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Master

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Biochemistry

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Biochemistry

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Profile and Settings

Profile and Settings

  • Name (Japanese)

    Tsukiyama

  • Name (Kana)

    Tadasuke

  • Name

    201301055249911542

Alternate Names

Achievement

Research Interests

  • 細胞生物学   分子生物学   タンパク質分解   生化学   Wnt   がん   免疫   シグナル伝達   発生工学   遺伝学   

Research Areas

  • Life sciences / Tumor biology
  • Life sciences / Molecular biology
  • Life sciences / Cell biology
  • Life sciences / Immunology
  • Life sciences / Developmental biology
  • Life sciences / Medical biochemistry

Research Experience

  • 2017/04 - Today Hokkaido University Faculty of Medicine and Graduate School of Medicine
  • 2007/04 - 2017/03 Hokkaido University Graduate School of Medicine
  • 2005/04 - 2006/03 Hokkaido University Graduate School of Medicine
  • 2005/03 - 2005/03 NCI-Frederick/NIH Visiting Fellow
  • 2003/03 - 2005/02 NIH NIH Supplemental Visiting Fellow
  • 2003/03 - 2005/02 日本学術振興会 NIH派遣研究者
  • 2001/04 - 2003/02 NCI-Frederick/NIH Visiting Fellow

Education

  • 1997/04 - 2001/03  九州大学大学院
  • 1995/04 - 1997/03  Meiji University  Graduate School of Agriculture
  • 1991/04 - 1995/03  Meiji University  School of Agriculture  Department of Agriculture

Awards

  • 2021/02 北海道大学大学院医学研究院 優秀論文賞
     
    受賞者: 築山忠維
  • 2015/12 公益財団法人 日本膵臓病研究財団 膵臓病研究奨励賞
     
    受賞者: 築山 忠維

Published Papers

  • Tadasuke Tsukiyama
    In Vitro Cellular & Developmental Biology - Animal 1071-2690 2024/02/21 [Refereed][Invited]
     
    Abstract Wnt signaling plays a crucial role in embryonic development and homeostasis maintenance. Delicate and sensitive fine-tuning of Wnt signaling based on the proper timings and positions is required to balance cell proliferation and differentiation and maintain individual health. Therefore, homeostasis is broken by tissue hypoplasia or tumor formation once Wnt signal dysregulation disturbs the balance of cell proliferation. The well-known regulatory mechanism of Wnt signaling is the molecular reaction associated with the cytoplasmic accumulation of effector β-catenin. In addition to β-catenin, most Wnt effector proteins are also regulated by ubiquitin-dependent modification, both qualitatively and quantitatively. This review will explain the regulation of the whole Wnt signal in four regulatory phases, as well as the different ubiquitin ligases and the function of deubiquitinating enzymes in each phase. Along with the recent results, the mechanism by which RNF43 negatively regulates the surface expression of Wnt receptors, which has recently been well understood, will be detailed. Many RNF43 mutations have been identified in pancreatic and gastrointestinal cancers and examined for their functional alteration in Wnt signaling. Several mutations facilitate or activate the Wnt signal, reversing the RNF43 tumor suppressor function into an oncogene. RNF43 may simultaneously play different roles in classical multistep tumorigenesis, as both wild-type and mutant RNF43 suppress the p53 pathway. We hope that the knowledge obtained from further research in RNF43 will be applied to cancer treatment in the future despite the fully unclear function of RNF43.
  • Kosumi, Hideyuki, Watanabe, Mika, Shinkuma, Satoru, Fujimura, Yu, Tsukiyama, Tadasuke, Donati, Giacomo, Iwata, Hiroaki, Ujiie, Hideyuki, Natsuga, Ken M
    Journal of Investigative Dermatology 142 (6) 1576 - 1586 2022/06/01 [Refereed][Not invited]
     
    Hemidesmosomes (HDs) are adhesion complexes that promote epithelial-stromal attachment in stratified and complex epithelia, including the epidermis. In various biological processes, such as differentiation and migration of epidermal keratinocytes during wound healing or carcinoma invasion, quick assembly and disassembly of HDs are prerequisites. In this study, we show that inhibition of Wnt/β-catenin signaling disturbs HD organization in keratinocytes. Screening with inhibitors identified the depletion of HD components and HD-like structures through Wnt inhibition, but keratinocyte differentiation was not affected. Wnt inhibition significantly diminished plectin and type XVII collagen expression in the basal side of Wnt-inhibited cells and the dermo-epidermal junction of the Wnt-inactive murine basal epidermis. Similar to Wnt inhibition, PLEC-knockout cells or cells with plectin-type XVII collagen binding defects showed type XVII collagen reduction in the basal side of the cells, implying the possible involvement of Wnt/β-catenin signaling in HD assembly. Atypical protein kinase C inhibition ameliorated the phenotypes of Wnt-inhibited cells. These findings show that Wnt/β-catenin signaling regulates the localization of HD components in keratinocytes and that the atypical protein kinase C pathway is involved in Wnt inhibition‒induced HD disarrangement. Our study suggests that the Wnt signaling pathway could be a potential therapeutic target for treating HD-defective diseases, such as epidermolysis bullosa.
  • Tadasuke Tsukiyama, Bon‐Kyoung Koo, Shigetsugu Hatakeyama
    BioEssays 43 (4) 2000297 - 2000297 0265-9247 2021/02/11 [Refereed][Invited]
     
    Wnt signaling plays pivotal roles during our entire lives, from conception to death, through the regulation of morphogenesis in developing embryos and the maintenance of tissue homeostasis in adults. The regulation of Wnt signaling occurs on several levels: at the receptor level on the plasma membrane, at the β-catenin protein level in the cytoplasm, and through transcriptional regulation in the nucleus. Several recent studies have focused on the mechanisms of Wnt receptor regulation, following the discovery that the Wnt receptor frizzled (Fzd) is a target of the ubiquitin ligases, RNF43 and ZNRF3. RNF43 and ZNRF3 are homologous genes that are mutated in several cancers. The details underlying their mechanism of action continue to unfold, while at the same time raising many new questions. In this review, we discuss advances and controversies in our understanding of Wnt receptor regulation.
  • Tadasuke Tsukiyama, Juqi Zou, Jihoon Kim, Shohei Ogamino, Yuki Shino, Takamasa Masuda, Alessandra Merenda, Masaki Matsumoto, Yoichiro Fujioka, Tomonori Hirose, Sayuri Terai, Hidehisa Takahashi, Tohru Ishitani, Keiichi I. Nakayama, Yusuke Ohba, Bon-Kyoung Koo, Shigetsugu Hatakeyama
    Nature Communications 11 (1) 4586 - 4586 2020/09/15 [Refereed][Not invited]
     
    Abstract Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.
  • Hidehisa Takahashi, Amol Ranjan, Shiyuan Chen, Hidefumi Suzuki, Mio Shibata, Tomonori Hirose, Hiroko Hirose, Kazunori Sasaki, Ryota Abe, Kai Chen, Yanfeng He, Ying Zhang, Ichigaku Takigawa, Tadasuke Tsukiyama, Masashi Watanabe, Satoshi Fujii, Midori Iida, Junichi Yamamoto, Yuki Yamaguchi, Yutaka Suzuki, Masaki Matsumoto, Keiichi I Nakayama, Michael P Washburn, Anita Saraf, Laurence Florens, Shigeo Sato, Chieri Tomomori-Sato, Ronald C Conaway, Joan W Conaway, Shigetsugu Hatakeyama
    Nature communications 11 (1) 1063 - 1063 2020/02/26 [Refereed][Not invited]
     
    Mediator is a coregulatory complex that regulates transcription of Pol II-dependent genes. Previously, we showed that human Mediator subunit MED26 plays a role in the recruitment of Super Elongation Complex (SEC) or Little Elongation Complex (LEC) to regulate the expression of certain genes. MED26 plays a role in recruiting SEC to protein-coding genes including c-myc and LEC to small nuclear RNA (snRNA) genes. However, how MED26 engages SEC or LEC to regulate distinct genes is unclear. Here, we provide evidence that MED26 recruits LEC to modulate transcription termination of non-polyadenylated transcripts including snRNAs and mRNAs encoding replication-dependent histone (RDH) at Cajal bodies. Our findings indicate that LEC recruited by MED26 promotes efficient transcription termination by Pol II through interaction with CBC-ARS2 and NELF/DSIF, and promotes 3' end processing by enhancing recruitment of Integrator or Heat Labile Factor to snRNA or RDH genes, respectively.
  • Mika Watanabe, Ken Natsuga, Wataru Nishie, Yasuaki Kobayashi, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Hideki Nakamura, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona M. Watt, Hiroshi Shimizu
    ELIFE 6 (e26635) 1 - 24 2050-084X 2017/07 [Refereed][Not invited]
     
    Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
  • Yukiko Kanno, Takahiko Mitsui, Takeya Kitta, Kimihiko Moriya, Tadasuke Tsukiyama, Shigetsugu Hatakeyama, Katsuya Nonomura
    NEUROUROLOGY AND URODYNAMICS 35 (3) 377 - 381 0733-2467 2016/03 [Refereed][Not invited]
     
    AimsWe investigated the relationship between IL-1 and morphological and functional changes following partial bladder outlet obstruction (pBOO). MethodsFemale wild-type C57/BL6 mice (WT) and IL-1-/- mice (KO) were used. Animals were sacrificed either 1 or 3 weeks after pBOO or sham surgery, and their bladders were harvested to determine bladder weight, for RT-PCR to measure interleukin-1 (IL-1), insulin growth factor-1 (IGF-1), and transforming growth factor- (TGF-) levels, and for histological analysis with Hematoxylin-Eosin (HE) staining. Cystometry was performed on conscious animals 3 weeks after surgery to evaluate urodynamic parameters. IGF-1 was also administered intraperitoneally to KO with pBOO, and bladder weight was then investigated. ResultsIL-1-mRNA levels were significantly higher in WT-pBOO than in WT-sham. IGF-1-mRNA and TGF--mRNA levels were also significantly higher in WT-pBOO than in WT-sham; however, these increases were smaller in KO-pBOO than in WT-pBOO. Bladder weight was significantly higher in WT-pBOO than in WT-sham, while increases in bladder weight were significantly suppressed in KO-pBOO. HE staining revealed the thickened bladder wall in WT-pBOO, and this phenomenon was less in KO-pBOO than in WT-pBOO. Regarding the urodynamic parameters examined, micturition pressure and bladder capacity were significantly higher in WT-pBOO than in WT-sham, but remained unchanged in KO-pBOO. The administration of IGF-1 to KO-pBOO led to similar increases in bladder weight and the thickened bladder wall as those observed in WT-pBOO. ConclusionIL-1 has the potential to induce bladder remodeling and deteriorate urodynamic parameters in pBOO. Neurourol. Urodynam. 35:377-381, 2016. (c) 2015 Wiley Periodicals, Inc.
  • Tadasuke Tsukiyama, Akimasa Fukui, Sayuri Terai, Yoichiro Fujioka, Keisuke Shinada, Hidehisa Takahashi, Terry P. Yamaguchi, Yusuke Ohba, Shigetsugu Hatakeyama
    MOLECULAR AND CELLULAR BIOLOGY 35 (11) 2007 - 2023 0270-7306 2015/06 [Refereed][Not invited]
     
    Wnt signaling pathways are tightly regulated by ubiquitination, and dysregulation of these pathways promotes tumorigenesis. It has been reported that the ubiquitin ligase RNF43 plays an important role in frizzled-dependent regulation of the Wnt/beta-catenin pathway. Here, we show that RNF43 suppresses both Wnt/beta-catenin signaling and noncanonical Wnt signaling by distinct mechanisms. The suppression of Wnt/beta-catenin signaling requires interaction between the extracellular protease-associated (PA) domain and the cysteine-rich domain (CRD) of frizzled and the intracellular RING finger domain of RNF43. In contrast, these N-terminal domains of RNF43 are not required for inhibition of noncanonical Wnt signaling, but interaction between the C-terminal cytoplasmic region of RNF43 and the PDZ domain of dishevelled is essential for this suppression. We further show the mechanism by which missense mutations in the extracellular portion of RNF43 identified in patients with tumors activate Wnt/beta-catenin signaling. Missense mutations of RNF43 change their localization from the endosome to the endoplasmic reticulum (ER), resulting in the failure of frizzled-dependent suppression of Wnt/beta-catenin signaling. However, these mutants retain the ability to suppress noncanonical Wnt signaling, probably due to interaction with dishevelled. RNF43 is also one of the potential target genes of Wnt/beta-catenin signaling. Our results reveal the molecular role of RNF43 and provide an insight into tumorigenesis.
  • Hidehisa Takahashi, Ichigaku Takigawa, Masashi Watanabe, Delnur Anwar, Mio Shibata, Chieri Tomomori-Sato, Shigeo Sato, Amol Ranjan, Chris W. Seidel, Tadasuke Tsukiyama, Wataru Mizushima, Masayasu Hayashi, Yasuyuki Ohkawa, Joan W. Conaway, Ronald C. Conaway, Shigetsugu Hatakeyama
    NATURE COMMUNICATIONS 6 (5941) 2041-1723 2015/01 [Refereed][Not invited]
     
    Regulation of transcription elongation by RNA polymerase II (Pol II) is a key regulatory step in gene transcription. Recently, the little elongation complex (LEC)-which contains the transcription elongation factor ELL/EAF-was found to be required for the transcription of Pol II-dependent small nuclear RNA (snRNA) genes. Here we show that the human Mediator subunit MED26 plays a role in the recruitment of LEC to a subset of snRNA genes through direct interaction of EAF and the N-terminal domain (NTD) of MED26. Loss of MED26 in cells decreases the occupancy of LEC at a subset of snRNA genes and results in a reduction in their transcription. Our results suggest that the MED26-NTD functions as a molecular switch in the exchange of TBP-associated factor 7 (TAF7) for LEC to facilitate the transition from initiation to elongation during transcription of a subset of snRNA genes.
  • Variation in the bacterial conditions inside cages is correlated with intracage humidity and ammonia levels.
    Tosa N, Yoshimatsu K, Tadasuke Tsukiyama, Hatakeyama S, Arikawa J
    Lab Animal and Environ 21 (2) 87 - 98 2013 [Refereed][Not invited]
  • Tadasuke Tsukiyama, Mayuko Matsuda-Tsukiyama, Miyuki Bohgaki, Sayuri Terai, Shinya Tanaka, Shigetsugu Hatakeyama
    MOLECULAR MEDICINE 18 (4) 587 - 597 1076-1551 2012/04 [Refereed][Not invited]
     
    The nuclear factor (NF)-kappa B family of transcription factors regulates diverse cellular functions, including inflammation, oncogenesis and apoptosis. It was reported that A20 plays a critical role in the termination of NF-kappa B signaling after activation. Previously, we showed that Ymer interacts and collaborates with A20, followed by degradation of receptor-interacting protein (RIP) and attenuation of NF-kappa B signaling. Here we show the function of Ymer in regulation of several signaling pathways including NF-kappa B on the basis of results obtained by using Ymer transgenic (Ymer Tg) mice. Ymer Tg mice exhibited impaired immune responses, including NF-kappa B and mitogen-activated protein kinase (MAPK) activation, cell proliferation and cytokine production, to tumor necrosis factor (TNF)-alpha, polyl:C or lipopolysaccharide ([PS) stimulation. Ymer Tg mice were more resistant to LPS-induced septic shock than wild-type mice. Transgene of Ymer inhibited the onset of glomerulonephritis in Ipr/Ipr mice as an autoimmune disease model. In contrast to the inflammatory immune response to LPS, Fas-mediated cell death was strongly induced in liver cells of Ymer Tg mice in which Ymer is abundantly expressed. These findings suggest that Ymer acts as a regulator downstream of several receptors and that Ymer functions as a positive or negative regulator in a signaling pathway-dependent manner. Online address: hffp://www.molmed.org doi: 10.2119/molmed.2011.00435
  • Tadasuke Tsukiyama, Terry P. Yamaguchi
    NEUROSCIENCE LETTERS 512 (1) 48 - 52 0304-3940 2012/03 [Refereed][Not invited]
     
    Wnts are secreted glycoproteins that play important roles in embryonic development. Wnt2b is transiently expressed in the primitive streak (PS) during gastrulation and in several organs during organogenesis. To determine the biological function of Wnt2b during mouse development, we established a conditional null allele of Wnt2b. Mice lacking Wnt2b were viable, fertile, and displayed a normal life span, however, the olfactory bulb in adult Wnt2b mutant mice was significantly reduced in length. Our results suggest that Wnt2b primarily plays a supportive role in gastrulation and organogenesis, functioning redundantly with canonical Wnts, such as Wnt2, in numerous tissues. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
  • Takuya Sho, Tadasuke Tsukiyama, Tomonobu Sato, Takeshi Kondo, Jun Cheng, Takashi Saku, Masahiro Asaka, Shigetsugu Hatakeyama
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 1813 (6) 1245 - 1253 0167-4889 2011/06 [Refereed][Not invited]
     
    Ataxia-telangiectasia (AT) is an autosomal recessive genetic disease characterized by immunological deficiencies, neurological degeneration, developmental abnormalities and an increased risk of cancer. Ataxia-telangiectasia group D (ATDC) was initially described as a gene related to AT. Ataxia-telangiectasia group D. also known as TRIM29, is structurally a member of the tripartite motif (TRIM) family of proteins, some of which have been reported to be highly expressed in some human carcinomas, but the involvement of TRIM29 in carcinogenesis has not been fully elucidated. In this study, we found by using yeast two-hybrid screening that TRIM29 binds to Tip60, which has been reported as a cellular acetyltransferase protein. Overexpression of TRIM29 promoted degradation and changed localization of Tip60 and reduced acetylation of p53 at lysine 120 by Tip60, resulting in enhancement of cell growth and transforming activity. In addition, we found that TRIM29 suppresses apoptosis induced by UV irradiation in HCT116 cell lines. These findings suggest that TRIM29 functions as an oncogene that promotes tumor growth. (C) 2011 Elsevier B.V. All rights reserved.
  • Noriyuki Sugiyama, Tadasuke Tsukiyama, Terry P. Yamaguchi, Takahiko Yokoyama
    KIDNEY INTERNATIONAL 79 (9) 957 - 965 0085-2538 2011/05 [Refereed][Not invited]
     
    Recent studies have identified several genes whose defects cause hereditary renal cystic diseases with most of the gene products located in the primary cilia. It has been suggested that primary cilia are involved in signaling pathways, defects of which result in abnormal cell proliferation and randomization of oriented cell division in the kidney leading to cyst formation. Mice with a mutation in the inv gene are a model for human nephronophthisis type 2 and develop multiple renal cysts. Inv protein (also called inversin) is located in the base of primary cilia and acts as a switch from canonical to non-canonical Wnt signaling. Here, we studied the orientation of cell division and proliferation in the kidneys of inv mutant mice, as its loss is thought to maintain activation of the canonical Wnt signaling. To establish if canonical signaling was involved in this process, we mated inv mutant with BATlacZ mice to measure canonical Wnt activity. Based on these reporter mice, nuclear localization and phosphorylation of beta-catenin, and responsiveness to Wnt ligands in inv mutant cells, we found that random oriented cell division is an initial event for renal tubule expansion and precedes cell proliferation. Thus, our results do not support the hypothesis that canonical Wnt signaling causes renal cyst development in these mice. Kidney International (2011) 79, 957-965; doi:10.1038/ki.2010.534; published online 19 January 2011
  • Keisuke Shinada, Tadasuke Tsukiyama, Takuya Sho, Fumihiko Okumura, Masahiro Asaka, Shigetsugu Hatakeyama
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 404 (1) 143 - 147 0006-291X 2011/01 [Refereed][Not invited]
     
    The ubiquitin-proteasomal system plays a crucial role in oncogenesis in colorectal tissues. Recent studies have shown that stability of beta-catenin, which functions as an oncogene for colorectal cancer, is regulated by ubiquitin-mediated degradation. It has been reported that a putative E3 ubiquitin ligase, RNF43, is highly expressed in human colorectal carcinoma and that RNF43 promotes cell growth. However, the involvement of RNF43 in carcinogenesis has not been fully elucidated. In this study, we found by using yeast two-hybrid screening that RNF43 binds to NEDD-4-like ubiquitin-protein ligase-1 (NEDL1), which enhances pro-apoptotic activity by p53. In addition, we found that RNF43 also interacts with p53 and that RNF43 suppresses transcriptional activity of p53 in H1299 cells and attenuates apoptosis induced by ultraviolet irradiation. These findings suggest that RNF43 is associated with p53-mediated apoptosis in collaboration with NEDL1 in colorectal carcinogenesis. (C) 2010 Elsevier Inc. All rights reserved.
  • Misato Kikuchi, Fumihiko Okumura, Tadasuke Tsukiyama, Masashi Watanabe, Naoto Miyajima, Junji Tanaka, Masahiro Imamura, Shigetsugu Hatakeyama
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 1793 (12) 1828 - 1836 0167-4889 2009/12 [Refereed][Not invited]
     
    The androgen receptor (AR) is a ligand-dependent transcription factor that belongs to the family of nuclear receptors, and its activity is regulated by numerous AR coregulators. AR plays an important role in prostate development and cancer. In this study, we found that TRIM24/transcriptional intermediary factor lot (T1F1 alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with AR and enhances transcriptional activity of AR by dihydrotestosterone in prostate cancer cells. We showed that TRIM24 functionally interacts with TIP60, which acts as a coactivator of AR and synergizes with TIP60 in the transactivation of AR. We also showed that TRIM24 binds to bromodomain containing 7 (BRD7), which can negatively regulate cell proliferation and growth. A luciferase assay indicated that BRD7 represses the AR transactivation activity upregulated by TRIM24. These findings indicate that TRIM24 regulates AR-mediated transcription in collaboration with TIP60 and BRD7. (C) 2009 Elsevier B.V. All rights reserved.
  • Masashi Watanabe, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 388 (2) 422 - 427 0006-291X 2009/10 [Refereed][Not invited]
     
    Tripartite motif-containing protein (TRIM) family proteins are involved in a broad range of biological processes and, consistently, their alterations result in diverse pathological conditions such as genetic diseases, viral infection and cancer development. In this study, we found that one of the TRIM family proteins, TRIM31, is highly expressed in the gastrointestinal tract and interacts with p52(Shc), one of the signal transducers. We also found by a binding assay that almost the whole region other than the RING domain is required for the binding to p52(Shc) but found by pulse-chase analysis that overexpression of TRIM31 does not affect the stability of p52(Shc). Moreover, we found that overexpression of TRIM31 suppresses anchorage-independent cell growth induced by the active form of c-Src. These results suggest that TRIM31 attenuates c-Src signaling via p52(Shc) under anchorage-independent growth conditions and is potentially associated with growth activity of cells in the gastrointestinal tract. (C) 2009 Elsevier Inc. All rights reserved.
  • Hiroyuki Maeda, Naoto Miyajima, Satoshi Kano, Tadasuke Tsukiyama, Fumihiko Okumura, Satoshi Fukuda, Shigetsugu Hatakeyama
    MOLECULAR CANCER RESEARCH 7 (9) 1553 - 1562 1541-7786 2009/09 [Refereed][Not invited]
     
    The ubiquitin-proteasome system has a crucial role in maintaining and regulating cellular homeostasis including carcinogenesis. UBE2Q2, also designated Ubci, is one of the ubiquitin-conjugating enzymes (E2), and it has been reported that mRNA of UBE2Q2 is highly expressed in human head and neck squamous cell carcinoma, particularly hypopharyngeal carcinoma. However, the involvement of UBE2Q2 in carcinogenesis has not been fully elucidated. Most cases of head and neck carcinoma are treated with cis-diamminedichloroplatinum (II; CDDP) or docetaxel, which are the most effective chemotherapeutic agents against squamous cell carcinomas. Nevertheless, some head and neck cancers develop resistance to these drugs, although the causes and mechanisms remain unknown. In this study, we found high expression levels of UBE2Q2 in human head and neck carcinoma cell lines and cancer tissues by using an anti-UBE2Q2 antibody at the protein level. We also found that the expression level of UBE2Q2 is decreased in cell lines and cancer tissues that have resistance to CDDP or docetaxel and in cancer tissues treated with CDDP or docetaxel. Furthermore, we found that overexpression of UBE2Q2 affects cell proliferation and anchorage-independent cell growth. These findings suggest that UBE2Q2 is a novel oncosuppressor that inhibits tumor growth and is related to the resistance to anticarcinoma agents and that UBE2Q2 likely functions as a novel diagnostic tool and a potentially therapeutic target for head and neck squamous cell carcinoma. (Mol Cancer Res 2009;7(9):1553-62)
  • Ashley M. Goss, Ying Tian, Tadasuke Tsukiyama, Ethan David Cohen, Diane Zhou, Min Min Lu, Terry P. Yamaguchi, Edward E. Morrisey
    DEVELOPMENTAL CELL 17 (2) 290 - 298 1534-5807 2009/08 [Refereed][Not invited]
     
    Patterning of the primitive foregut promotes appropriate organ specification along its anterior-posterior axis. However, the molecular pathways specifying foregut endoderm progenitors are poorly understood. We show here that Wnt2/2b signaling is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b expression exhibit complete lung agenesis and do not express Nkx2.1, the earliest marker of the lung endoderm. In contrast, other foregut endoderm-derived organs, including the thyroid, liver, and pancreas, are correctly specified. The phenotype observed is recapitulated by an endoderm-restricted deletion of beta-catenin, demonstrating that Wnt2/2b signaling through the canonical Writ pathway is required to specify lung endoderm progenitors within the foregut. Moreover, activation of canonical Wnt/beta-catenin signaling results in the reprogramming of esophagus and stomach endoderm to a lung endoderm progenitor fate. Together, these data reveal that canonical Wnt2/2b signaling is required for the specification of lung endoderm progenitors in the developing foregut.
  • Kentaro Suzuki, Yuji Yamaguchi, Mylah Villacorte, Kenichiro Mihara, Masashi Akiyama, Hiroshi Shimizu, Makoto M. Taketo, Naomi Nakagata, Tadasuke Tsukiyama, Terry P. Yamaguchi, Walter Birchmeier, Shigeaki Kato, Gen Yamada
    DEVELOPMENT 136 (3) 367 - 372 0950-1991 2009/02 [Refereed][Not invited]
     
    beta-catenin signaling is one of the key factors regulating the fate of hair follicles (HFs). To elucidate the regulatory mechanism of embryonic HF fate determination during epidermal development/differentiation, we analyzed conditional mutant mice with keratinocytes expressing constitutively active beta-catenin (K5-Cre Catnb((ex3)fl/+)). The mutant mice developed scaly skin with a thickened epidermis and showed impaired epidermal stratification. The hair shaft keratins were broadly expressed in the epidermis but there was no expression of the terminal differentiation markers K1 and loricrin. Hair placode markers (Bmp2 and Shh) and follicular dermal condensate markers ( noggin, patched 1 and Pdgfra) were expressed throughout the epidermis and the upper dermis, respectively. These results indicate that the embryonic epidermal keratinocytes have switched extensively to the HF fate. A series of genetic studies demonstrated that the epidermal switching to HF fate was suppressed by introducing the conditional mutation K5-Cre Catnb((ex3)fl/+) Shh(fl/-) ( with additional mutation of Shh signaling) or K5-Cre Catnb((ex3)fl/+) BmprIA(fl/fl) ( with additional mutation of Bmp signaling). These results demonstrate that Wnt/beta-catenin signaling relayed through Shh and Bmp signals is the principal regulatory mechanism underlying the HF cell fate change. Assessment of Bmp2 promoter activities suggested a putative regulation by beta-catenin signaling relayed by Shh signaling towards Bmp2. We also found that Shh protein expression was increased and expanded in the epidermis of K5-Cre Catnb((ex3)fl/+) BmprIAfl/fl mice. These results indicate the presence of growth factor signal cross-talk involving beta- catenin signaling, which regulates the HF fate.
  • Hiroyuki Kameda, Masashi Watanabe, Miyuki Bohgaki, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 378 (4) 744 - 749 0006-291X 2009/01 [Refereed][Not invited]
     
    Cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-kappa B activation. We have reported that Ymer interacts with A20 and lysine (K)-63-linked polyubiquitin chain and that Ymer inhibits NF-kappa B signaling in collaboration with A20. It has also been reported that Ymer is phosphorylated by EGF stimulation. We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappa B signaling. Furthermore, a soft agar colony formation assay showed that the combination of SFCY527F and YmerY217/279/304F has no ability for anchorage-independent growth, suggesting that tyrosine phosphorylation of Ymer is important for inhibition of the NF-kappa B-mediated apoptotic pathway. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-kappa B signaling pathway. (C) 2008 Elsevier Inc. All rights reserved
  • Bohgaki M, Tsukiyama T, Nakajima A, Maruyama S, Watanabe M, Koike T, Hatakeyama S
    Biochimica et biophysica acta 5 1783 826 - 837 0006-3002 2008/05 [Refereed][Not invited]
  • Miyuki Bohgaki, Tadasuke Tsukiyama, Ayako Nakajima, Satoru Maruyama, Masashi Watanabe, Takao Koike, Shigetsugu Hatakeyama
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 1783 (5) 826 - 837 0167-4889 2008/05 [Refereed][Not invited]
     
    It is known that the cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-kappa B activation and biochemically acts as a unique ubiquitin-modifying protein with dcubiquitmating activity and ubiquitin ligase activity. However, the molecular mechanisms of A20-modulated signal transduction that influence normal immune responses or tumor immunity have not been fully elucidated. Using a yeast two-hybrid system to search for proteins interacting with A20, we identified one novel binding protein, Ymer. Ymer, which has been reported to be highly phosphorylated on tyrosine residues via EGF stimulation, bound to lysine (K)-63-linked polyubiquitin chain on receptor-interacting serine/threonine-protein kinase 1 (RIP 1), which is essential for NF-kappa B signaling in collaboration with A20. A luciferase assay showed that NF-kappa B signaling was down-regulated by overexpression of Ymer, whereas knock-down of Ymer up-egulated NF-kappa B signaling even without stimulation. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-kappa B signaling pathway. (C)007 Elsevier B.V All rights reserved.
  • Mutsumi Takahata, Miyuki Bohgaki, Tadasuke Tsukiyama, Takeshi Kondo, Masahiro Asaka, Shigetsugu Hatakeyama
    MOLECULAR IMMUNOLOGY 45 (7) 2045 - 2054 0161-5890 2008/04 [Refereed][Not invited]
     
    The 52-kDa form of SSA/Ro protein (Ro52) is one of autoantigens associated with autoimmune disorders such as systemic lupus erythematosus and Sjogren's syndrome. Anti-SSA/Ro antibodies, the biological function of which remains unknown, are frequently found in the serum of these patients. Recent functional genomic approaches have shown that Ro52/TRIM21 is one of the TRIM family proteins with a RING-finger domain which is closely associated with E3 ubiquitin ligase activity. We found by using yeast-two hybrid screening that Ro52 has an E3 activity in vitro and interacts with human IgG1 heavy chain. We also found that IgG1 heavy chain was modified with polyubiquitination by Ro52 and degraded through the ubiquitin-proteasome system in mammalian cells. Our results also showed that Ro52 interacts with the molecular chaperone p97/VCP, which is thought to function in the endoplasmic reticulum associated degradation (ERAD) system. It is likely that Ro52 plays a role in proteasomal degradation of unfolded IgG1, which is retrogradely transferred from the endoplasmic reticulum to the cytosol. Taken together, our findings suggest that Ro52 plays a significant role in quality control of IgG1 through the ERAD system. (C) 2007 Elsevier Ltd. All rights reserved.
  • Satoru Maruyama, Naoto Miyajima, Miyuki Bohgaki, Tadasuke Tsukiyama, Masahiko Shigemura, Katsuya Nonomura, Shigetsugu Hatakeyama
    MOLECULAR AND CELLULAR BIOCHEMISTRY 307 (1-2) 73 - 82 0300-8177 2008/01 [Refereed][Not invited]
     
    Ubiquitylation appears to be involved in the membrane trafficking system including endocytosis, exocytosis, and ER-to-Golgi transport. We found that PIRH2, which was identified as an interacting protein for androgen receptor or p53, interacts with and ubiquitylates the epsilon-subunit of coatmer complex, epsilon-COP. PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP. The interaction between PIRH2 and epsilon-COP is affected by the presence of androgen, and PIRH2 in the presence of androgen promotes ubiquitylation of epsilon-COP in vivo. Furthermore, overexpression of the wild type of PIRH2 in prostate cancer cells causes downregulation of the secretion of prostate-specific antigen (PSA), a secretory protein in prostate epithelial cells and one of diagnostic markers for prostate cancer. Our results indicate that PIRH2 functions as a regulator for COP I complex.
  • Ayako Nakajima, Satoru Maruyama, Miyuki Bohgaki, Naoto Miyajima, Tadasuke Tsukiyama, Noriaki Sakuragi, Shigetsugu Hatakeyama
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 357 (1) 245 - 251 0006-291X 2007/05 [Refereed][Not invited]
     
    Estrogen-mediated ubiquitylation and subsequent degradation of the estrogen receptor alpha (ER alpha) appears to be involved in the transcriptional activity of ER alpha. We show that the estrogen-responsive finger protein (EFP) interacts with and ubiquitylates ER alpha. EFP promoted the ubiquitylation of ER alpha in vitro and in vivo and consequently promoted the degradation of ER alpha. The interaction between EFP and ER alpha was greatly enhanced in the presence of estrogen. The action of EFP on ER alpha in the presence of estrogen resulted in a robust interaction between ER alpha and Tip60, one of the transcriptional coactivators, leading to activation of ER alpha transcriptional activity. However, a dominant negative mutant of EFP lacking the RING domain prolonged the half-life of ER alpha and inhibited the transcription by ER alpha. Our results indicate that EFP functions as a cofactor for ER alpha-mediated transcription, thus suggesting that ER alpha-mediated transcription is closely linked to he ubiquitylation of ER alpha. (c) 2007 Elsevier Inc. All rights reserved.
  • Mayuko Matsuda, Tadasuke Tsukiyama, Miyuki Bohgaki, Katsuya Nonomura, Shigetsugu Hatakeyama
    IMMUNOLOGY LETTERS 109 (2) 175 - 181 0165-2478 2007/04 [Refereed][Not invited]
     
    The transcription factor nuclear factor-kappa B (NF-kappa B) plays roles in apoptosis, inflammation and oncogenesis. It is important for biological and medical research to understand when proteins of interest are activated in cells, leading to the establishment of a luciferase/EGFP assay to monitor the activation of transcription factors. Here, we describe an improved reporter system for NF-kappa B, the NF-kappa B-activated transgene (NAT) system that can detect NF-kappa B signalling with high sensitivity and specificity. The NAT system consists of large copy numbers of NF-kappa B consensus sequence and a minimal promoter derived from the mouse interleukin-2 (IL-2) gene. Furthermore, we generated NAT systems with stable or unstable luciferase/EGFP proteins. Stable and unstable types of luciferase/EGFP are suitable for analyzing the accumulation of and the real-time activity of NF-kappa B signal, respectively. Our findings suggest that the NAT system is effective for in vivo imaging of NF-kappa B signalling using cells or animals. (c) 2007 Elsevier B.V. All rights reserved.
  • Masashi Watanabe, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
    NEUROSCIENCE LETTERS 411 (3) 228 - 232 0304-3940 2007/01 [Refereed][Not invited]
     
    The slow Wallerian degeneration protein (Wld(S)), a fusion protein containing amino-terminal E4B and full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by physical damages, toxins and genetic mutations which result in patients being diagnosed with neurodegenerative diseases. It is still controversial whether the suppression of axonal degeneration by Wld(S) is due to Nmnat1 or other portion. We generated Wld(S) or Nmnat1-overexpressing Neuro2A cell lines, in which neuronal differentiation including neurite elongation can be induced by retinoic acid. The overexpression of Wld(S) delayed the neurite degeneration by vincristine, whereas that of Nmnat1 did not delay it much. Taken together, Nmnat1 is considerably weaker than Wld(S) for protection from toxic injury in vitro, suggesting that amino-terminal region of Wld(S) is likely to be more significant for protection from axonal degeneration. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Makiko Fujii, Lyudmila A. Lyakh, Cameron P. Bracken, Junya Fukuoka, Morisada Hayakawa, Tadasuke Tsukiyama, Steven J. Soil, Melissa Harris, Sonia Rocha, Kevin C. Roche, Shin-ichi Tominaga, Jin Jen, Neil D. Perkins, Robert J. Lechleider, Anita B. Roberts
    MOLECULAR CELL 24 (5) 771 - 783 1097-2765 2006/12 [Refereed][Not invited]
     
    Using a yeast two-hybrid screen, we found that SNIP1 (Smad nuclear-interacting protein 1) associates with c-Myc, a key regulator of cell proliferation and transformation. We demonstrate that SNIP1 functions as an important regulator of c-Myc activity, binding the N terminus of c-Myc through its own C terminus, and that SNIP1 enhances the transcriptional activity of c-Myc both by stabilizing it against proteosomal degradation and by bridging the c-Myc/p300 complex. These effects of SNIP1 on c-Myc likely contribute to synergistic effects of SNIP1, c-Myc, and H-Ras in inducing formation of foci in an in vitro transformation assay and also in supporting anchorage-independent growth. The significant association of SNIP1 and c-Myc staining in a non-small cell lung cancer tissue array is further evidence that their activities might be linked and suggests that SNIP1 might be an important modulator of c-Myc activity in carcinogenesis.
  • MA Nakaya, K Biris, T Tsukiyama, S Jaime, JA Rawls, TP Yamaguchi
    DEVELOPMENT 132 (24) 5425 - 5436 0950-1991 2005/12 [Refereed][Not invited]
     
    The alignment of the left-right (LR) body axis relative to the anteroposterior (AP) and dorsoventral (DV) axes is central to the organization of the vertebrate body plan and is controlled by the node/organizer. Somitogenesis plays a key role in embryo morphogenesis as a principal component of AP elongation. How morphogenesis is coupled to axis specification is not well understood. We demonstrate that Wnt3a is required for LR asymmetry. Wnt3a activates the Delta/Notch pathway to regulate perinodal expression of the left determinant Nodal, while simultaneously controlling the segmentation clock and the molecular oscillations of the Wnt/beta-catenin and Notch pathways. We provide evidence that Wnt3a, expressed in the primitive streak and dorsal posterior node, acts as a long-range signaling molecule, directly regulating target gene expression throughout the node and presomitic mesoderm. Wnt3a may also modulate the symmetry-breaking activity of mechanosensory cilia in the node. Thus, Wnt3a links the segmentation clock and AP axis elongation with key left-determining events, suggesting that Wnt3a is an integral component of the trunk organizer.
  • M Nishiyama, K Nakayama, R Tsunematsu, T Tsukiyama, A Kikuchi, KI Nakayama
    MOLECULAR AND CELLULAR BIOLOGY 24 (19) 8386 - 8394 0270-7306 2004/10 [Refereed][Not invited]
     
    The Wnt signaling pathway plays a pivotal role in vertebrate early development and morphogenesis. Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to Tcf, thereby inhibiting downstream Wnt signaling. Here we show that Duplin is expressed predominantly from early- to mid-stage mouse embryogenesis, and we describe the generation of mice deficient in Duplin. Duplin(-/-) embryos manifest growth retardation from embryonic day 5.5 (E5.5) and developmental arrest accompanied by massive apoptosis at E7.5. The mutant embryos develop into an egg cylinder but do not form a primitive streak or mesoderm. Expression of beta-catenin target genes, including those for T (brachyury), Axing, and cyclin D1, was not increased in Duplin(-/-) embryos, suggesting that the developmental defect is not simply attributable to upregulation of Wnt signaling caused by the lack of this inhibitor. These results suggest that Duplin plays an indispensable role, likely by a mechanism independent of inhibition of Wnt signaling, in mouse embryonic growth and differentiation at an early developmental stage.
  • A Miyamoto, K Nakayama, H Imaki, S Hirose, Y Jiang, M Abe, T Tsukiyama, H Nagahama, S Ohno, S Hatakeyama, KI Nakayama
    NATURE 416 (6883) 865 - 869 0028-0836 2002/04 [Refereed][Not invited]
     
    Protein kinase C (PKC), which comprises 11 closely related isoforms, has been implicated in a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis and tumour development(1-4). Among the PKC isotypes, PKC-delta is unique in that its overexpression results in inhibition of cell growth(5-11). Here we show that mice that lack PKC-delta exhibit expansion of the B-lymphocyte population with the formation of numerous germinal centres in the absence of stimulation. The rate of proliferation in response to stimulation was greater for B cells from PKC-delta-deficient mice than for those from wild-type mice. Adoptive transfer experiments suggested that the hyperproliferation phenotype is B-cell autonomous. Production of interleukin-6 was markedly increased in B cells of PKC-delta-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-delta-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs. These results suggest that PKC-delta has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.
  • T Tsukiyama, N Ishida, M Shirane, YA Minamishima, S Hatakeyama, M Kitagawa, K Nakayama, K Nakayama
    JOURNAL OF IMMUNOLOGY 166 (1) 304 - 312 0022-1767 2001/01 [Refereed][Not invited]
     
    The proliferation of T cells is regulated in a development-dependent manner, but it has been unclear whether proliferation is essential for T cell differentiation, The cyclin-dependent kinase inhibitor p27(Kip1) is abundant throughout development in cells of the T cell lineage, with the exception of late stage CD4(-)CD8(-) thymocytes and activated mature T cells, both of which show a high rate of proliferation. The role of down-regulation of p27(Kip1) expression in T cell development and function has now been investigated by the generation and characterization of three strains of p27 transgenic mice that express the transgene at various levels specifically in the T cell lineage. The numbers of thymocytes at CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) stages of development as well as those of mature T cells in peripheral lymphoid tissues were reduced in transgenic mice in a manner dependent on the level of p27(Kip1) expression. The development of thymocytes in the transgenic strain in which p27(Kip1) is most abundant p27-Tg(high) mice) appeared to be blocked at the CD4(-)CD8(-)CD25(+)CD44(low) stage. Peripheral T cells from p27-Tg(high) mice exhibited a reduced ability to proliferate in response to mitogenic stimulation compared with wild-type T cells, Moreover, Ag-induced formation of germinal centers and Ig production were defective in p27-Tg(high) mice. These results suggest that down-regulation of p27(Kip1) expression is required for the development, proliferation, and immunoresponsiveness of T cells.
  • H Hara, K Kishihara, G Matsuzaki, H Takimoto, T Tsukiyama, RE Tigelaar, K Nomoto
    JOURNAL OF IMMUNOLOGY 165 (7) 3695 - 3705 0022-1767 2000/10 [Refereed][Not invited]
     
    One of the most intriguing features of gamma delta T cells that reside in murine epithelia is the association of a specific V gamma/V delta usage with each epithelial tissue. Dendritic epidermal T cells (DETCs) in the murine epidermis, are predominantly derived from the "first wave" V gamma 5(+) fetal thymocytes and overwhelmingly express the canonical V gamma 5/V delta 1-TCRs lacking junctional diversity, Targeted disruption of the V delta 1 gene resulted in a markedly impaired development of V gamma 5(+) fetal thymocytes as precursors of DETCs; however, gamma delta TCR+ DETCs with a typical dendritic morphology were observed in V delta 1(-/-) mice and their cell densities in the epidermis were slightly lower than those in V delta 1(+/-) epidermis, Moreover, the V delta 1-deficient DETCs were functionally competent in their ability to up-regulate cytokines and keratinocyte growth factor-expression in response to keratinocytes, V gamma 5(+) DETCs were predominant in the V delta 1(-/-) epidermis, though V gamma 5(-) gamma delta TCR+ DETCs were also detected, The V gamma 5(+) DETCs showed a typical dendritic shape, gamma delta TCRhigh, and age-associated expansion in epidermis as observed in conventional DETCs of normal mid, whereas the V gamma 5(-) gamma delta TCR+ DETCs showed a less dendritic shape, gamma delta TCRlow, and no expansion in the epidermis, consistent with their immaturity. These results suggest that optimal DETC development does not require a particular V gamma/V delta-chain usage but requires expression of a limited diversity of gamma delta TCRs, which allow DETC precursors to mature and expand within the epidermal microenvironment.
  • K Kitagawa, T Kawamoto, N Kunugita, T Tsukiyama, K Okamoto, A Yoshida, K Nakayama, K Nakayama
    FEBS LETTERS 476 (3) 306 - 311 0014-5793 2000/07 [Refereed][Not invited]
     
    A principal pathway of 2-methoxyethanol (ME) metabolism is to the toxic oxidative product, methoxyacetaldehyde (MALD). To assess the role of aldehyde dehydrogenase (ALDH) in MALD metabolism, in vitro MALD oxidation was examined with liver subcellular fractions from Japanese subjects who carried three different ALDH2 genotypes and Aldh2 knockout mice, which were generated in this study. The activity was distributed in mitochondrial fractions of ALDH2*11*1 and wild type (Aldh2+/+) mice but not ALDH2*11*2, *2/*2 subjects or Aldh2 homozygous mutant (Aldh2-/-) mice. These data suggest that ALDH2 is a key enzyme for MALD oxidation and ME susceptibility may be influenced by the ALDH2 genotype. (C) 2000 Federation of European Biochemical Societies, Published by Elsevier Science B.V. All rights reserved.
  • H Takai, K Tominaga, N Motoyama, YA Minamishima, H Nagahama, T Tsukiyama, K Ikeda, K Nakayama, N Nakanishi, K Nakayama
    GENES & DEVELOPMENT 14 (12) 1439 - 1447 0890-9369 2000/06 [Refereed][Not invited]
     
    The recent discovery of checkpoint kinases has suggested the conservation of checkpoint mechanisms between yeast and mammals. In yeast, the protein kinase Chk1 is thought to mediate signaling associated with the DNA damage checkpoint of the cell cycle. However, the function of Chk1 in mammals has remained unknown. Targeted disruption of Chk1 in mice showed that Chk1(-/-) embryos exhibit gross morphologic abnormalities in nuclei as early as the blastocyst stage. In culture, Chk1(-/-) blastocysts showed a severe defect in outgrowth of the inner cell mass and died of apoptosis. DNA replication block and DNA damage failed to arrest the cell cycle before initiation of mitosis in Chk1(-/-) embryos. These results may indicate that Chk1 is indispensable for cell proliferation and survival through maintaining the G(2) checkpoint in mammals.
  • K Nakayama, H Nagahama, YA Minamishima, M Matsumoto, Nakamichi, I, K Kitagawa, M Shirane, R Tsunematsu, T Tsukiyama, N Ishida, M Kitagawa, K Nakayama, S Hatakeyama
    EMBO JOURNAL 19 (9) 2069 - 2081 0261-4189 2000/05 [Refereed][Not invited]
     
    The ubiquitin-proteasome pathway plays an important role in control of the abundance of cell cycle regulators. Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-bos protein (SCF) ubiquitin ligase, were generated. Although Skp2(-/-) animals are viable, cells in the mutant mice contain markedly enlarged nuclei with polyploidy and multiple centrosomes, and show a reduced growth rate and increased apoptosis, Skp2(-/-) cells also exhibit increased accumulation of both cyclin E and p27(Kip1). The elimination of cyclin E during S and G(2) phases is impaired in Skp2(-/-) cells, resulting in loss of cyclin E periodicity. Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCFSkp2 ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators.
  • S Nagafuchi, H Katsuta, K Kogawa, T Akashi, S Kondo, Y Sakai, T Tsukiyama, D Kitamura, Y Niho, T Watanabe
    FEBS LETTERS 455 (1-2) 101 - 104 0014-5793 1999/07 [Refereed][Not invited]
     
    A non-obese diabetic (NOD) mouse-derived embryonic stem (ES) cell line has been stably maintained in an undifferentiated state with a characteristic ES cell-like morphology, expressing the stem cell marker alkaline phosphatase, and displaying a normal diploid karyotype, After injecting the NODES cells into blastocysts, chimeric mice were obtained. Small but significant numbers of lymphocytes expressed the NOD-derived MHC allele, When a chimeric mouse was mated with C57BL/6 mice, an agouti mouse was obtained, having the NOD-derived H-2 I-A(beta)(g7) haplotype. Thus, an NOD-ES cell line which cao differentiate into lymphocytes with potential for germ line transmission was successfully established. (C) 1999 Federation of European Biochemical Societies.
  • 築山 忠維, 新谷 真美, 尾川 昭三
    明治大学農学部研究報告 明治大学農学部 113 (113) 17 - 27 0465-6083 1997/09 [Refereed][Not invited]

MISC

Presentations

  • 代謝がWntシグナルに及ぼす影響の検討  [Not invited]
    築山忠維
    Wnt研究会  2023/12
  • 築山忠維, 畠山鎮次
    第46回日本分子生物学会年会  2023/12
  • 築山忠維, 畠山鎮次
    第82回日本癌学会学術総会  2023/09
  • Tadasuke Tsukiyama
    CGE International Seminar Series 2023  2023/03
  • 築山忠維
    北海道がん若手研究者交流会  2023/03
  • Tadasuke Tsukiyama
    Wnt 2022  2022/11
  • Tadasuke Tsukiyama, Shigetsugu Hatakeyama
    Wnt 2022  2022/11
  • 築山忠維, 畠山鎮次
    第81回日本癌学会学術総会  2022/09
  • Wnt受容体調節の破綻が多段階発がん過程で果たす複雑な役割  [Invited]
    築山忠維
    第59回日本生化学会北海道支部例会  2022/07
  • Wnt受容体の発現調節異常と発がん機構の解明  [Invited]
    築山忠維, 石谷太, 高橋秀尚, 松本雅記, 大場雄介, 中山敬一, Koo Bonkyoung, 畠山鎮次
    第94回日本生化学会大会  2021/11
  • Wnt receptor regulation  [Not invited]
    築山忠維
    Wnt研究会2021  2021/01
  • 単一遺伝子変異による多段階発がんの起動と完成  [Not invited]
    築山忠維
    第79回日本癌学会学術総会  2020/10
  • RNF43の遺伝子変異は多段階発がんステップにおいてWntとp53経路の変異を代償する  [Not invited]
    築山 忠維
    第42回日本分子生物学会年会  2019/12
  • 幹細胞特異的ユビキチンリガーゼRNF43の遺伝子変異による多段階発がんステップの起動と完成  [Not invited]
    築山 忠維
    第78回日本癌学会学術総会  2019/09
  • A broken tumor suppressor RNF43 is repaired by phosphorylation.  [Not invited]
    Tadasuke Tsukiyama
    第77回日本癌学会学術総会  2018/09
  • Phosphorylation of RNF43 is an essential switch to suppress Wnt signalling a nd regulates embryonic development, stem cell maintenance and tumorigenesis.  [Not invited]
    Tadasuke Tsukiyama
    第91回日本生化学会大会  2018/09
  • RNF43のリン酸化によるWntシグナルの活性制御は個体の恒常性を制御する  [Not invited]
    築山 忠維
    Wnt研究会2017  2017/12
  • Aberrant Wnt signaling and tumorigenesis by RNF43 mutation in animal models  [Not invited]
    Tadasuke Tsukiyama
    ConBio2017  2017/12
  • Stem cell ubiquitin ligase RNF43 governs morphogenesis and tumorigenesis thorough Wnt signaling  [Not invited]
    Tadasuke Tsukiyama
    第76回日本癌学会学術総会  2017/09
  • Diverse functions of Wnt signaling in our life  [Invited]
    Tadasuke Tsukiyama
    第39回日本分子生物学会年会  2016/11
  • Post-translational modification of RNF43; a molecular switch of Wnt signaling  [Invited]
    Tadasuke Tsukiyama
    第39回日本分子生物学会年会  2016/11
  • RNF43の翻訳後修飾はWntシグナル調節のスイッチとして機能する  [Not invited]
    築山 忠維
    第75回日本癌学会学術総会  2016/10
  • Post-translational modification of RNF43; a molecular switch of Wnt signaling  [Not invited]
    Tadasuke Tsukiyama
    Wnt meeting 2016  2016/09
  • カエルモデルを用いたRNF43のリン酸化によるWntシグナル調節機構の解明  [Not invited]
    築山 忠維
    平成27年度「個体レベルでのがん研究支援活動」ワークショップ  2016/02
  • カエルモデルを用いたRNF43のWntシグナル調節と発がんにおける機能検討  [Not invited]
    築山 忠維
    第74回日本癌学会学術総会  2015/10
  • カエルモデルから明らかになったWntシグナル調節とがんにおけるRNF43の機能  [Not invited]
    築山 忠維
    日本生化学会北海道支部 第52回支部例会  2015/07
  • Missense mutations of RNF43 establish a positive feedback loop of Wnt/βcatenin signaling  [Not invited]
    Tadasuke Tsukiyama
    2015「個体レベルでのがん研究支援活動」ワークショップ  2015/02
  • Missense mutations of RNF43 establish a positive feedback loop of Wnt/βcatenin signaling  [Not invited]
    Tadasuke Tsukiyama
    第37回日本分子生物学会年会  2014/11
  • RNF43のミスセンス変異はWnt/βcateninシグナルの正のフィードバックループを形成する  [Not invited]
    築山 忠維
    第73回日本癌学会年会  2014/09
  • RNF43遺伝子のミスセンス変異によるWnt/βcatenin経路のポジティブフィードバックループ形成  [Not invited]
    築山 忠維
    日本生化学会北海道支部 第51回支部例会  2014/07
  • Missense mutations convert RNF43 tumour suppressor into an oncogene  [Not invited]
    Tadasuke Tsukiyama
    第36回日本分子生物学会年会  2013/12
  • RNF43 negatively regulates Wnt/beta-catenin and noncanonical Wnt signallin g pathways through distinct mechanisms  [Not invited]
    Tadasuke Tsukiyama
    第72回日本癌学会学術総会  2013/10
  • RNF43はcanonical/noncanonical Wntシグナルの両方を抑制する  [Not invited]
    築山 忠維
    第35回日本分子生物学会年会  2012/12  マリンメッセ福岡・福岡
  • RNF43はNEDL1と結合し、p53依存性の転写を調節する  [Not invited]
    築山 忠維
    第71回日本癌学会学術総会  2012/09  札幌
  • Ymer functions as a multifunctional regulator in NF-kB and Fas signaling pathways.  [Not invited]
    築山 忠維
    41st Australasian Society for Immunology Annual Meeting  2011/12  アデレード･オーストラリア
  • ポリユビキチン結合タンパク質Ymer は 炎症反応を抑制する  [Not invited]
    築山 忠維
    第48回日本生化学会北海道支部例会  2011/08  札幌
  • Ymerトランスジェニックマウスの解析  [Not invited]
    築山 忠維
    第32回日本分子生物学会年会  2009/12
  • がん抑制遺伝子としてのWnt5a  [Invited]
    築山 忠維
    Wntシグナルシンポジウム  2009/03
  • K63-ポリユビキチン鎖を介してNF-kBシグナルを抑制するYmerの機能解析  [Not invited]
    築山 忠維
    第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会 （BMB2008）  2008/12
  • 改良型NF-κB活性検出システムの構築  [Not invited]
    築山 忠維
    第73回日本インターフェロン・サイトカイン学会学術集会  2008/07
  • 改良型NF-kB活性検出システムの構築  [Not invited]
    築山 忠維
    第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会 （BMB2007）  2007/12
  • Wnt5a is a haploinsufficient tumor suppressor that cooperates with Tcf1 to suppress T cell lymphomas  [Not invited]
    築山 忠維
    20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress  2006/06
  • Wnt5a synergizes with Tcf1 to suppress T-cell lymphoma  [Not invited]
    築山 忠維
    日本分子生物学会年会  2004/12
  • Evidence that Wnt5a functions as a tumor suppressor in T-cell lymphoma  [Not invited]
    築山 忠維
    Cold Spring Harboer-Mouse molecular Genetics meeting  2004/09
  • Wnt5a is a tumor suppressor in T-cell lymphoma  [Not invited]
    築山 忠維
    Wnt meeting  2004/05
  • Wnt signaling regulates mammalian body plan and tumorigenesis.  [Not invited]
    築山 忠維
    NCI retreat  2003/10
  • Wnt signaling pathway and anterior- posterior body axis formation  [Not invited]
    築山 忠維
    Society for Developmental Biology Annual Meeting  2003/08
  • Downregulation of p27Kip1 is required for T cell development  [Not invited]
    築山 忠維
    Cold Spring Harbor Laboratory-The cell cycle meeting  2000/05
  • T細胞の分化と細胞周期：p27Kip1トランスジェニックマウスの解析  [Not invited]
    築山 忠維
    日本分子生物学会年会  1999/12
  • 胸腺細胞特異的発現p27Kip1トランスジェニックマウスの作製と解析  [Not invited]
    築山 忠維
    日本分子生物学会年会  1998/12
  • DNA-リポソームcomplexの前核注入によるTgマウス胚の作出  [Not invited]
    築山 忠維
    日本繁殖学会  1996/10
  • DNA-リポソームcomplexの前核注入によるTgマウス胚の作出  [Not invited]
    築山 忠維
    日本畜産学会  1996/03

Association Memberships

  • 日本生化学会   Wnt研究会   日本癌学会   THE MOLECULAR BIOLOGY SOCIETY OF JAPAN   

Research Projects

  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2023/04 -2026/03 
    Author : 築山 忠維
  • 発がん過程におけるRNF43をハブとしたWntシグナルとp53経路のクロストーク機構の解明
    東京大学医科学研究所：東京大学医科学研究所共同研究
    Date (from‐to) : 2023/04 -2025/03 
    Author : 築山忠維
  • RNF43の遺伝子変異を標的とした新たながん治療法の開発（継続）
    金沢大学がん進展制御研究所：金沢大学がん進展制御研究所 共同利用・共同研究
    Date (from‐to) : 2023/04 -2024/03 
    Author : 築山忠維
  • RNF43の遺伝子変異を標的とした新たながん治療法の開発
    金沢大学がん進展制御研究所：令和４年度 共同研究
    Date (from‐to) : 2022/04 -2023/03
  • Wnt受容体の発現調節破綻による発がん機構の解明をがん治療に応用する ための基礎的研究
    公益財団法人 武田科学振興財団：ビジョナリーリサーチ助成
    Date (from‐to) : 2021/04 -2023/03
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : 築山 忠維
  • 糖代謝が個体の恒常性維持に関与するメカニズムの解明
    群馬大学：内分泌・代謝学共同研究拠点 共同研究
    Date (from‐to) : 2020/04 -2021/03
  • Wntシグナル調節因子が代謝変化を通して発がんに関与するメカニズムの解明
    大阪大学：大阪大学微生物病研究所共同研究課題
    Date (from‐to) : 2020/04 -2021/03
  • 糖代謝がWntシグナルによる恒常性維持に及ぼす影響の検討
    群馬大学：生体・調節研究所内分泌 代謝学共同研究拠点共同研究
    Date (from‐to) : 2019/04 -2020/03
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2016/04 -2020/03 
    Author : Tsukiyama Tadasuke
     
    We show in this research that; 1, CK1 phosphorylates RNF43 on multiple serines. 2, Phosphorylation activates ubiquitinating function of RNF43. 3, Mutation of RNF43 in these serines induces the excess of Wnt signaling. 4, Such mutations do not change the function of RNF43 in suppression of p53-dependent cellular reactions. These results suggest that mutations in serine on RNF43 act concurrently in the first step: Wnt activation and in the 3rd step: p53 inactivation. Furthermore, we propose a new model of tumorigenesis: two mutations, in RNF43 and Ras, is sufficient for the onset of tumor.
  • Wntシグナルが恒常性維持に果たす役割のゼブラフィッシュモデルを用いた解明
    群馬大学：生体・調節研究所内分泌 代謝学共同研究拠点共同研究
    Date (from‐to) : 2018/04 -2019/03
  • ユビキチン化酵素RNF43による発がん制御機構の解明
    公益財団法人 日本応用酵素協会：酵素研究助成
    Date (from‐to) : 2016/09 -2017/08 
    Author : 築山 忠維
  • ゼブラフィッシュモデルを用いたRNF43の機能解析
    九州大学：生体防御医学研究所 発生工学共同研究課題
    Date (from‐to) : 2016/04 -2017/03
  • Wntシグナル調節メカニズムの解明と膵臓がんの診断治療への応用
    公益財団法人 日本膵臓病研究財団：膵臓病研究奨励賞
    Date (from‐to) : 2015/10 -2016/10 
    Author : 築山 忠維
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2013/04 -2016/03 
    Author : Tsukiyama Tadasuke, Hatakeyama Shigetsugu, Takahashi Hidehisa
     
    Wnt signaling pathways are tightly regulated by ubiquitination of their signal transducers and dysregulation of these pathways promotes the tumorigenesis. It has been reported that an ubiquitin ligase RNF43 plays important role in the Fzd-dependent regulation of Wnt signaling pathways. We recently reported that N-terminal of RNF43 is indespensable to regulate Fzd-dependent suppression of Wnt signaling pathways although C-terminal of RNF43 is able to inhibit noncanonical Wnt signaling in a Fzd-independent but Dvl-dependent fashion. In addition missense mutations found in cancer patients convert the function of RNF43 to the positive regulator of Wnt/βcatenin signaling and establish a positive feedback loop of Wnt/βcatenin signaling to accelerate tumorigenesis. These results have been published in a scientific journal [ Tsukiyama, MCB, 35:2007 (2015)].
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : HATAKEYAMA Shigetsugu, TSUKIYAMA Tadasuke, TAKAHASHI Hidehisa
     
    TRIM family ubiquitin ligases are important for regulation of carcinogenesis in several cancers. It has been reported that TRIM family ubiquitin ligases regulate the activity of transcription factors in the process of cell proliferation and differentiation. By using proteomics analysis, we comprehensively analyzed TRIM family ubiquitin ligases which are related to ubiquitination of transcription factors. The analysis clarified the molecular mechanism in carcinogenesis of several cancers, maybe leading to the contribution to clinical applications for diagnosis and therapies.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2011 
    Author : HATAKEYAMA Shigetsugu, OKUMURA Fumihiko, TSUKIYAMA Tadasuke
     
    Ubiquitination is one of the posttranslational modifications used by eukaryotic cells, and the ubiquitin-mediated proteolytic pathway plays a crucial role in the elimination of short-lived regulatory proteins. Members of the family of tripartite motif (TRIM)-containing proteins are idefined as E3 ubiquitin ligases. There are now more than 70 known TRIM proteins in humans and mice. In this study, we analyzed the relationship between TRIM proteins and cancinogenesis.
  • Ministry of Education, Culture, Sports, Science and Technology：Grants-in-Aid for Scientific Research(若手研究(B))
    Date (from‐to) : 2008/04 -2010/03 
    Author : Tadasuke TSUKIYAMA
     
    We have established and reported for cNAT system, which can detect the activity of NF-κB signaling. Next, we generated cNAT reporter transgenic mice and cNotch reporter system/transgenic mice to detect NF-κB signaling and Notch signaling respectively, in living mice.
  • マウス生体内におけるシグナル経路のin vivo イメ ージングシステムの確立と応用
    秋山財団：生命科学研究助成金
    Date (from‐to) : 2007/04 -2008/03 
    Author : 築山 忠維
  • 日本学術振興会：科学研究費補助金・若手研究(B)
    Date (from‐to) : 2006/04 -2008/03 
    Author : 築山 忠維
     
    全ての生物においてシグナル伝達システムの厳密な制御は、生命を維持することに決定的に重要である。我々は、本研究において生体内でこれらのシグナル活性を蛍光・発光によりイメージングするためのシステム構築を目指し、様々なシグナル活性変化を検出するレポーターとして活用することで、個体の形態形成から恒常性維持までに至る生命現象を対象とした幅広い研究に対応させることを目的とした。まず我々はガン、免疫異常、炎症などの多くの疾患に重要な役割を果たすNF-kBシグナルに注目し、その活性を検出するためのシステム構築を行った。NF-kBシグナルを高感度・特異的に検出するレポーターシステムの確立には、NF-kB結合配列とNF-kBシグナルの下流において特異的と考えられるIL-2遺伝子由来ミニマルプロモーターを用い、改良型NF-kBレポーター:NATシステムを構築した。さらにシグナルの蓄積とリアルタイムでのシグナル活性変化検出ため、レポーター遺伝子として安定型・不安定型のルシフェラーゼ・EGFPと組み合わせ細胞レベルでの検討を行った結果、従来のNF-kBシグナルレポーターシステムに対し検出感度で18倍、特異性で5倍高い値を示し、またシグナルの蓄積とリアルタイムでのシグナル活性変化を同時に測定出来るシステムであることが示された(Matsuda et al., Immunology Letters、 200...
  • Ministry of Education, Culture, Sports, Science and Technology：Grants-in-Aid for Scientific Research(基盤研究(B))
    Date (from‐to) : 2006 -2007 
    Author : Shigetsugu HATAKEYAMA, 築山 忠維
     
    Ubiquitination is a versatile post-translational modification mechanism used by eukaryotic cells mainly to control protein levels through proteasome-mediated proteolysis. Ubiquitin conjugation is achieved by several enzymes that act in concert, a ubiquitin-protein ligase (E3). E3 is thought to be the component of the ubiquitin conjugation system that is most directly responsible for substrate recognition. Enzymes belonging to class E3 that have so far been identified include members of the HECT (homologous to E6-AP carboxyl terminus), RING-finger and U-box families of proteins. So far; we h...
  • 文部科学省：科学研究費補助金(萌芽研究)
    Date (from‐to) : 2006 -2007 
    Author : 畠山 鎮次, 築山 忠維
     
    多くの細胞質・核質に存在するタンパク質の分解に関わっているのはユビキチン-プロテアソーム系である。この分解系の特徴は、基質特異性が高く、分解速度が速いことである。分解されるべきタンパク質はユビキチンが鎖状に結合され(ポリユビキチン鎖)、タンパク質分解装置であるプロテアソームがポリユビキチン鎖を認識して標的タンパク質ごと分解する。標的タンパク質のユビキチン化に必要な酵素群の中で、特にユビキチンリガーゼは標的タンパク質を認識し、最終的にユビキチンを付加する重要な因子である。本研究課題においては、各ポリグルタミン病関連タンパク質(ハンチンティン、Atrophin-1、Ataxin(ATX)-1,-2,-3,-17等)には特異的に結合するタンパク質が同定されているので、この結合タンパク質とユビキチンリガーゼであるU-ボックスタンパク質のキメラ酵素(人工ハイブリッドユビキチンリガーゼ)を作製し、ポリグルタミン含有タンパク質が人工ハイブリッドユビキチンリガーゼによってユビキチン化を受け、プロテアソームによって分解される系を構築する。さらに実際の遺伝子治療に応用できるかどうかを検討するために、ウイルスベクターを利用して細胞やマウスへの導入実験を行い、神経機能異常に対する効果を判定する。特に、ATX-3/MJD1とVCP/p97の結合に注目し、VCPにおける最小結合領域を同定しているところで...

Media Coverage

  • 大腸がんの進行抑制できるタンパク質の働きを初解明
    Date : 2020/10/13
    Writer: Other than myself
    Publisher, broadcasting station: NHK
    Program, newspaper magazine: 北海道のがん研究最前線・ほっとニュース北海道
    Media report
  • 大腸がん発症のスイッチを発見 北大
    Date : 2020/10/09
    Writer: Other than myself
    Publisher, broadcasting station: 東京メトロポリタンテレビジョン
    Program, newspaper magazine: MEDICAL NEWS LINE
    Media report
  • Date : 2020/09/18
    Writer: Other than myself
    Publisher, broadcasting station: QlifePro
    Program, newspaper magazine: 医療NEWS
    http://www.qlifepro.com/news/20200917/rnf43-tumorigenesis.html Internet
  • Date : 2020/09/18
    Writer: Other than myself
    Publisher, broadcasting station: NHK
    Program, newspaper magazine: NHKニュース・おはよう北海道
    Media report
  • Molecular basis underlying colorectal cancer revealed
    Date : 2020/09/15
    Publisher, broadcasting station: bioengineer.org
    Program, newspaper magazine: Bioengineer
    https://bioengineer.org/molecular-basis-underlying-colorectal-cancer-revealed/ Internet
  • Molecular basis underlying colorectal cancer revealed
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: 7thspace.com
    Program, newspaper magazine: 7thSpace
    http://7thspace.com/headlines/1309965/molecular_basis_underlying_colorectal_cancer_revealed.html Internet
  • The Wnt pathway gets even more complicated
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: American Association for the Advancement of Science (AAAS)
    Program, newspaper magazine: EurekAlart!
    https://www.eurekalert.org/pub_releases/2020-09/iiom-twp091520.php Internet
  • Molecular basis underlying colorectal cancer revealed
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: bionewscentral.com
    Program, newspaper magazine: BioNews CENTRAL
    https://bionewscentral.com/molecular-basis-underlying-colorectal-cancer-revealed/ Internet
  • The Wnt pathway gets even more complicated
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: alphagalileo.org
    Program, newspaper magazine: Alpha Galileo
    https://www.alphagalileo.org/en-gb/Item-Display/ItemId/197278?returnurl=https://www.alphagalileo.org/en-gb/Item-Display/ItemId/197278 Internet
  • Molecular basis underlying colorectal cancer revealed by Hokkaido University
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: Oncology & Cancer
    Program, newspaper magazine: medicalxpress.com
    https://medicalxpress.com/news/2020-09-molecular-basis-underlying-colorectal-cancer.html Internet
  • Molecular basis underlying colorectal cancer revealed
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: asiaresearchnews.com
    Program, newspaper magazine: Asia Research News
    https://www.asiaresearchnews.com/content/molecular-basis-underlying-colorectal-cancer-revealed Internet
  • Scientists unravel the molecular mechanism underlying the causes of colorectal cancer
    Date : 2020/09/15
    Writer: Other than myself
    Publisher, broadcasting station: news-medical.net
    Program, newspaper magazine: The Medical News
    https://www.news-medical.net/news/20200915/Scientists-unravel-the-molecular-mechanism-underlying-the-causes-of-colorectal-cancer.aspx Internet

Academic Contribution

  • Wnt研究会 世話人
    Date (from-to) :2016/11/30-2019/02/02
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 築山忠維・その他
  • 日本分子生物学会年会シンポジウム 企画（Wntシグナル：私たちのからだを作る・支えるユーティリティプレイヤー ）
    Date (from-to) :2016/11/30
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 日本分子生物学会
  • Wnt研究会 設立
    Date (from-to) :2016/11/30
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 築山忠維・石谷太
  • セッション３ Wntシグナルと発癌
    Date (from-to) :2009/03/24
    Role: Panel chair etc
    Type: Academic society etc
    Organizer, responsible person: Wntシグナルシンポジウム

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