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Last Updated :2024/07/25

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Master

Affiliation (Master)

  • Faculty of Medicine　Pathological Science　Pathology

Affiliation (Master)

  • Faculty of Medicine　Pathological Science　Pathology

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Profile and Settings

Affiliation

  • Hokkaido University, Department of Pathology, Faculty of Medicine and Graduate School of Medicine

Profile and Settings

  • Name (Japanese)

    Taniguchi

  • Name (Kana)

    Koji

  • Name

    202101011791738461

Alternate Names

Affiliation

  • Hokkaido University, Department of Pathology, Faculty of Medicine and Graduate School of Medicine

Achievement

Research Interests

  • 消化器   炎症記憶   腫瘍惹起性炎症   炎症   がん   組織再生   病理学   免疫   

Research Areas

  • Life sciences / Tumor biology
  • Life sciences / Digestive surgery
  • Life sciences / Pathobiochemistry
  • Life sciences / Experimental pathology
  • Life sciences / Immunology

Research Experience

  • 2021 - Today Hokkaido University
  • 2020 - 2021 Keio University School of Medicine
  • 2017 - 2019 慶應義塾大学 医学部 特任准教授
  • 2009 - 2016 米国カリフォルニア大学サンディエゴ校 ポスドク/Project Scientist

Education

  •        - 2007  九州大学大学院医学系学府 博士課程修了 博士（医学）
  •        - 2000  東京大学医学部医学科

Published Papers

  • Katsuya Toshida, Shinji Itoh, Norifumi Iseda, Takahiro Tomiyama, Shohei Yoshiya, Takeo Toshima, Yu-Chen Liu, Takeshi Iwasaki, Daisuke Okuzaki, Koji Taniguchi, Yoshinao Oda, Masaki Mori, Tomoharu Yoshizumi
    Liver international : official journal of the International Association for the Study of the Liver 44 (4) 1011 - 1023 2024 
    BACKGROUND & AIMS: Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl-CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood. METHODS: We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC. RESULTS: Patients were divided into ACSL4-positive (n = 72, 20.1%) and ACSL4-negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α-fetoprotein (p = .0180) and more histological liver fibrosis (p = .0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p < .0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer-associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC. CONCLUSION: ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer-associated fibroblasts and anti-tumour immunity.
  • Shimpei Nakagawa, Aya Fukui-Miyazaki, Takuma Yoshida, Yasushi Ishii, Eri Murata, Koji Taniguchi, Akihiro Ishizu, Masanori Kasahara, Utano Tomaru
    The American journal of pathology 194 (6) 1033 - 1046 2024 
    Low-grade chronic inflammation contributes to both aging and the pathogenesis of age-related diseases. White adipose tissue (WAT) in obese individuals exhibits chronic inflammation, which is associated with obesity-related disorders. Aging exacerbates obesity-related inflammation in WAT; however, the molecular mechanisms underlying chronic inflammation and its exacerbation by aging remain unclear. Age-related decline in activity of the proteasome, a multisubunit proteolytic complex, has been implicated in age-related diseases. This study employed a mouse model with decreased proteasomal function that exhibits age-related phenotypes to investigate the impact of adipocyte senescence on WAT inflammation. Transgenic mice expressing proteasomal subunit β5t with weak chymotrypsin-like activity experience reduced lifespan and develop age-related phenotypes. Mice fed with a high-fat diet and experiencing proteasomal dysfunction exhibited increased WAT inflammation, increased infiltration of proinflammatory M1-like macrophages, and increased proinflammatory adipocytokine-like monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and tumor necrosis factor-α, which are all associated with activation of endoplasmic reticulum (ER) stress-related pathways. Impaired proteasomal activity also activated ER stress-related molecules and induced expression of proinflammatory adipocytokines in adipocyte-like cells differentiated from 3T3-L1 cells. Collectively, the results suggesed that impaired proteasomal activity increases ER stress and that subsequent inflammatory pathways play pivotal roles in WAT inflammation. Because proteasomal function declines with age, age-related proteasome impairment may be involved in obesity-related inflammation among elderly individuals.
  • Naoki Kosaka, Takanori Uchiyama, Masahiro Onozawa, Jun Nagai, Jiro Koya, Suguru Ishizaka, Toshiyuki Nagai, Yohei Ikebe, Kenjiro Kato, Zen-Ichi Tanei, Jun Sakakibara-Konishi, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Hideki Ujiie, Satoshi Hirano, Satoshi Konno, Toshihisa Anzai, Koji Taniguchi, Shinya Tanaka, Takanori Teshima
    Internal medicine (Tokyo, Japan) 2024 
    We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.
  • Keishi Makita, Noriyuki Otsuka, Utano Tomaru, Koji Taniguchi, Masanori Kasahara
    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 71 (2) 61 - 72 2023 
    Pressure ulcers represent a crucial clinical problem, especially in hospitalized patients. Ischemia-reperfusion (I-R) is an important cause of these lesions. Natural killer (NK), invariant NK T (iNKT), and dendritic epidermal T-cells, which express the natural killer group 2, member D (NKG2D) receptor, have been reported to have physiological roles in skin tissue repair and wound healing. However, a role for NKG2D-NKG2D ligand interactions in I-R-induced skin injury has not been determined. Using a murine pressure ulcer model, we demonstrated that I-R-induced ulcers in NKG2D-deficient mice were larger than those in wild-type or T-cell receptor δ knockout mice. Histopathological evaluation revealed that accumulation of macrophages and neutrophils at the peripheral deep dermis and subcutaneous tissue of the ulcers was enhanced in NKG2D-deficient mice. Rae-1 mRNA, which encodes an NKG2D ligand, was induced, and RAE-1 protein was detected immunohistochemically in fibroblasts and inflammatory cells in the dermis after reperfusion. RAE-1 expression was also increased in primary mouse fibroblasts treated with sodium arsenite. These results suggested that NKG2D ligand expression was induced by oxidative stress after I-R injury and support a putative role for this ligand in wound repair. Furthermore, the influx of NKG2D-positive cells at I-R sites may mitigate pressure ulcers via NKG2D-NKG2D ligand interactions.
  • Xichen Hu, Tadahito Yasuda, Noriko Yasuda-Yosihara, Atsuko Yonemura, Terumasa Umemoto, Yutaka Nakachi, Kohei Yamashita, Takashi Semba, Kota Arima, Tomoyuki Uchihara, Akiho Nishimura, Luke Bu, Lingfeng Fu, Feng Wei, Jun Zhang, Yilin Tong, Huaitao Wang, Kazuya Iwamoto, Takaichi Fukuda, Hayato Nakagawa, Koji Taniguchi, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto
    JHEP reports : innovation in hepatology 5 (12) 100892 - 100892 2023 
    BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. METHODS: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. RESULTS: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. CONCLUSIONS: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. IMPACT AND IMPLICATIONS: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.
  • Keiko Ishikawa, Shinya Sugimoto, Mayumi Oda, Masayuki Fujii, Sirirat Takahashi, Yuki Ohta, Ai Takano, Kazuhiro Ishimaru, Mami Matano, Kosuke Yoshida, Hikaru Hanyu, Kohta Toshimitsu, Kazuaki Sawada, Mariko Shimokawa, Megumu Saito, Kenta Kawasaki, Ryota Ishii, Koji Taniguchi, Takeshi Imamura, Takanori Kanai, Toshiro Sato
    Gastroenterology 0016-5085 2022
  • Nao Nagai, Yotaro Kudo, Daisuke Aki, Hayato Nakagawa, Koji Taniguchi
    International journal of molecular sciences 22 (5) 2021 
    Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.
  • Sana Hibino, Tetsuro Kawazoe, Hidenori Kasahara, Shinji Itoh, Takatsugu Ishimoto, Mamiko Sakata-Yanagimoto, Koji Taniguchi
    International journal of molecular sciences 22 (11) 2021 
    Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
  • Jerry Wong, Ricard Garcia-Carbonell, Matija Zelic, Samuel B Ho, Brigid S Boland, Shih-Jing Yao, Shalin A Desai, Soumita Das, Núria Planell, Philip A Harris, Joan Font-Burgada, Koji Taniguchi, John Bertin, Azucena Salas, Manolis Pasparakis, Pete J Gough, Michelle Kelliher, Michael Karin, Monica Guma
    Cellular and molecular gastroenterology and hepatology 9 (2) 295 - 312 2020 
    BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- κB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice. METHODS: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKβ in IEC (Ikkβ(EE)IEC), Ripk1D138N/D138N knockin mice, and Ripk3-/- mice were injected with TNF or lipopolysaccharide. Enteroids were also isolated from these mice and challenged with TNF with or without RIPK1 and RIPK3 inhibitors or butylated hydroxyanisole. Ripoptosome-mediated caspase-8 activation was assessed by immunoprecipitation. RESULTS: NF-κB activation in human IBD correlated with appearance of cleaved caspase-3. Congruently, unlike normal mouse IECs that are TNF-resistant, IECs in Ikkβ(EE)IEC mice and enteroids were susceptible to TNF-dependent apoptosis, which depended on the protein kinase function of RIPK1. Constitutively active IKKβ facilitated ripoptosome formation, a RIPK1 signaling complex that mediates caspase-8 activation by TNF. Butylated hydroxyanisole treatment and RIPK1 inhibitors attenuated TNF-induced and ripoptosome-mediated caspase-8 activation and IEC death in vitro and in vivo. CONCLUSIONS: Contrary to common expectations, chronic NF-κB activation induced intestinal crypt apoptosis after TNF stimulation, resulting in severe mucosal erosion. RIPK1 kinase inhibitors selectively inhibited TNF destructive properties while preserving its survival and proliferative properties, which do not require RIPK1 kinase activity. RIPK1 kinase inhibition could be a potential treatment for IBD.
  • Feng He, Laura Antonucci, Shinichiro Yamachika, Zechuan Zhang, Koji Taniguchi, Atsushi Umemura, Georgia Hatzivassiliou, Merone Roose-Girma, Miguel Reina-Campos, Angeles Duran, Maria T Diaz-Meco, Jorge Moscat, Beicheng Sun, Michael Karin
    Journal of hepatology 72 (6) 1182 - 1195 2020 
    BACKGROUND & AIMS: Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown. METHODS: Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology. RESULTS: Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly. CONCLUSIONS: NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY: Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
  • Jelena Todoric, Giuseppe Di Caro, Saskia Reibe, Darren C Henstridge, Courtney R Green, Alison Vrbanac, Fatih Ceteci, Claire Conche, Reginald McNulty, Shabnam Shalapour, Koji Taniguchi, Peter J Meikle, Jeramie D Watrous, Rafael Moranchel, Mahan Najhawan, Mohit Jain, Xiao Liu, Tatiana Kisseleva, Maria T Diaz-Meco, Jorge Moscat, Rob Knight, Florian R Greten, Lester F Lau, Christian M Metallo, Mark A Febbraio, Michael Karin
    Nature metabolism 2 (10) 1034 - 1045 2020 
    Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
  • Tetsuro Kawazoe, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Yoshihiko Maehara, Masaki Mori, Koji Taniguchi
    Molecular cancer research : MCR 18 (12) 1876 - 1888 2020 
    The IL6 family of cytokines, including IL6 and leukemia-inhibitory factor (LIF), are induced during inflammation and are also expressed in many types of cancer where they play an important role in tumor development. IL6 family cytokines mainly activate the JAK-STAT3 pathway via the coreceptor, gp130, and IL6 is known to activate the Src family kinase (SFK)-Yes-associated protein (YAP) pathway. The current study investigated the role of autocrine LIF in human esophageal squamous cell carcinoma (ESCC) that highly expresses LIF. LIF knockdown had various effects on cancer cells, including profound changes in gene expression, suppression of cell proliferation, migration/invasion and sphere formation, and induction of apoptosis. Similar to IL6, LIF activated the SFK-YAP pathway as well as the JAK-STAT3 pathway. LIF-induced YAP activation was more important for cancer cell proliferation than LIF-induced STAT3 activation, and concomitant YAP and STAT3 activation completely compensated for the role of LIF in human ESCC growth. We also confirmed that SFK activation and LIF expression were correlated with YAP activation in human ESCC clinical samples. Furthermore, simultaneous inhibition of the SFK-YAP and JAK-STAT3 pathways in human ESCC cells was more effective at suppressing cell proliferation than single inhibition, and autocrine LIF signaling promoted human ESCC growth in vivo. Therefore, the LIF-SFK-YAP axis may represent a new therapeutic target for human ESCC. IMPLICATIONS: Autocrine LIF signaling promotes human ESCC progression via SFK-dependent YAP activation and is a new potential target of treatment for human ESCC.
  • Tetsuro Kawazoe, Koji Taniguchi
    Cancer science 110 (5) 1525 - 1535 2019 
    The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.
  • Koji Taniguchi, Michael Karin
    Nature reviews. Immunology 18 (5) 309 - 324 2018 
    Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.
  • Michelle Dow, Rachel M Pyke, Brian Y Tsui, Ludmil B Alexandrov, Hayato Nakagawa, Koji Taniguchi, Ekihiro Seki, Olivier Harismendy, Shabnam Shalapour, Michael Karin, Hannah Carter, Joan Font-Burgada
    Proceedings of the National Academy of Sciences of the United States of America 115 (42) E9879-E9888  2018 
    Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.
  • Koji Taniguchi, Toshiro Moroishi, Petrus R de Jong, Michal Krawczyk, Britta Moyo Grebbin, Huiyan Luo, Rui-Hua Xu, Nicole Golob-Schwarzl, Caroline Schweiger, Kepeng Wang, Giuseppe Di Caro, Ying Feng, Eric R Fearon, Eyal Raz, Lukas Kenner, Henner F Farin, Kun-Liang Guan, Johannes Haybaeck, Christian Datz, Kang Zhang, Michael Karin
    Proceedings of the National Academy of Sciences of the United States of America 114 (7) 1643 - 1648 2017 
    Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.
  • Petrus R de Jong, Koji Taniguchi, Alexandra R Harris, Samuel Bertin, Naoki Takahashi, Jen Duong, Alejandro D Campos, Garth Powis, Maripat Corr, Michael Karin, Eyal Raz
    Nature communications 7 11551 - 11551 2016 
    The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC.
  • Atsushi Umemura, Feng He, Koji Taniguchi, Hayato Nakagawa, Shinichiro Yamachika, Joan Font-Burgada, Zhenyu Zhong, Shankar Subramaniam, Sindhu Raghunandan, Angeles Duran, Juan F Linares, Miguel Reina-Campos, Shiori Umemura, Mark A Valasek, Ekihiro Seki, Kanji Yamaguchi, Kazuhiko Koike, Yoshito Itoh, Maria T Diaz-Meco, Jorge Moscat, Michael Karin
    Cancer cell 29 (6) 935 - 948 2016 
    p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.
  • Koji Taniguchi, Shinichiro Yamachika, Feng He, Michael Karin
    FEBS letters 590 (15) 2375 - 97 2016 
    p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.
  • Junli Liu, Dorina Ibi, Koji Taniguchi, Jaemin Lee, Hilde Herrema, Bedia Akosman, Patrick Mucka, Mario Andres Salazar Hernandez, Muhemmet Fatih Uyar, Sang Won Park, Michael Karin, Umut Ozcan
    Cell 167 (4) 1052 - 1066 2016 
    It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.
  • Koji Taniguchi, Li-Wha Wu, Sergei I Grivennikov, Petrus R de Jong, Ian Lian, Fa-Xing Yu, Kepeng Wang, Samuel B Ho, Brigid S Boland, John T Chang, William J Sandborn, Gary Hardiman, Eyal Raz, Yoshihiko Maehara, Akihiko Yoshimura, Jessica Zucman-Rossi, Kun-Liang Guan, Michael Karin
    Nature 519 (7541) 57 - 62 2015 
    Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
  • Toshiro Moroishi, Hyun Woo Park, Baodong Qin, Qian Chen, Zhipeng Meng, Steven W Plouffe, Koji Taniguchi, Fa-Xing Yu, Michael Karin, Duojia Pan, Kun-Liang Guan
    Genes & development 29 (12) 1271 - 84 2015 
    YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.
  • Joan Font-Burgada, Shabnam Shalapour, Suvasini Ramaswamy, Brian Hsueh, David Rossell, Atsushi Umemura, Koji Taniguchi, Hayato Nakagawa, Mark A Valasek, Li Ye, Janel L Kopp, Maike Sander, Hannah Carter, Karl Deisseroth, Inder M Verma, Michael Karin
    Cell 162 (4) 766 - 79 2015 
    Compensatory proliferation triggered by hepatocyte loss is required for liver regeneration and maintenance but also promotes development of hepatocellular carcinoma (HCC). Despite extensive investigation, the cells responsible for hepatocyte restoration or HCC development remain poorly characterized. We used genetic lineage tracing to identify cells responsible for hepatocyte replenishment following chronic liver injury and queried their roles in three distinct HCC models. We found that a pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries. Despite their high regenerative potential, these so-called hybrid hepatocytes do not give rise to HCC in chronically injured livers and thus represent a unique way to restore tissue function and avoid tumorigenesis. This specialized set of pre-existing differentiated cells may be highly suitable for cell-based therapy of chronic hepatocyte-depleting disorders.
  • Shlomi Finkin, Detian Yuan, Ilan Stein, Koji Taniguchi, Achim Weber, Kristian Unger, Jeffrey L Browning, Nicolas Goossens, Shigeki Nakagawa, Ganesh Gunasekaran, Myron E Schwartz, Masahiro Kobayashi, Hiromitsu Kumada, Michael Berger, Orit Pappo, Klaus Rajewsky, Yujin Hoshida, Michael Karin, Mathias Heikenwalder, Yinon Ben-Neriah, Eli Pikarsky
    Nature immunology 16 (12) 1235 - 44 2015 
    Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.
  • Hayato Nakagawa, Yohko Hikiba, Yoshihiro Hirata, Joan Font-Burgada, Kei Sakamoto, Yoku Hayakawa, Koji Taniguchi, Atsushi Umemura, Hiroto Kinoshita, Kosuke Sakitani, Yuji Nishikawa, Kenji Hirano, Tsuneo Ikenoue, Hideaki Ijichi, Debanjan Dhar, Wataru Shibata, Masao Akanuma, Kazuhiko Koike, Michael Karin, Shin Maeda
    Proceedings of the National Academy of Sciences of the United States of America 111 (3) 1090 - 5 2014 
    E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the loss of E-cadherin is a real culprit or a bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here we demonstrate that liver-specific E-cadherin knockout mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial-mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial-mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.
  • Koji Taniguchi, Michael Karin
    Seminars in immunology 26 (1) 54 - 74 2014 
    Inflammatory responses play pivotal roles in cancer development, including tumor initiation, promotion, progression, and metastasis. Cytokines are now recognized as important mediators linking inflammation and cancer, and are therefore potential therapeutic and preventive targets as well as prognostic factors. The interleukin (IL)-6 family of cytokines, especially IL-6 and IL-11, is highly up-regulated in many cancers and considered as one of the most important cytokine families during tumorigenesis and metastasis. This review discusses molecular mechanisms linking the IL-6 cytokine family to solid malignancies and their treatment.
  • Tomohiro Fukaya, Kazue Someya, Sana Hibino, Masahiro Okada, Humitsugu Yamane, Koji Taniguchi, Akihiko Yoshimura
    Biochemical and biophysical research communications 447 (3) 471 - 8 2014 
    Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. To gain pathogenicity, however, Th17 cells require IL-1β and IL-23. The underlying mechanism by which these confer pathogenicity is not well understood. Here we show that Sprouty4, an inhibitor of the PLCγ-ERK pathway, critically regulates inflammatory Th17 (iTh17) cell differentiation. Sprouty4-deficient mice, as well as mice adoptively transferred with Sprouty4-deficient T cells, were resistant to experimental autoimmune encephalitis (EAE) and showed decreased Th17 cell generation in vivo. In vitro, Sprouty4 deficiency did not severely affect TGF-β/IL-6-induced Th17 cell generation but strongly impaired Th17 differentiation induced by IL-1/IL-6/IL-23. Analysis of Th17-related gene expression revealed that Sprouty4-deficient Th17 cells expressed lower levels of IL-1R1 and IL-23R, while RORγt levels were similar. Consistently, overexpression of Sprouty4 or pharmacological inhibition of ERK upregulated IL-1R1 expression in primary T cells. Thus, Sprouty4 and ERK play a critical role in developing iTh17 cells in Th17 cell-driven autoimmune diseases.
  • Atsushi Umemura, Eek Joong Park, Koji Taniguchi, Jun Hee Lee, Shabnam Shalapour, Mark A Valasek, Mariam Aghajan, Hayato Nakagawa, Ekihiro Seki, Michael N Hall, Michael Karin
    Cell metabolism 20 (1) 133 - 44 2014 
    Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.
  • Sayaka Inokuchi-Shimizu, Eek Joong Park, Yoon Seok Roh, Ling Yang, Bi Zhang, Jingyi Song, Shuang Liang, Michael Pimienta, Koji Taniguchi, Xuefeng Wu, Kinji Asahina, William Lagakos, Mason R Mackey, Shizuo Akira, Mark H Ellisman, Dorothy D Sears, Jerrold M Olefsky, Michael Karin, David A Brenner, Ekihiro Seki
    The Journal of clinical investigation 124 (8) 3566 - 78 2014 
    The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.
  • Petrus R de Jong, Naoki Takahashi, Alexandra R Harris, Jihyung Lee, Samuel Bertin, James Jeffries, Michael Jung, Jen Duong, Amy I Triano, Jongdae Lee, Yaron Niv, David S Herdman, Koji Taniguchi, Chang-Whan Kim, Hui Dong, Lars Eckmann, Stephanie M Stanford, Nunzio Bottini, Maripat Corr, Eyal Raz
    The Journal of clinical investigation 124 (9) 3793 - 806 2014 
    The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (Apc(Min/+) mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in Apc(Min/+) mice, similar to--as well as in conjunction with--a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.
  • Hayato Nakagawa, Atsushi Umemura, Koji Taniguchi, Joan Font-Burgada, Debanjan Dhar, Hisanobu Ogata, Zhenyu Zhong, Mark A Valasek, Ekihiro Seki, Juan Hidalgo, Kazuhiko Koike, Randal J Kaufman, Michael Karin
    Cancer cell 26 (3) 331 - 343 2014 
    Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.
  • Mei-Fei Yueh, Koji Taniguchi, Shujuan Chen, Ronald M Evans, Bruce D Hammock, Michael Karin, Robert H Tukey
    Proceedings of the National Academy of Sciences of the United States of America 111 (48) 17200 - 5 2014 
    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.
  • Kepeng Wang, Min Kyoung Kim, Giuseppe Di Caro, Jerry Wong, Shabnam Shalapour, Jun Wan, Wei Zhang, Zhenyu Zhong, Elsa Sanchez-Lopez, Li-Wha Wu, Koji Taniguchi, Ying Feng, Eric Fearon, Sergei I Grivennikov, Michael Karin
    Immunity 41 (6) 1052 - 63 2014 
    Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.
  • Helena Shaked, Lorne J Hofseth, Alena Chumanevich, Alexander A Chumanevich, Jin Wang, Yinsheng Wang, Koji Taniguchi, Monica Guma, Steve Shenouda, Hans Clevers, Curtis C Harris, Michael Karin
    Proceedings of the National Academy of Sciences of the United States of America 109 (35) 14007 - 12 2012 
    The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE)(IEC) transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkβ(EE)(IEC) mice exhibited more β-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkβ(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin(+) lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.
  • Sergei I Grivennikov, Kepeng Wang, Daniel Mucida, C Andrew Stewart, Bernd Schnabl, Dominik Jauch, Koji Taniguchi, Guann-Yi Yu, Christoph H Osterreicher, Kenneth E Hung, Christian Datz, Ying Feng, Eric R Fearon, Mohamed Oukka, Lino Tessarollo, Vincenzo Coppola, Felix Yarovinsky, Hilde Cheroutre, Lars Eckmann, Giorgio Trinchieri, Michael Karin
    Nature 491 (7423) 254 - 8 2012 
    Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
  • Takuma Ishizaki, Taiga Tamiya, Koji Taniguchi, Rimpei Morita, Reiko Kato, Fuyuki Okamoto, Kazuko Saeki, Masatoshi Nomura, Yoshihisa Nojima, Akihiko Yoshimura
    Genes to cells : devoted to molecular & cellular mechanisms 16 (7) 803 - 14 2011 
    The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain-containing protein) has been identified as a negative regulator of growth factor-induced ERK/mitogen-activated protein kinase activation. Spred1 has also been implicated as the target of microRNA-126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down-regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up-regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcεRI-mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell-specific Spred1-conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1-deficient bone marrow-derived mast cells were highly activated by cross-linking of Fcε-R stimulation as well as by IL-3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126.
  • Koji Taniguchi, Ken-ichiro Sasaki, Kousuke Watari, Hideo Yasukawa, Tsutomu Imaizumi, Toranoshin Ayada, Fuyuki Okamoto, Takuma Ishizaki, Reiko Kato, Ri-ichiro Kohno, Hiroshi Kimura, Yasufumi Sato, Mayumi Ono, Yoshikazu Yonemitsu, Akihiko Yoshimura
    PloS one 4 (5) e5467  2009 
    Sprouty proteins (Sproutys) inhibit receptor tyrosine kinase signaling and control various aspects of branching morphogenesis. In this study, we examined the physiological function of Sproutys in angiogenesis, using gene targeting and short-hairpin RNA (shRNA) knockdown strategies. Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects. The number of peripheral blood vessels, but not that of lymphatic vessels, was increased in Sprouty4 KO mice compared with wild-type (WT) mice. Sprouty4 KO mice were more resistant to hind limb ischemia and soft tissue ischemia than WT mice were, because Sprouty4 deficiency causes accelerated neovascularization. Moreover, suppression of Sprouty2 and Sprouty4 expression in vivo by shRNA targeting accelerated angiogenesis and has a therapeutic effect in a mouse model of hind limb ischemia. These data suggest that Sproutys are physiologically important negative regulators of angiogenesis in vivo and novel therapeutic targets for treating peripheral ischemic diseases.
  • Koji Taniguchi, Takuma Ishizaki, Toranoshin Ayada, Yuki Sugiyama, Yu Wakabayashi, Takashi Sekiya, Ryusuke Nakagawa, Akihiko Yoshimura
    Cancer science 100 (9) 1648 - 54 2009 
    Sprouty proteins have been shown to negatively regulate a variety of receptor tyrosine kinase (RTK) signaling pathways and are considered to be tumor suppressor proteins. The pathophysiological functions of Sproutys in vivo remain to be investigated. In this study, we examined the physiological function of Sprouty4 as an angiogenic regulator, using Sprouty4 knockout (KO) mice and cells. We found that transplanted tumor cells grow much faster in Sprouty4 KO mice than in wild type (WT) mice, which we associate with enhanced neovascularization in the tumors transplanted into Sprouty4 KO mice. Moreover, vascular endothelial growth factor (VEGF)-A-induced angiogenesis and vascular permeability in vivo were enhanced in Sprouty4 KO mice compared with WT mice. Ex vivo angiogenesis, which we induced by VEGF-A, basic fibroblast growth factor (bFGF), and sphingosine-1-phosphate (S1P), was also enhanced in the aortas of Sprouty4 KO mice. We demonstrated that Sprouty4 suppresses Ras-independent VEGF-A and S1P signaling, while it does not affect Ras-dependent VEGF-C signaling. These data indicate that Sprouty4 selectively suppresses Ras-independent angiogenic factor signals and is an important negative regulator of pathophysiological angiogenesis.
  • Ludwine Messiaen, Suxia Yao, Hilde Brems, Tom Callens, Achara Sathienkijkanchai, Ellen Denayer, Emily Spencer, Pamela Arn, Dusica Babovic-Vuksanovic, Carolyn Bay, Gary Bobele, Bruce H Cohen, Luis Escobar, Deborah Eunpu, Theresa Grebe, Robert Greenstein, Rachel Hachen, Mira Irons, David Kronn, Edmond Lemire, Kathleen Leppig, Cynthia Lim, Marie McDonald, Vinodh Narayanan, Amy Pearn, Robert Pedersen, Berkley Powell, Lawrence R Shapiro, David Skidmore, David Tegay, Heidi Thiese, Elaine H Zackai, Raymon Vijzelaar, Koji Taniguchi, Toranoshin Ayada, Fuyuki Okamoto, Akihiko Yoshimura, Annabel Parret, Bruce Korf, Eric Legius
    JAMA 302 (19) 2111 - 8 2009 
    CONTEXT: Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. OBJECTIVE: To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. MAIN OUTCOME MEASURES: Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. RESULTS: Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. CONCLUSIONS: A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.
  • Koji Taniguchi, Ri-Ichiro Kohno, Toranoshin Ayada, Reiko Kato, Kenji Ichiyama, Tohru Morisada, Yuichi Oike, Yoshikazu Yonemitsu, Yoshihiko Maehara, Akihiko Yoshimura
    Molecular and cellular biology 27 (12) 4541 - 50 0270-7306 2007/06 
    Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk(-/-) and SLP-76(-/-) mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.
  • Koji Taniguchi, Toranoshin Ayada, Kenji Ichiyama, Ri-Ichiro Kohno, Yoshikazu Yonemitsu, Yasuhiro Minami, Akira Kikuchi, Yoshihiko Maehara, Akihiko Yoshimura
    Biochemical and biophysical research communications 352 (4) 896 - 902 0006-291X 2007/01/26 
    Sprouty genes encode cytoplasmic membrane-associated proteins that inhibit receptor tyrosine kinase signaling. Four orthologs of Drosophila Sprouty (dSpry) (Sprouty1-4) have been identified in mammals. Physiological function of Sprouty1 and Sprouty2 has been investigated using gene targeting approaches, however to date detailed examination of Sprouty4 knockout (KO) mice has not been reported. In this study, Sprouty4 KO mice were generated and characterized. Although a significant fraction of Sprouty4 KO mice died shortly after birth due to mandible defects, the remainder were viable and fertile. Growth retardation was observed for most Sprouty4-deficient mice, with nearly all Sprouty4 KO mice having polysyndactyly. ERK activation was sustained in Sprouty4 KO mouse embryonic fibroblasts (MEFs) in response to FGF, but not to EGF. Sprouty2 and Sprouty4 double KO (DKO) mice were embryonic lethal and showed severe defects in craniofacial, limb, and lung morphogenesis. These findings suggest both redundant and non-redundant functions for Sprouty2 and Sprouty4 on embryonic development and FGF signaling.
  • Hilde Brems, Magdalena Chmara, Mourad Sahbatou, Ellen Denayer, Koji Taniguchi, Reiko Kato, Riet Somers, Ludwine Messiaen, Sofie De Schepper, Jean-Pierre Fryns, Jan Cools, Peter Marynen, Gilles Thomas, Akihiko Yoshimura, Eric Legius
    Nature genetics 39 (9) 1120 - 6 1061-4036 2007 
    We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.
  • Hiromasa Inoue, Reiko Kato, Satoru Fukuyama, Atsushi Nonami, Koji Taniguchi, Koichiro Matsumoto, Takako Nakano, Miyuki Tsuda, Mikiko Matsumura, Masato Kubo, Fumihiko Ishikawa, Byoung-gon Moon, Kiyoshi Takatsu, Yoichi Nakanishi, Akihiko Yoshimura
    The Journal of experimental medicine 201 (1) 73 - 82 0022-1007 2005 
    T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play a critical role in allergic asthma. These cytokines transmit signals through the Janus kinase/signal transducer and activator of transcription (STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. Although the suppressor of cytokine signaling (SOCS) family proteins have been shown to regulate the STAT pathway, the mechanism regulating the ERK pathway has not been clarified. The Sprouty-related Ena/VASP homology 1-domain-containing protein (Spred)-1 has recently been identified as a negative regulator of growth factor-mediated, Ras-dependent ERK activation. Here, using Spred-1-deficient mice, we demonstrated that Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness, without affecting helper T cell differentiation. Biochemical assays indicate that Spred-1 suppresses IL-5-dependent cell proliferation and ERK activation. These data indicate that Spred-1 negatively controls eosinophil numbers and functions by modulating IL-5 signaling in allergic asthma.
  • Masanobu Ohishi, Yumiko Matsumura, Daisuke Aki, Ryuichi Mashima, Koji Taniguchi, Takashi Kobayashi, Toshio Kukita, Yukihide Iwamoto, Akihiko Yoshimura
    Journal of immunology (Baltimore, Md. : 1950) 174 (5) 3024 - 31 0022-1767 2005 
    Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physiological roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-gamma-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deficient BMMs, but was diminished in SOCS1-overexpressing BMMs. Moreover, LPS-induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1(+/-) mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-gamma on osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and IkappaB were drastically reduced and receptor activator of the NF-kappaB ligand-induced IkappaB phosphorylation was severely impaired in the presence of IL-6. These data suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-kappaB ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction.
  • Takaharu Taketomi, Daigo Yoshiga, Koji Taniguchi, Takashi Kobayashi, Atsushi Nonami, Reiko Kato, Mika Sasaki, Atsuo Sasaki, Hitoshi Ishibashi, Maiko Moriyama, Kei-ichiro Nakamura, Junji Nishimura, Akihiko Yoshimura
    Nature neuroscience 8 (7) 855 - 7 1097-6256 2005 
    We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line-derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.
  • Atsushi Nonami, Takaharu Taketomi, Akiko Kimura, Kazuko Saeki, Hiromi Takaki, Takahito Sanada, Koji Taniguchi, Mine Harada, Reiko Kato, Akihiko Yoshimura
    Genes to cells : devoted to molecular & cellular mechanisms 10 (9) 887 - 95 1356-9597 2005 
    Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1.
  • Atsushi Nonami, Reiko Kato, Koji Taniguchi, Daigo Yoshiga, Takaharu Taketomi, Satoru Fukuyama, Mine Harada, Atsuo Sasaki, Akihiko Yoshimura
    The Journal of biological chemistry 279 (50) 52543 - 51 0021-9258 2004 
    Sprouty/Spred family proteins have been identified as negative regulators of growth factor-induced ERK/mitogen-activated protein (MAP) kinase activation. However, it has not been clarified whether these proteins regulate cytokine-induced ERK activity. We found that Spred-1 is highly expressed in interleukin-3 (IL-3)-dependent hematopoietic cell lines and bone marrow-derived mast cells. To investigate the roles of Spred-1 in hematopoiesis, we expressed wild-type Spred-1 and a dominant negative form of Spred-1, DeltaC-Spred, in IL-3- and stem cell factor (SCF)-dependent cell lines as well as hematopoietic progenitor cells from mouse bone marrow by retrovirus gene transfer. In IL-3-dependent Ba/F3 cells expressing c-kit, forced expression of Spred-1 resulted in a reduced proliferation rate and ERK activation in response to not only SCF but also IL-3. In contrast, DeltaC-Spred augmented IL-3-induced cell proliferation and ERK activation. Wild-type Spred-1 inhibited colony formation of bone marrow cells in the presence of cytokines, whereas DeltaC-Spred-1 expression enhanced colony formation. Augmentation of ERK activation and proliferation in response to IL-3 was also observed in Spred-1-deficient bone marrow-derived mast cells. These data suggest that Spred-1 negatively regulates hematopoiesis by suppressing not only SCF-induced but also IL-3-induced ERK activation.
  • Yoshihiko Maehara, Yoshihiro Kakeji, Takaaki Masuda, Taro Sakoguchi, Msakazu Imamura, Kippei Ohgaki, Koji Taniguchi, Masato Sakurai, Motonori Futatsugi, Yasue Kimura, Toshihiko Nakamura, Eriko Tokunaga, Eiji Oki, Shin Ushiro, Masayuki Watanabe, Shinya Oda, Shuji Tanaka, Hideo Baba
    Fukuoka igaku zasshi = Hukuoka acta medica 94 (10) 285 - 95 0016-254X 2003
  • M Ogawa, Y Hiraoka, K Taniguchi, Y Sakai, S Aiso
    Biochimica et biophysica acta 1519 (3) 235 - 40 0006-3002 2001 
    Paxillin is a cytoskeletal protein found in structures of focal adhesions where cells adhere to the extracellular matrix. We isolated paxillin cDNA from the Xenopus laevis ovary. The cDNA sequence encodes a protein of 539 amino acids with four LIM and five LD motifs. 80% of the amino acids of frog paxillin are shared by human and chicken paxillins. Northern analysis showed that the frog gene is expressed in the spleen, kidney, testis and ovary. Immunocytochemistry showed that paxillin protein is accumulated in the nucleus as well as in the periphery of the cytoplasm of the A6 cell. This intriguing result shows that paxillin, which has been characterized as a cytoskeletal protein, is capable of translocating to the nucleus.
  • K Taniguchi, Y Hiraoka, M Ogawa, Y Sakai, S Kido, S Aiso
    Biochimica et biophysica acta 1445 (2) 225 - 31 0006-3002 1999 
    SOX is a family of SRY-related genes, which encode transcriptional factors involved in development. In this study, we newly isolated and sequenced mouse cDNA clones for mSox7. The mSox7 gene encodes 380 amino acids containing an SRY-type HMG box. Genomic Southern analysis suggested that the mSox7 gene was a single-copy gene. Tissue specific expression of mSox7 was investigated by Northern analysis. The expression was restricted to the ovary and heart, and the size of the transcripts was estimated to be 3.6 knt. Electrophoretic mobility shift assay indicated that recombinant mSox7 polypeptide was capable of binding to a nucleotide sequence, AACAAT. Immunohistochemical study revealed that mSox7 protein was localized in oocytes in the mouse ovary.
  • M Ogawa, Y Hiraoka, K Taniguchi, S Aiso
    Biochimica et biophysica acta 1395 (2) 151 - 8 0006-3002 1998 
    The Drosophila Polycomb group (Pc-G) genes encode transcriptional factors involved in development. Little is known about members of the vertebrate Pc-G genes. In this study, we have isolated a cDNA encoding a human Pc-G protein and the mouse equivalent. The human and mouse genes, which were named ENX-2 and Enx-2, encode 702 and 750 amino acids, respectively. ENX-2/Enx-2 protein exhibits a high homology (53-55% identity) to Drosophila Enhancer of zeste [E(z)] protein belonging to the Pc-G. The expression of Enx-2 was observed in mouse kidney, adrenal gland, testis and brain at high levels by Northern blot analysis. A cell line of mouse neuroblastoma, Neuro-2a, also expresses Enx-2 mRNA and its level is elevated by induction of neuronal differentiation of the cell.
  • Y Hiraoka, M Ogawa, Y Sakai, K Taniguchi, T Fujii, A Umezawa, J Hata, S Aiso
    Biochimica et biophysica acta 1396 (2) 132 - 7 0006-3002 1998 
    SOX is a family of genes related to the testis-determining gene, SRY. We have isolated and sequenced an hSOX20 cDNA from a cell line of human embryonic carcinoma. This cDNA contains an open reading frame (ORF) encoding 233 amino acids. The protein encompasses an SRY-type HMG box exhibiting strong homologies to those of mouse Sox15 and Sox16. Various adult and fetal tissues were tested for hSOX20 mRNA by Northern analysis. Its expression is restricted to the fetal testis and the size of the transcript is 1.5 knt. Electrophoretic mobility shift assay indicated that recombinant hSOX20 polypeptide is capable of binding to AACAAT sequence.

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