthermore, 3-methylcholanthrene, an AhR agonist, induces low bone mass with increased bone resorption in control mice, but not in AhR(ΔOc/ΔOc) mice. Taken together, cell type specific in vivo evidence for AhR functions indicates that osteoclastic AhR plays a significant role in maintenance of bone homeostasis, suggesting that inhibition of AhR in osteoclasts can be beneficial in the treatment of osteoporosis.
    Preview · Article · Jun 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.Immunology and Cell Biology advance online publication, 11 February 2014; doi:10.1038/icb.2014.2.
    No preview · Article · Feb 2014 · Immunology and Cell Biology
  • Togo Ikuta · Yasuhito Kobayashi · Yoshiaki Fujii-Kuriyama · Kaname Kawajiri
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels as both a ligand-activated transcription factor and a ligand-dependent E3 ubiquitin ligase. We showed that the AhR E3 ubiquitin ligase has a role in the suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent β-catenin degradation pathway. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and which suppresses intestinal tumor development in Apc Min/+ mice. To elucidate whether the tumors develop autonomously in AhR −/− mice as a result of impaired β-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR −/− mice or compound mutant mice lacking genes for AhR and adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which play an essential role in caspase-1 activation in inflammasomes. Both GF AhR −/− and AhR −/− •ASC −/− mice showed considerably reduced tumor development compared with that in AhR −/− mice, albeit in a “cancer-prone” state with aberrant β-catenin accumulation. These results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in mouse intestinal tumorigenesis. Furthermore, they also suggest a possible chemical therapeutic intervention that involves AhR ligands and inhibitors of the inflammation pathway.
    No preview · Chapter · Jan 2014
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    ABSTRACT: Aryl hydrocarbon receptor (AhR) is crucial for various immune responses. The relationship between AhR and infection with the intracellular bacteria Listeria monocytogenes (LM) is poorly understood. Here, we show that in response to LM infection, AhR is required for bacterial clearance by promoting macrophage survival and reactive oxygen species (ROS) production. AhR-deficient mice were more susceptible to listeriosis, and AhR deficiency enhances bacterial growth in vivo and in vitro. On the other hand, pro-inflammatory cytokines were increased in AhR-deficient macrophages infected with LM despite enhanced susceptibility to LM infection in AhR-deficient mice. Subsequent studies demonstrate that AhR protects against macrophage cell death induced by LM infection through the induction of the antiapoptotic factor, the apoptosis inhibitor of macrophages, which promotes macrophage survival in the setting of LM infection. Furthermore, AhR promotes ROS production for bacterial clearance. Our results demonstrate that AhR is essential to the resistance against LM infection as it promotes macrophage survival and ROS production. This suggests that the activation of AhR by its ligands may be an effective strategy against listeriosis.
    Preview · Article · Dec 2013 · International Immunology
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    ABSTRACT: The aryl hydrocarbon receptor (AhR), a ligand-activated nuclear transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants, while AhR has been shown to protect animals from various types of tissue injury. ConA-induced hepatitis is known as a mouse model of acute liver injury. Here, we found a protective role of AhR in ConA-induced hepatitis. AhR is induced in the liver during ConA-induced hepatitis, and Ahr (-/-) mice were highly sensitive to this model. Bone marrow chimera experiments indicate that Ahr (-/-) hematopoietic cells are responsible for hypersensitivity to ConA-induced hepatitis. We found that IFN-γ from invariant NKT cells was up-regulated and IL-22 from innate lymphoid cells (ILCs) was abolished in Ahr (-/-) mice. In addition, IL-22 production was still observed in Rag2 (-/-) mice but it was severely reduced in Ahr (-/-) Rag2 (-/-) mice. ConA-induced IL-22 production was also dependent on retinoic acid-related orphan receptor γt. These results show that AhR has crucial protective roles in ConA-induced liver injury via promoting IL-22 production from ILCs and suppressing IFN-γ expression from NKT cells.
    Preview · Article · Oct 2013 · International Immunology
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of β-catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR-/-) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR-/- mice due to impaired β-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR-/- mice and compound mutant mice lacking genes for AhR and ASC which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR-/- and AhR-/-•ASC-/- mice showed considerably reduced tumor development compared with that in AhR-/- mice albeit in a "cancer-prone" state with aberrant β-catenin accumulation. Blocking of the IL-1β signaling pathway by treatment with a caspase-1 inhibitor, YVAD reduced cecal tumorigenesis in AhR-/- mice. STAT3 activation was detected in the cecal epithelium of the AhR-/- mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in ApcMin/+ mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR-ligands and inhibitors of the inflammation pathway.
    No preview · Article · Mar 2013 · Carcinogenesis
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    N Okudaira · T Okamura · M Tamura · K Iijma · M Goto · A Matsunaga · M Ochiai · H Nakagama · S Kano · Y Fujii-Kuriyama · Y Ishizaka
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    ABSTRACT: A single human cell contains more than 5.0 × 10(5) copies of long interspersed element-1 (L1), 80-100 of which are competent for retrotransposition (L1-RTP). Recent observations have revealed the presence of de novo L1 insertions in various tumors, but little is known about its mechanism. Here, we found that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), food-borne carcinogens that are present in broiled meats, induced L1-RTP. This induction was dependent on a cellular cascade comprising the aryl hydrocarbon receptor (AhR), a mitogen-activated protein kinase, and CCAAT/enhancer-binding protein β. Notably, these compounds exhibited differential induction of L1-RTP. MeIQx-induced L1-RTP was dependent on AhR nuclear translocator 1 (ARNT1), a counterpart of AhR required for gene expression in response to environmental pollutants. By contrast, PhIP-induced L1-RTP did not require ARNT1 but was dependent on estrogen receptor α (ERα) and AhR repressor. In vivo studies using transgenic mice harboring the human L1 gene indicated that PhIP-induced L1-RTP was reproducibly detected in the mammary gland, which is a target organ of PhIP-induced carcinoma. Moreover, picomolar levels of each compound induced L1-RTP, which is comparable to the PhIP concentration detected in human breast milk. Data suggest that somatic cells possess machineries that induce L1-RTP in response to the carcinogenic compounds. Together with data showing that micromolar levels of heterocyclic amines (HCAs) were non-genotoxic, our observations indicate that L1-RTP by environmental compounds is a novel type of genomic instability, further suggesting that analysis of L1-RTP by HCAs is a novel approach to clarification of modes of carcinogenesis.Oncogene advance online publication, 3 December 2012; doi:10.1038/onc.2012.516.
    Preview · Article · Dec 2012 · Oncogene
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    ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ligand with high affinity for the aryl hydrocarbon receptor (AhR). It suppresses 17β-estradiol (E2)-induced cell proliferation in human breast cancer cells. Although it has been theorized that the AhR is involved in TCDD-induced antiestrogenic activity and antiproliferation in human breast cancer cells, some evidence suggests that these activities of chlorinated aromatic compounds also occur by AhR-independent pathways. Here, we investigated the possibility of TCDD-induced antiproliferative responses in human breast cancer cells through AhR-independent pathways. Compared with that in vehicle-treated controls, DNA synthesis was significantly suppressed in MCF-7 cells and ZR75-1 cells treated with TCDD at a very low concentration (0.01 nM), whereas that in human ovarian carcinoma OVCAR3 cells, human cervical carcinoma HeLa cells and human choriocarcinoma JEG-3 cells was unaffected, even by exposure to 10 nM TCDD. The suppression induced by TCDD was not associated with the estrogen receptor α-signaling pathway. Another AhR agonist, 3,3',4,4',5-pentachlorobiphenyl, had no effect on DNA synthesis in MCF-7 cells at concentrations high enough to induce the transactivation function of the AhR. Furthermore, in MCF-7 cells, knockdown of the AhR by RNA interference had no effect on TCDD-induced antiproliferation. These findings suggest that the principal pathways of TCDD-induced antiproliferation in breast cancer cells are not AhR dependent.
    Full-text · Article · Apr 2012 · Toxicology Letters
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the mice are 6 mo of age, there are usually two or three stones with diameters of 3-4 mm. The urate concentration in the serum was normal but in the urine the concentration was 40-50 mg/dL, which is 10 times higher than that in the WT littermates. There were no apparent histological pathologies in the kidney or joints and the levels of enzymes involved in elimination of purines were normal. The source of the uric acid was therefore judged to be from degradation of nucleic acids due to a high turnover of cells in the bladder itself. The bladder was fibrotic and the luminal side of the bladder epithelium was filled with eosinophilic granules. There was loss of E-cadherin between some epithelial cells, with an enlarged submucosal area filled with immune cells and sometimes invading epithelial cells. We hypothesize that in the absence of AhR there is loss of detoxifying enzymes, which leads to accumulation of unconjugated cytotoxins and carcinogens in the bladder. The presence of bladder toxins may have led to the increased apoptosis and inflammation as well as invasion of epithelial cells in the bladders of older mice.
    Full-text · Article · Jan 2012 · Proceedings of the National Academy of Sciences
  • Yoshiaki Fujii-Kuriyama · Kaname Kawajiri
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    ABSTRACT: This chapter contains sections titled: IntroductionStructure and Evolution of AHRRRegulatory Mechanisms of AHRR ExpressionMolecular Mechanisms by which AHRR Inhibits AHR ActivityPhysiological Functions and Polymorphisms of AHRRSummaryReferences
    No preview · Chapter · Nov 2011
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    ABSTRACT: The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis have not been elucidated. Here, we show that Ahr deficiency ameliorated collagen-induced arthritis, a mouse model of RA. Collagen-immunized Ahr KO mice showed decreased serum levels of such proinflammatory cytokines as IL-1β and IL-6. The Th17 and Th1 cell populations in lymph nodes from these mice decreased and increased, respectively, whereas the percentage of regulatory T cells was unchanged. Interestingly, a lack of Ahr specifically in T cells significantly suppressed collagen-induced arthritis development, whereas Ahr deficiency in macrophages had no effect. These finding indicate that the development of experimental autoimmune arthritis depends on the presence of Ahr in T cells, and that Th1/Th17 balance may be particularly important for this process.
    Full-text · Article · Aug 2011 · Proceedings of the National Academy of Sciences
  • Yoshiaki Fujii-Kuriyama
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    ABSTRACT: Aryl hydrocarbon receptor (AhR, also named dioxin receptor) was originally identiteid as a ligand-activated transcription factor with characteristic structural motifs of bHLH (basic helix-loop-helix) and PAS (conserved sequence among Per, Arnt and Sim) which is involved in induction of drug-metabolizing CYP1A1 in response to xenobiotics, such as 3-methylcholanthrene (3MC) and TCDD. Under normal conditions, AhR exists in the cytoplasm in association with a HSP90 complex. Upon binding with added TCDD, the activated AhR translocates into the nuclei where it forms a heterodimer with Arnt after dissociating from the HSP90 complex, leading to binding with an XRE sequence in the promoter of its target genes to enhance their expressions. One of the target genes is AhR repressor (AhRR) whose expression in turn inhibits the activity of AhR by competitively forming a heterodimer with Arnt and subsequently binding with the XRE sequence. Thus, the AhR signaling system is found to be precisely regulated by the feed-back inhibition mechanism. In addition to the transcription function, AhR has been found to form a complex with CUL4B, Rbx (Roc) and TBL3, and function as an E3 ubiquitin ligase. When supplemented with E1 and E2 ligases, the AhR complex exhibited ubiquitin ligase activity towards ERs and AR, which is independent of the conventional ER ubiquitylation and degradation system. The AhR-ubiquitylation system has also been shown to ubiquitylate beta-catenin and function as a tumor suppressor in colon in parallel to, but independently of the APC system. Cecal cancers were spontaneously developed in the AhR-null mice. This work was performed in collaboration with Dr. H. Sekine ( University of Tsukuba), Drs. F. Ohtake and S. Kato (University of Tokyo), and Dr. K. Kawajiri (Saitama Cancer Center). This work was supported in part by SORST and CREST of JST.
    No preview · Conference Paper · May 2011
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    ABSTRACT: The aryl hydrocarbon receptor (AhR), which is a member of the basic helix-loop-helix/Per-Arnt-Sim homology superfamily, plays an important role in multiple biological functions, and AhR knockout (AhR KO) animals suffer from a variety of organ disorders including a decline in the efficacy of their immune system. In addition, AhR activation is known to aid the maintenance of homeostasis in vivo. In this study, we investigated whether AhR is functionally associated with intestinal immunity. In in vivo experiments, it was found that dextran sodium sulfate (DSS)-evoked colitis was more severe in AhR KO mice than in C57BL/6J wild type mice. It was also revealed that the administration of DSS increased the expression levels of AhR and CYP1A1 mRNA in the colon epithelium. In addition, oral administration of β-naphthoflavone (βNF), a non-toxic agonist of AhR, suppressed the pathogenesis of DSS-induced colitis. βNF also attenuated DSS-induced colitis. In cell culture experiments, downregulation of AhR in human colon carcinoma SW480 cells enhanced the inflammatory responses evoked by lipopolysaccharide (LPS), and furthermore, AhR activation attenuated LPS-induced inflammatory responses, suggesting that AhR expressing intestinal epithelial cells are involved in the prevention of colitis. Our findings about the potential role of AhR activators in epithelial immune regulation aid our understanding of mucosal homeostasis and inflammatory bowl disease (IBD) and suggest that AhR activation has therapeutic value for the treatment of IBD.
    No preview · Article · Mar 2011 · Digestive Diseases and Sciences
  • Fumiaki Ohtake · Yoshiaki Fujii-Kuriyama · Kaname Kawajiri · Shigeaki Kato
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    ABSTRACT: The arylhydrocarbon receptor (AhR) is a ligand-dependent transcription factor mediating the adverse effects of dioxins. Although cross-talk of dioxins with estrogen and androgen signaling pathways are well described, the underlying molecular mechanisms have been largely elusive. Recent studies showed that modulation of estrogen/androgen signaling by dioxins is exerted in part through direct association of AhR with estrogen (ER) or androgen (AR) receptors. Agonist-bound AhR and ERα work as a functional unit to regulate expression of target genes. In addition to such genomic actions, AhR mediates non-genomic actions of AhR-ligands through the assembly of a CUL4B-based ubiquitin ligase complex and promotes the degradation of ERα and AR. These findings reveal the roles of the ubiquitin system in sensing and biological response to environmental chemicals, in which AhR acts as a ubiquitin ligase component to enhance the destruction of specific substrates.
    No preview · Article · Mar 2011 · The Journal of steroid biochemistry and molecular biology
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    ABSTRACT: Although an immunoregulatory role of aryl hydrocarbon receptor (Ahr) has been demonstrated in T cells and macrophages, little is known about its function in dendritic cells (DC). Here, we show that lipopolysaccharide (LPS) and CpG stimulate Ahr expression in bone marrow-derived dendritic cells (BMDC). Furthermore, we found that Ahr is required to induce indoleamine 2,3-dioxygenase (IDO) expression, an immunosuppressive enzyme that catabolizes tryptophan into kynurenine (Kyn) and other metabolites in DC. In the presence of LPS or CpG, Ahr-deficient (Ahr(-/-)) mature BMDC induced immune responses characterized by reduced Kyn and IL-10 production compared with results observed with tolerogenic mature WT BMDC. In a coculture system with LPS- or CpG-stimulated BMDC and naive T cells, Ahr(-/-) BMDC inhibited naive T-cell differentiation into regulatory T (Treg) cells, which likely facilitated Th17 cell development and promoted naive T-cell proliferation. Addition of synthetic L-Kyn to the coculture system skewed the differentiation of naive T cells to Treg cells rather than Th17 cells. Taken together, our results demonstrate a previously unknown negatively regulatory role for Ahr in DC-mediated immunogenesis in the presence of LPS or CpG, which, in turn, alters the Kyn-dependent generation of Treg cells and Th17 cells from naive T cells.
    Full-text · Article · Nov 2010 · Proceedings of the National Academy of Sciences
  • Yoshiaki Fujii-Kuriyama
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    ABSTRACT: The dioxin receptor (also named aryl hydrocarbon receptor or AhR) was originally identified as a ligand-activated transcription factor with structurally characteristic motifs of bHLH and PAS that is involved in induction of xenobiotic-metabolizing P4501A1 (CYP1A1) in response to polycyclic aromatic hydrocarbons (PAH). The ligand-activated AhR translocates from the cytoplasm to the nuclei where it forms a heterodimer with another bHLH-PAS protein, Arnt (AhR nuclear translocator) to enhance the expression of AhR-target genes through binding the XRE sequence in their promoter. For past several decades, AhR research was mainly focused on the functions related to pharmacology and toxicology. Recently, however, more research efforts have been devoted to physiological functions of AhR. The AhR signaling activity can be precisely regulated by a feedback inhibitory mechnism in which AhR repressor (AhRR), whose expression is enhanced by the activated AhR/Arnt heterodimer, represses the transcriptional activity of AhR through SUMOylation and subsequent recruitment of corepressor, ANKRA2, HDAC4 and HDAC5. Recent progress in our AhR research reveals that AhR is involved in the regulation of estrous cycle by acting as an activator in transcription of P450 aromatase (CYP19) gene and in the Treg and Th17 cell differentiations from naive T cells. With a novel finding that AhR functions as an E3 ubiquitin ligase, our knowledge on the AhR functions further extends to tumor suppression and regulation of the steroid hormone activities. I would like to summarize and discuss our recent work on the AhR research with an attention to inhibitory mechanisms of AhRR and physiological functions of AhR. [This work has been performed in collaboration with Dr. H. Sekine (Univ. of Tsukuba), Drs. F. Ohtake, S. Kato (Univ. of Tokyo), and Dr. K. Kawajiri (Saitama Cancer Center), and financially supported in part by CREST and SORST of JST].
    No preview · Conference Paper · Aug 2010
  • Togo Ikuta · Motoi Ohba · Christos C Zouboulis · Yoshiaki Fujii-Kuriyama · Kaname Kawajiri
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. When environmental pollutants, including chemical carcinogens, bind to AhR, the receptor translocates to nucleus and transcriptionally activates target genes including drug metabolizing enzymes such as P450s. Recent studies have shown that AhR mediates various responses, including cellular growth, differentiation, immune system and development. In this study, we investigated the physiological function of AhR in skin. Distribution of AhR in murine skin was examined by immunohistochemistry. Expression of a target gene which is transcriptionally activated by AhR is analysed by RT-PCR. We found that AhR co-localizes with the transcriptional repressor B lymphocyte maturation protein 1 (Blimp1) in sebaceous gland. In this report, we show that expression of Blimp1 is induced by treatment with AhR ligands, such as methylcolanthrene (MC) in sebocyte and keratinocyte cell lines. Exposure to ultraviolet B, which has been reported to generate AhR ligand intracellularly, also increased Blimp1 mRNA. This ligand-dependent induction of Blimp1 requires the expression of both AhR and ARNT, since transfection of siRNA specific to either AhR or ARNT significantly reduced Blimp1 mRNA in response to MC. Analysis using kinase inhibitors revealed that ligand-dependent induction of Blimp1, but not that of CYP1A1, is inhibited by staurosporine. TPA, a potent activator of protein kinase C, increased Blimp1 mRNA but not CYP1A1. These data indicate that Blimp1 is a novel AhR-target gene in epidermal keratinocyte and sebocyte.
    No preview · Article · Jun 2010 · Journal of dermatological science
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    Yoshiaki Fujii-Kuriyama · Kaname Kawajiri
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) was originally identified as a ligand-activated transcription factor that is involved in the induction of xenobiotic-metabolizing Cytochrome P4501A1 (CYP1A1). For several decades, AhR has been studied in relation to toxicology and pharmacology. With recent discoveries on novel AhR functions, AhR research has expanded into multiple aspects of physiology, such as reproduction, innate immunity and tumor suppression. In this review, we summarize and discuss recent progress in mechanistic and functional studies on AhR with particular emphasis on physiological processes.
    Preview · Article · Jan 2010 · Proceedings of the Japan Academy Ser B Physical and Biological Sciences
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    ABSTRACT: Down-regulation of carcinogen detoxifying enzymes might be a critical factor in tumour formation by increasing the carcinogen concentration in the target organ. Previous reports revealed that the expression of UGT1A mRNA is either lost or decreased in certain human cancer tissues, including urinary bladder cancer. To elucidate this down-regulation mechanism, we used an N-nitrosobutyl (4-hydroxybutyl) amine (BBN)-induced mouse urinary bladder carcinogenesis model. Similar to human cancer, the expressions of Ugt1a6, Ugt1a9 and total Ugt1a mRNA in the BBN-induced bladder cancer were markedly decreased compared with those of normal mice. BBN down-regulated the basal Ugt1a mRNA expression in a time-dependent manner and this was reversible in the first 2 weeks of BBN treatment. However, after 4 weeks of BBN treatment the repression became persistent after the cessation of BBN treatment. Aryl hydrocarbon receptor (AhR) regulates the constitutive and inducible expression of Ugt1a mRNA. We found that the constitutive Ugt1a mRNA expression is decreased in the bladder of AhR knockout (KO) mice. Furthermore, BBN-induced Ugt1a down-regulation was lost in AhR KO mice, and the canonical AhR target gene Cyp1a1 was similarly down-regulated by BBN in the bladder. These results demonstrate that BBN repressed Ugt1a mRNA expression via suppression of AhR signaling pathway during BBN-induced carcinogenesis.
    No preview · Article · Oct 2009 · Journal of Biochemistry

Publication Stats

19k Citations
1,271.59 Total Impact Points


  • 2010-2015
    • Tokyo Medical and Dental University
      • Medical Research Institute
      Edo, Tōkyō, Japan
  • 2013-2014
    • Karolinska Institutet
      • Department of Cell and Molecular Biology
      Solna, Stockholm, Sweden
  • 2007-2014
    • The University of Tokyo
      • Institute of Molecular and Cellular Biosciences
      白山, Tōkyō, Japan
  • 2009
    • Okayama University
      • Laboratory of Membrane Biochemistry
      Okayama, Okayama, Japan
  • 2003-2009
    • University of Tsukuba
      • Institute of Basic Medical Sciences
      Tsukuba, Ibaraki, Japan
  • 1986-2007
    • Tohoku University
      • • Department of Biomolecular Sciences
      • • Department of Chemistry
      Sendai, Kagoshima, Japan
  • 2000
    • Osaka City University
      • Department of Neuropsychiatry
      Ōsaka, Ōsaka, Japan
  • 1997
    • Hokkaido University
      • Faculty of Pharmaceutical Sciences
      Sapporo-shi, Hokkaido, Japan
  • 1991
    • University of Cincinnati
      • Department of Environmental Health
      Cincinnati, Ohio, United States
  • 1980-1990
    • Japanese Foundation for Cancer Research
      Edo, Tokyo, Japan
  • 1989
    • Research Institute of Tuberculosis
      Edo, Tōkyō, Japan
  • 1988
    • Kyushu University
      • Department of Biology
      Hukuoka, Fukuoka, Japan
    • Tokai University
      • Department of Pathology
      Hiratuka, Kanagawa, Japan
  • 1984
    • Saitama Cancer Center
      Саитама, Saitama, Japan
  • 1983
    • Kyoto University
      • Primate Research Institute
      Kioto, Kyōto, Japan
  • 1978-1979
    • The University of Tokushima
      • Department of Biochemistry
      Tokusima, Tokushima, Japan
  • 1976-1979
    • Kansai Medical University
      • Department of Physiology
      Moriguchi, Ōsaka, Japan