Watanabe Masashi
Faculty of Medicine Physiological Science Biochemistry | Lecturer |
Last Updated :2025/06/07
■Researcher basic information
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Educational Organization
- Bachelor's degree program, Departments of Medicine, School of Medicine
- Master's degree program, Graduate School of Medicine
- Doctoral (PhD) degree program, Graduate School of Medicine
■Career
■Research activity information
Papers
- 脳炎・肥厚性硬膜炎【WS】免疫沈降法とショットガンプロテオミクスによる自己抗体測定方法の開発
工藤 彰彦, 矢口 裕章, 渡部 昌, 藤井 信太朗, 野村 太一, 上床 恵, 上床 尚, 白井 慎一, 岩田 育子, 松島 理明, 田中 惠子, 高橋 秀尚, 畠山 鎮次, 矢部 一郎
神経免疫学, 29, 1, 218, 218, (一社)日本神経免疫学会, Oct. 2024
Japanese - 鼻副鼻腔粘膜悪性黒色腫におけるTRIM27の検討
木村 将吾, 中丸 裕爾, 鈴木 正宣, 中薗 彬, 本間 あや, 渡邉 良亮, 加納 里志, 対馬 那由多, 鈴木 崇祥, 井戸川 寛志, 本間 明宏, 渡部 昌, 近藤 豪, 畠山 鎮次
日本鼻科学会会誌, 63, 3, 336, 336, (一社)日本鼻科学会, Sep. 2024
Japanese - 自己免疫性小脳失調症に対する免疫沈降法と質量分析法を用いた網羅的自己抗体測定方法の開発
工藤 彰彦, 矢口 裕章, 渡部 昌, 上床 尚, 白井 慎一, 岩田 育子, 松島 理明, 高橋 秀尚, 畠山 鎮次, 矢部 一郎
神経免疫学, 28, 1, 217, 217, (一社)日本神経免疫学会, Sep. 2023
Japanese - FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA.
Yusuke Kasuga, Ryota Ouda, Masashi Watanabe, Xin Sun, Miki Kimura, Shigetsugu Hatakeyama, Koichi S Kobayashi
Proceedings of the National Academy of Sciences of the United States of America, 120, 24, e2218955120, 13 Jun. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin-proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11-deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11, along with CIITA, is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer. - Sez6l2 autoimmunity in a large cohort study.
Megumi Abe, Hiroaki Yaguchi, Akihiko Kudo, Azusa Nagai, Shinichi Shirai, Ikuko Takahashi-Iwata, Masaaki Matsushima, Naoko Nakamura, Kenji Isahaya, Yoshihisa Yamano, Shinji Ashida, Takashi Kasai, Keiko Tanaka, Masashi Watanabe, Takeshi Kondo, Hidehisa Takahashi, Shigetsugu Hatakeyama, Akira Takekoshi, Akio Kimura, Takayoshi Shimohata, Ichiro Yabe
Journal of neurology, neurosurgery, and psychiatry, 94, 8, 667, 668, 01 Jun. 2023, [Peer-reviewed], [International Magazine]
English - TRIM27 expression is associated with poor prognosis in sinonasal mucosal melanoma.
S Kimura, M Suzuki, Y Nakamaru, S Kano, M Watanabe, A Honma, A Nakazono, N Tsushima, S Hatakeyama, A Homma
Rhinology, 09 Mar. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUND: Tripartite motif-containing 27 (TRIM27) has been implicated in the progression of various cancers. However, the role of TRIM27 in sinonasal mucosal melanoma (SNMM) remains poorly understood. MATERIALS & METHODS: We retrospectively examined 28 patients with SNMM treated with between 2003 and 2021. We undertook immunohistochemical analysis of TRIM27, Ki-67, and p-Akt1 expression in SNMM tissues. We also investigated the relationship between TRIM27 expression and clinical characteristics, prognosis, Ki-67 as a tumor growth potential marker, and p-Akt1 as one of the prognostic factors in mucosal melanoma. RESULTS: TRIM27 expression was significantly higher in T4 disease than in T3 disease and was higher in stage IV than in stage III. Patients with high-TRIM27 SNMM had a significantly poorer prognosis in terms of overall survival (OS) and disease-free survival.There was also a significantly higher rate of distant metastasis. Univariate analysis for OS revealed that TRIM27 and T classification were significant poor prognostic factors. In addition, the Ki-67 positive score and the p-Akt1 total staining score were significantly higher in the high-TRIM27 group than in the low-TRIM27 group. CONCLUSIONS: High TRIM27 expression in SNMM was associated with advanced T classification, poor prognosis and distant metastasis. We suggest that TRIM27 has potential as a novel biomarker for prognosis in SNMM. - TRIM22 negatively regulates MHC-II expression.
Ayano Inoue, Masashi Watanabe, Takeshi Kondo, Satoshi Hirano, Shigetsugu Hatakeyama
Biochimica et biophysica acta. Molecular cell research, 1869, 10, 119318, 119318, 28 Jun. 2022, [Peer-reviewed], [International Magazine]
English, Scientific journal, The development of cancer treatment has recently achieved a remarkable breakthrough, and checkpoint blockade immunotherapy has received much attention. To enhance the therapeutic efficacy of checkpoint blockade immunotherapy, recent studies have revealed the importance of activation of CD4+ T cells via an increase in major histocompatibility complex (MHC) class II molecules in cancer cells. Here, we demonstrate that tripartite motif-containing (TRIM) 22, negatively regulates MHC-II expression. Gene knockout of TRIM22 using Cas9-sgRNAs led to an increase of MHC-II proteins, while TRIM22 overexpression remarkably decreased MHC-II proteins. mRNA levels of MHC-II and class II transactivator (CIITA), which plays an essential role in the regulation of MHC-II transcription, were not affected by TRIM22. Furthermore, TRIM22 knockout did not suppress the degradation of MHC-II protein but rather promoted it. These results suggest that TRIM22 decreases MHC-II protein levels through a combination of multiple mechanisms other than transcription or degradation. We showed that inhibition of TRIM22 can increase the amount of MHC-II expression in cancer cells, suggesting a possibility of providing the biological basis for a possible therapeutic target to potentiate checkpoint blockade immunotherapy. - Loss of FAM83H promotes cell migration and invasion in cutaneous squamous cell carcinoma via impaired keratin distribution.
Keiko Tokuchi, Shinya Kitamura, Takuya Maeda, Masashi Watanabe, Shigetsugu Hatakeyama, Satoshi Kano, Shinya Tanaka, Hideyuki Ujiie, Teruki Yanagi
Journal of dermatological science, 104, 2, 112, 121, 30 Sep. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUNDS: FAM83H is essential for amelogenesis, but recent reports implicate that FAM83H is involved in the tumorigenesis. We previously clarified that TRIM29 binds to FAM83H to regulate keratin distribution and squamous cell migration. However, little is known about FAM83H in normal/malignant skin keratinocytes. OBJECTIVE: To investigate the expression of FAM83H in cutaneous squamous cell carcinoma (SCC) and its physiological function. METHODS: Immunohistochemical analysis and RT-PCR of human SCC tissues were performed. Next, we examined the effect of FAM83H knockdown/overexpression in SCC cell lines using cell proliferation, migration, and invasion assay. To investigate the molecular mechanism, immunoprecipitation of FAM83H was examined. Further, Immunofluorescence staining was performed. Finally, we examined the correlation between the expressions of FAM83H and the keratin distribution. RESULTS: FAM83H expression was lower in SCC lesions than in normal epidermis and correlated with differentiation grade. The mRNA expression levels of FAM83H in SCC tumors were also lower than in normal epidermis. The knockdown of FAM83H enhanced SCC cell migration and invasion, whereas the overexpression of FAM83H led to decreases in both. Furthermore, the knockdown of FAM83H enhanced the cancer cell metastasis in vivo. FAM83H formed a complex with TRIM29 and keratins. The knockdown of FAM83H altered keratin distribution and solubility. Clinically, the loss of FAM83H correlates with an altered keratin distribution. CONCLUSION: Our findings reveal a critical function for FAM83H in regulating keratin distribution, as well as in the migration/invasion of cutaneous SCC, suggesting that FAM83H could be a crucial molecule in the tumorigenesis of cutaneous SCC. - Fluticasone Propionate Suppresses Poly(I:C)-Induced ACE2 in Primary Human Nasal Epithelial Cells.
Akira Nakazono, Yuji Nakamaru, Mahnaz Ramezanpour, Takeshi Kondo, Masashi Watanabe, Shigetsugu Hatakeyama, Shogo Kimura, Aya Honma, P J Wormald, Sarah Vreugde, Masanobu Suzuki, Akihiro Homma
Frontiers in cellular and infection microbiology, 11, 655666, 655666, 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, Background: From the first detection in 2019, SARS-CoV-2 infections have spread rapidly worldwide and have been proven to cause an urgent and important health problem. SARS-CoV-2 cell entry depends on two proteins present on the surface of host cells, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). The nasal cavity is thought to be one of the initial sites of infection and a possible reservoir for dissemination within and between individuals. However, it is not known how the expression of these genes is regulated in the nasal mucosa. Objective: In this study, we examined whether the expression of ACE2 and TMPRSS2 is affected by innate immune signals in the nasal mucosa. We also investigated how fluticasone propionate (FP), a corticosteroid used as an intranasal steroid spray, affects the gene expression. Methods: Primary human nasal epithelial cells (HNECs) were collected from the nasal mucosa and incubated with Toll-like receptor (TLR) agonists and/or fluticasone propionate (FP), followed by quantitative PCR, immunofluorescence, and immunoblot analyses. Results: Among the TLR agonists, the TLR3 agonist Poly(I:C) significantly increased ACE2 and TMPRSS2 mRNA expression in HNECs (ACE2 36.212±11.600-fold change, p<0.0001; TMPRSS2 5.598±2.434-fold change, p=0.031). The ACE2 protein level was also increased with Poly(I:C) stimulation (2.884±0.505-fold change, p=0.003). The Poly(I:C)-induced ACE2 expression was suppressed by co-incubation with FP (0.405±0.312-fold change, p=0.044). Conclusion: The activation of innate immune signals via TLR3 promotes the expression of genes related to SARS-CoV2 cell entry in the nasal mucosa, although this expression is suppressed in the presence of FP. Further studies are required to evaluate whether FP suppresses SARS-CoV-2 viral cell entry. - Role of intracellular zinc in molecular and cellular function in allergic inflammatory diseases.
Masanobu Suzuki, Takayoshi Suzuki, Masashi Watanabe, Shigetsugu Hatakeyama, Shogo Kimura, Akira Nakazono, Aya Honma, Yuji Nakamaru, Sarah Vreugde, Akihiro Homma
Allergology international : official journal of the Japanese Society of Allergology, 70, 2, 190, 200, 27 Oct. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems. In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions. In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases. - A substrate-trapping strategy to find E3 ubiquitin ligase substrates identifies Parkin and TRIM28 targets.
Masashi Watanabe, Yasushi Saeki, Hidehisa Takahashi, Fumiaki Ohtake, Yukiko Yoshida, Yusuke Kasuga, Takeshi Kondo, Hiroaki Yaguchi, Masanobu Suzuki, Hiroki Ishida, Keiji Tanaka, Shigetsugu Hatakeyama
Communications biology, 3, 1, 592, 592, 20 Oct. 2020, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal, The identification of true substrates of an E3 ligase is biologically important but biochemically difficult. In recent years, several techniques for identifying substrates have been developed, but these approaches cannot exclude indirect ubiquitination or have other limitations. Here we develop an E3 ligase substrate-trapping strategy by fusing a tandem ubiquitin-binding entity (TUBE) with an anti-ubiquitin remnant antibody to effectively identify ubiquitinated substrates. We apply this method to one of the RBR-type ligases, Parkin, and to one of the RING-type ligases, TRIM28, and identify previously unknown substrates for TRIM28 including cyclin A2 and TFIIB. Furthermore, we find that TRIM28 promotes cyclin A2 ubiquitination and degradation at the G1/S phase and suppresses premature entry into S phase. Taken together, the results indicate that this method is a powerful tool for comprehensively identifying substrates of E3 ligases. - The role of Mediator and Little Elongation Complex in transcription termination.
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, 26 Feb. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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. - Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Cell Carcinoma.
Teruki Yanagi, Masashi Watanabe, Hiroo Hata, Shinya Kitamura, Keisuke Imafuku, Hiroko Yanagi, Akihiro Homma, Lei Wang, Hidehisa Takahashi, Hiroshi Shimizu, Shigetsugu Hatakeyama
Cancer research, 78, 24, 6795, 6806, 15 Dec. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, : TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated. Here, we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immunoprecipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29-keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics. SIGNIFICANCE: These findings identify TRIM29 as a novel diagnostic and prognostic marker in stratified epithelial tissues. - Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure.
Junichi Matsumoto, Shingo Takada, Shintaro Kinugawa, Takaaki Furihata, Hideo Nambu, Naoya Kakutani, Masaya Tsuda, Arata Fukushima, Takashi Yokota, Shinya Tanaka, Hidehisa Takahashi, Masashi Watanabe, Shigetsugu Hatakeyama, Masaki Matsumoto, Keiichi I Nakayama, Yutaro Otsuka, Hisataka Sabe, Hiroyuki Tsutsui, Toshihisa Anzai
Circulation, 138, 18, 2064, 2066, 30 Oct. 2018, [Peer-reviewed], [International Magazine]
English - Anti-Sez6l2 antibody detected in a patient with immune-mediated cerebellar ataxia inhibits complex formation of GluR1 and Sez6l2.
Hiroaki Yaguchi, Ichiro Yabe, Hidehisa Takahashi, Masashi Watanabe, Taichi Nomura, Takahiro Kano, Masahiko Watanabe, Shigetsugu Hatakeyama
Journal of neurology, 265, 4, 962, 965, Dr. Dietrich Steinkopff Verlag GmbH and Co. KG, Apr. 2018, [Peer-reviewed], [International Magazine]
English - Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome.
Ichiro Yabe, Hiroaki Yaguchi, Yasutaka Kato, Yasuo Miki, Hidehisa Takahashi, Satoshi Tanikawa, Shinichi Shirai, Ikuko Takahashi, Mari Kimura, Yuka Hama, Masaaki Matsushima, Shinsuke Fujioka, Takahiro Kano, Masashi Watanabe, Shin Nakagawa, Yasuyuki Kunieda, Yoshio Ikeda, Masato Hasegawa, Hiroshi Nishihara, Toshihisa Ohtsuka, Shinya Tanaka, Yoshio Tsuboi, Shigetsugu Hatakeyama, Koichi Wakabayashi, Hidenao Sasaki
Scientific reports, 8, 1, 819, 819, 16 Jan. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Clinical diagnosis of progressive supranuclear palsy (PSP) is sometimes difficult because various phenotypes have been identified. Here, we report a mutation in the bassoon (BSN) gene in a family with PSP-like syndrome. Their clinical features resembled not only those of PSP patients but also those of individuals with multiple system atrophy and Alzheimer's disease. The neuropathological findings showed a novel three + four repeat tauopathy with pallido-luysio-nigral degeneration and hippocampal sclerosis. Whole-exome analysis of this family identified a novel missense mutation in BSN. Within the pedigree, the detected BSN mutation was found only in affected individuals. Further genetic analyses were conducted in probands from four other pedigrees with PSP-like syndrome and in 41 sporadic cases. Three missense mutations in BSN that are very rarely listed in databases of healthy subjects were found in four sporadic cases. Western blot analysis of tau following the overexpression of wild-type or mutated BSN revealed the possibility that wild-type BSN reduced tau accumulation, while mutated BSN lost this function. An association between BSN and neurological diseases has not been previously reported. Our results revealed that the neurodegenerative disorder associated with the original proband's pedigree is a novel tauopathy, differing from known dementia and parkinsonism syndromes, including PSP. - Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5
Masashi Watanabe, Shigetsugu Hatakeyama
CELLULAR & MOLECULAR IMMUNOLOGY, 14, 12, 957, 959, Dec. 2017, [Peer-reviewed], [Lead author]
English - Sez6l2 regulates phosphorylation of ADD and neuritogenesis
Hiroaki Yaguchi, Ichiro Yabe, Hidehisa Takahashi, Masashi Watanabe, Taichi Nomura, Takahiro Kano, Masaki Matsumoto, Keiichi I. Nakayama, Masahiko Watanabe, Shigetsugu Hatakeyama
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 494, 1-2, 234, 241, Dec. 2017, [Peer-reviewed]
English, Scientific journal - TRIM proteins and diseases
Masashi Watanabe, Shigetsugu Hatakeyama
JOURNAL OF BIOCHEMISTRY, 161, 2, 135, 144, Feb. 2017, [Peer-reviewed], [Lead author]
English - The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes
Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintaro Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furihata, Junichi Matsumoto, Masaya Tsuda, Ikuru Chiba, Shun Nagashima, Shigeru Yanagi, Masaki Matsumoto, Keiichi I. Nakayama, Hiroyuki Tsutsui, Shigetsugu Hatakeyama
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 100, 43, 53, Nov. 2016, [Peer-reviewed]
English, Scientific journal - p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex
Delnur Anwar, Hidehisa Takahashi, Masashi Watanabe, Masanobu Suzuki, Satoshi Fukuda, Shigetsugu Hatakeyama
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, 1859, 8, 975, 982, Aug. 2016, [Peer-reviewed]
English, Scientific journal - TRIM39 negatively regulates the NF kappa B-mediated signaling pathway through stabilization of Cactin
Masanobu Suzuki, Masashi Watanabe, Yuji Nakamaru, Dai Takagi, Hidehisa Takahashi, Satoshi Fukuda, Shigetsugu Hatakeyama
CELLULAR AND MOLECULAR LIFE SCIENCES, 73, 5, 1085, 1101, Mar. 2016, [Peer-reviewed]
English, Scientific journal - The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPAR gamma
Masashi Watanabe, Hidehisa Takahashi, Yasushi Saeki, Takashi Ozaki, Shihori Itoh, Masanobu Suzuki, Wataru Mizushima, Keiji Tanaka, Shigetsugu Hatakeyama
ELIFE, 4, Apr. 2015, [Peer-reviewed], [Lead author]
English, Scientific journal - MED26 regulates the transcription of snRNA genes through the recruitment of little elongation complex
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, Jan. 2015, [Peer-reviewed]
English, Scientific journal - Pathology of frontotemporal dementia with limb girdle muscular dystrophy caused by a DNAJB6 mutation
Ichiro Yabe, Mishie Tanino, Hiroaki Yaguchi, Akihiro Takiyama, Huaying Cai, Hiromi Kanno, Ikuko Takahashi, Yukiko K. Hayashi, Masashi Watanabe, Hidehisa Takahashi, Shigetsugu Hatakeyama, Shinya Tanak, Hidenao Sasaki
CLINICAL NEUROLOGY AND NEUROSURGERY, 127, 10, 12, Dec. 2014, [Peer-reviewed]
English, Scientific journal - TRIM29 as a novel prostate basal cell marker for diagnosis of prostate cancer
Yukiko Kanno, Masashi Watanabe, Taichi Kimura, Katsuya Nonomura, Shinya Tanaka, Shigetsugu Hatakeyama
ACTA HISTOCHEMICA, 116, 5, 708, 712, 2014, [Peer-reviewed]
English, Scientific journal - TRIM59 interacts with ECSIT and negatively regulates NF-kappa B and IRF-3/7-mediated signal pathways
Takeshi Kondo, Masashi Watanabe, Shigetsugu Hatakeyama
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 422, 3, 501, 507, Jun. 2012, [Peer-reviewed]
English, Scientific journal - TRIM24 mediates ligand-dependent activation of androgen receptor and is repressed by a bromodomain-containing protein, BRD7, in prostate cancer cells
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, Dec. 2009, [Peer-reviewed]
English, Scientific journal - ZNRF1 interacts with tubulin and regulates cell morphogenesis
Koichi Yoshida, Masashi Watanabe, Shigetsugu Hatakeyama
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 389, 3, 506, 511, Nov. 2009, [Peer-reviewed]
English, Scientific journal - TRIM31 interacts with p52(Shc) and inhibits Src-induced anchorage-independent growth
Masashi Watanabe, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 388, 2, 422, 427, Oct. 2009, [Peer-reviewed], [Lead author]
English, Scientific journal - Inhibition of NF-kappa B signaling via tyrosine phosphorylation of Ymer
Hiroyuki Kameda, Masashi Watanabe, Miyuki Bohgaki, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 378, 4, 744, 749, Jan. 2009, [Peer-reviewed]
English, Scientific journal - Involvement of Ymer in suppression of NF-kappaB activation by regulated interaction with lysine-63-linked polyubiquitin chain.
Bohgaki M, Tsukiyama T, Nakajima A, Maruyama S, Watanabe M, Koike T, Hatakeyama S
Biochimica et biophysica acta, 1783, 826, 837, 5, May 2008, [Peer-reviewed] - Involvement of Ymer in suppression of NF-kappa B activation by regulated interaction with lysine-63-linked polyubiquitin chain
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, May 2008, [Peer-reviewed]
English, Scientific journal - Protection of vincristine-induced neuropathy by Wld(S) expression and the independence of the activity of Nmnat1
Masashi Watanabe, Tadasuke Tsukiyama, Shigetsugu Hatakeyama
NEUROSCIENCE LETTERS, 411, 3, 228, 232, Jan. 2007, [Peer-reviewed], [Lead author]
English, Scientific journal - Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation
S Hatakeyama, M Watanabe, Y Fujii, KL Nakayama
CANCER RESEARCH, 65, 17, 7874, 7879, Sep. 2005, [Peer-reviewed]
English, Scientific journal
Other Activities and Achievements
- Proteolytic mechanism of the oncogene product PPM1D
渡部昌, 高橋正樹, 畠山鎮次, 日本分子生物学会年会プログラム・要旨集(Web), 46th, 2023 - Identification of a novel protein on MHC class I transcriptional regulation
應田涼太, 坐間のゆり, XIN Sun, 渡部昌, 畠山鎮次, 小林弘一, 日本分子生物学会年会プログラム・要旨集(Web), 45th, 2022 - 免疫介在性小脳失調症における新規自己抗体の検討
工藤彰彦, 矢口裕章, 阿部恵, 江口克紀, 長井梓, 脇田雅大, 白井慎一, 岩田育子, 松島理明, 水戸泰紀, 田島康敬, 渡部昌, 畠山鎮次, 米田誠, 田中惠子, 矢部一郎, 日本神経学会学術大会プログラム・抄録集, 63rd, 2022 - 扁平上皮癌におけるTripartite motif‐containing protein 29(TRIM29)の検討
柳輝希, 秦洋郎, 北村真也, 清水宏, 柳紘子, 本間明宏, 渡部昌, 畠山鎮次, 日本皮膚科学会雑誌, 129, 5, 1170, 1170, 15 May 2019
(公社)日本皮膚科学会, Japanese - 扁平上皮におけるTripartite motif‐containing protein 29(TRIM29)の機能解析
柳輝希, 秦洋郎, 北村真也, 今福恵輔, 清水宏, 柳紘子, 本間明宏, 渡部昌, 畠山鎮次, 日本皮膚科学会雑誌, 129, 1, 45, 45, 20 Jan. 2019
(公社)日本皮膚科学会, Japanese - メディエーター複合体による転写終結制御機構
高橋秀尚, 柴田美音, 瀧川一学, 渡部昌, 築山忠維, 山本淳一, 山口雄輝, 藤井聡, 飯田緑, RANJAN Amol, SATO Shigeo, TOMOMORI‐SATO Chieri, CONAWAY Joan, CONAWAY Ronald, 畠山鎮次, 日本生化学会大会(Web), 90th, ROMBUNNO.4P2T15‐06(3P‐0635) (WEB ONLY), 0635)], 2017
生命科学系学会合同年次大会運営事務局, Japanese - 髄膜炎・臍周囲炎・呼吸障害を呈したOTULIN‐related autoinflammatory syndrome(ORAS)の1例
植木将弘, 山田雅文, 戸澤雄介, 竹崎俊一郎, ABDRABOU ShimaaSaid MohamedAli, 小林一郎, 有賀正, 渡部昌, 畠山鎮次, 藤田宏明, 岩井一宏, 三宅紀子, 松本直通, 日本免疫不全症研究会プログラム・抄録, 10th, 12, 2017
Japanese - ユビキチンリガーゼTRIM23は非定型ポリユビキチン化によるPPARγの安定化を介して脂肪細胞分化を制御する
渡部昌, 高橋秀尚, 畠山鎮次, 日本生化学会大会(Web), 89th, ROMBUNNO.3T11‐02(3P‐108) (WEB ONLY), 02(3P, Sep. 2016
(公社)日本生化学会, Japanese - The novel heart-specific ring finger protein 207 regulates energy metabolism in cardiomyocytes
W. Mizushima, H. Takahashi, M. Watanabe, S. Kinugawa, S. Matsushima, S. Takada, T. Yokota, T. Furihata, J. Matsumoto, M. Tsuda, T. Katayama, T. Nakajima, S. Hatakeyama, H. Tsutsui, EUROPEAN HEART JOURNAL, 37, 34, 34, Aug. 2016
English, Summary international conference - The Novel Heart-specific Ring-finger Protein 207 Regulates Energy Metabolism in Cardiomyocytes
Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintarou Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furuhata, Junichi Matsumoto, M. Tsuda, T. Katayama, T. Nakajima, S. Hatakeyama, H. Tsutsui, CIRCULATION RESEARCH, 119, Jul. 2016
English, Summary international conference - ユビキチンE3リガーゼTRIM23は非定型ポリユビキチン化によるPPARγの安定化を介して脂肪細胞分化を制御する
渡部昌, 高橋秀尚, 畠山鎮次, 日本細胞生物学会大会(Web), 68th, ROMBUNNO.P1‐14 (WEB ONLY), 70, May 2016
(一社)日本細胞生物学会, Japanese - ユビキチンリガーゼTRIM23はPPARγの安定化を介して脂肪細胞分化を制御する
渡部昌, 高橋秀尚, 畠山鎮次, 日本内分泌学会雑誌, 92, 1, 201, 01 Apr. 2016
Japanese - Bechet病疾患感受性遺伝子Tripartite motif protein 39(TRIM39)の機能解析
鈴木 正宣, 渡部 昌, 中丸 裕爾, 高木 大, 本間 あや, 畠山 鎮次, 福田 諭, 耳鼻咽喉科免疫アレルギー, 33, 2, 38, 39, Jun. 2015
日本耳鼻咽喉科免疫アレルギー学会, Japanese - ベーチェット病感受性遺伝子Tripartite motif protein 39(TRIM39)の機能解析
SUZUKI MASANOBU, SUZUKI MASANOBU, WATANABE MASASHI, NAKAMARU YUJI, TAKAGI DAI, HONMA AYA, HATAKEYAMA SHIGETSUGU, FUKUDA SATOSHI, 日本耳鼻咽喉科免疫アレルギー学会プログラム・抄録集, 33rd, 82, 2015
Japanese - メディエーター複合体のサブユニットMED26はLittle elongation complexをリクルートすることでsnRNA遺伝子の転写を制御する
高橋秀尚, 瀧川一学, 渡部昌, Delnur Anwar, 柴田美音, 佐藤チエリ, 佐藤滋生, Amol Ranjan, Chris W. Seidel, 築山忠維, 水島航, 林正康, 大川恭行, Joan, W. Conaway,Ronal, C. Conaway, 畠山鎮次, 北海道医学雑誌, 90, 1, 76, 76, 2015
Japanese - Ubiquitin modification in otolaryngology
SUZUKI MASANOBU, SUZUKI MASANOBU, WATANABE MASASHI, NAKAMARU YUJI, TAKAGI DAI, KANO SATOSHI, HONMA AYA, HATAKEYAMA SHIGETSUGU, FUKUDA SATOSHI, 耳鼻咽喉科免疫アレルギー(Web), 33, 3, 185-192 (J-STAGE), 2015
Japanese - ベーチェット病感受性遺伝子Tripartite motif protein39(TRIM39)の機能解析
SUZUKI MASANOBU, WATANABE MASASHI, TAKAGI DAI, NAKAMARU YUJI, HATAKEYAMA SHIGETSUGU, FUKUDA SATOSHI, 日本耳鼻咽喉科学会会報, 117, 4, 504, 504, 20 Apr. 2014
(一社)日本耳鼻咽喉科学会, Japanese - Med26はLittle elongation complexをリクルートすることでsmall nuclear RNA遺伝子の発現を制御する
高橋秀尚, 瀧川一学, 渡部昌, ANWAR Delnur, 柴田美音, 佐藤チエリ, 佐藤滋生, RANJAN Amol, SEIDEL Chris, 築山忠維, 林正康, 大川恭行, CONAWAY Joan, CONAWAY Ronald, 畠山鎮次, 日本生化学会大会(Web), 87th, WEB ONLY 2T15P-16(3P-502), 16], 2014
(公社)日本生化学会, Japanese - メディエーター複合体による転写伸長制御
高橋秀尚, 瀧川一学, 渡部昌, ANWAR Delnur, 柴田美音, 佐藤チエリ, 佐藤滋生, RANJAN Amol, SEIDEL Chris W, 築山忠維, 林正康, 大川恭行, CONAWAY Joan, CONAWAY Ronald C, 畠山鎮次, 日本分子生物学会年会プログラム・要旨集(Web), 37th, 1W15-3(1P-0237) (WEB ONLY), 2014
Japanese - Med26はLittle elongation complexをリクルートすることでsmall nuclear RNA遺伝子の発現を制御する
TAKAHASHI Hidehisa, 瀧川一学, ANWAR Delnur, 柴田美音, TOMOMORI‐SATO Chieri, SATO Shigeo, RANJAN Amol, SEIDEL Chris, 築山忠維, 渡部昌, 林正康, 大川恭行, CONAWAY Joan, CONAWAY Ronald, 畠山鎮次, 日本分子生物学会年会プログラム・要旨集(Web), 36th, 1P-0182 (WEB ONLY), 2013
Japanese - ユビキチン修飾系の分子機構と疾患 TRIM型ユビキチンリガーゼと癌―TRIM蛋白質の多様性と特異性
渡部昌, 畠山鎮次, 医学のあゆみ, 243, 6, 508, 514, 10 Nov. 2012
医歯薬出版, Japanese - 「筋萎縮性側索硬化症の病態に基づく画期的治療法の開発」神経突起様伸長及び増殖を制御するTRIM‐EN1/2の機能解析
佐々木秀直, 矢口裕章, 矢口裕章, 奥村文彦, 加納崇裕, 加納崇裕, 渡部昌, 内ケ島基政, 渡邊雅彦, 畠山鎮次, 筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 平成22年度 総括研究報告書, 59-61, 2011
Japanese
Books and other publications
Lectures, oral presentations, etc.
- 自然免疫シグナルに関わるユビキチンリガーゼ群の網羅的な基質同定と解析
渡部 昌, 畠山鎮次
第92回日本生化学会大会, 19 Sep. 2019
[Invited] - The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARgamma
Masashi Watanabe
第39回日本分子生物学会年会, 01 Dec. 2016, English, Nominated symposium
[Invited], [Domestic Conference]
Affiliated academic society
Research Themes
- 新規に開発した基質同定法を用いたがんドライバーユビキチンリガーゼの機能解析
科学研究費助成事業
01 Apr. 2021 - 31 Mar. 2024
渡部 昌, 近藤 豪
(1)がん関連ユビキチンリガーゼ基質同定プローブの作製と安定発現細胞株の樹立:解析対象の18種類のユビキチンリガーゼ遺伝子を入手し、基質を捕獲するためのユビキチンリガーゼプローブをレトロウイルス発現ベクター上に組み込んだ。今年度は変異していない野生型のユビキチンリガーゼ遺伝子について作製を行った。作製したプローブベクターを用いてレトロウイルスを作製し、プローブを安定に発現する細胞株作製を試みたところ、13種類のプローブについて作製に成功した。残り5種については細胞毒性のために作製できなかった。
(2) イオントラップ・オービトラップ型質量分析器による基質・結合分子同定:樹立した13種類の細胞からユビキチン化タンパク質を精製し、高感度質量分析計にて網羅的な同定を行った。具体的には、それぞれの細胞を可溶化し、抗FLAG抗体で免疫沈降を行い、第一段階の精製を行った。トリクロロ酢酸を用いて沈殿後、アセトンによる洗浄、乾燥、ジチオスレイトールにて還元、ヨードアセタミドにてアルキル化を行った後にトリプシンにてペプチドへと分解後、脱塩処理を行った。さらに抗ユビキチンレムナント抗体で再度免疫沈降を行い、第二段階の精製を行い、再度脱塩処理を行った。得られたサンプルについて質量分析を行った。実験は全て3回繰り返した。得られた結果は、過去に我々が行い蓄積している同様の基質同定結果と比較してスコアを算出することで、個々のユビキチンリガーゼ特異的な基質候補を抽出した。抗ユビキチンレムナント抗体について、これまではアガロースビーズに結合したものを使用していたが、今年度はマグネットビーズに結合した抗体についても検討を行い、アガロースビーズと同等またはそれ以上の結果が得られることを確認した。
日本学術振興会, 基盤研究(B), 北海道大学, 21H02690 - Comprehensive identification of polyubiquitinated substrates for elucidation of the "ubiquitin code"
Grants-in-Aid for Scientific Research
28 Jun. 2019 - 31 Mar. 2022
watanabe masashi
Reversible modification of proteins by ubiquitin is one of the important post-translational modifications that support various life phenomena. In recent years, it has been focused on elucidating the relationship between the diverse polyubiquitin chain and its function via the seven lysine residues and amino-terminal methionine in ubiquitin itself. In this study, we developed several probes that efficiently capture polyubiquitin chains and verified their chain specificity. As a result, we obtained several probes that retain various specificities.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 19K22408 - Establishment of method for identification of ubiquitinated protein
Grants-in-Aid for Scientific Research
30 Jun. 2017 - 31 Mar. 2019
Hatakeyama Shigetsugu, TAKAHASHI Hidehisa, WATANABE Masashi
Ubiquitination is a chemical modification that controls protein degradation and is one of the most important post-translational modifications that support many biological phenomena. The reaction system is mediated by ubiquitin ligases (E3) selectively recognizing substrate proteins. Therefore, it is important to identify specific substrates of each E3 and to determine the ubiquitination site of substrate proteins in understanding the biological phenomenon that they are associated with. However, due to various problems, it is still far from standardizing ubiquitinated substrate identification methods. In this study, we challenged to establish a novel technology using TUBE (artificial protein exhibiting high affinity binding to polyubiquitin chain) and ubiquitin remnant antibody allows comprehensive application to various types of ubiquitin ligase (E3) and the E3-substrates relationship was analyzed.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 17K19506 - ゲノムに局在するユビキチン様修飾分子Ufm1による生活習慣病防御機構の解明
科学研究費補助金(若手研究(A))
2016 - 2019
渡部昌
文部科学省, Principal investigator, Competitive research funding - Regulation of signal transduction by TRIM family proteins
Grants-in-Aid for Scientific Research
01 Apr. 2015 - 31 Mar. 2018
Hatakeyama Shigetsugu, TAKAHASHI Hidehisa, WATANABE Masashi
Our previous studies have shown the importance of TRIM family ubiquitin ligase in intracellular signal transduction. Especially, we showed that TRIM family ubiquitin ligase regulates signal transduction involved in cell proliferation and differentiation. Therefore, in this application, we identified and analyzed TRIM family ubiquitin ligases which regulates the ubiquitination in various intracellular signalling pathways. Furthermore, we identified and analyzed candidate genes regulating metabolism and immune signal by comprehensive knockdown of TRIM family genes using their siRNA library.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 15H04690 - 自然免疫シグナルにおけるユビキチン化基質の網羅的同定と解析
科学研究費補助金(新学術領域研究)
2017 - 2018
渡部昌
文部科学省, Principal investigator, Competitive research funding - Devolopment of a novel method to identify E3 ligase substrates
Grants-in-Aid for Scientific Research
2015 - 2016
WATANABE MASASHI
Since ubiquitin ligase (E3) has the substrate specificity of ubiquitination, identifications of specific substrates of each E3 enzymes and of their ubiquitination sites are important for understanding various biological phenomena. In recent years, Toczyski and colleagues have proposed a ligase trap method using a fusion probe of an ubiquitin-binding domain (UBA) and an E3, and Yoshida and colleagues have proposed a TR-TUBE method combining Tandem Ubiquitin Binding Entity (TUBE) and K-εGG-specific antibody. We attempted to develop a more advanced substrate identification method by adding some improvements in their methods and succeeded in improving the sensitivity. By using this method, it is expected that the functional analysis of E3 would be accelerated.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, Principal investigator, Competitive research funding, 15K15058 - The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARgamma
Grants-in-Aid for Scientific Research
2013 - 2014
WATANABE masashi
Adipocyte differentiation is a tightly controlled process regulated by complex transcriptional activators. Multiple adipogenic signals activate early adipogenic activators and facilitate the transient formation of early enhanceosomes at target genes. These enhancer regions are subsequently inherited by the late adipogenic activators, which coordinate the formation of late enhanceosomes. PPARgamma is one of the late adipogenic activators and is considered the master regulator of adipogenesis. We showed that a novel ubiquitin E3 ligase, tripartite motif protein 23 (TRIM23), stabilizes PPARgamma protein and mediates atypical polyubiquitin conjugation. TRIM23 knockdown caused a marked decrease in PPARgamma protein abundance during preadipocyte differentiation, resulting in a severe defect in late adipogenic differentiation, whereas it did not affect the formation of early enhanceosomes. This adipogenic defect is rescued by ectopic expression of PPARgamma.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, Principal investigator, Competitive research funding, 25860201 - ユビキチン化による脂質代謝制御転写因子PPARガンマーの活性化制御機構の解明
科学研究費補助金(研究活動スタート支援)
2012 - 2012
渡部 昌
①PTRIMは直接PPARγをユビキチン化することを解明
申請者は、少なくとも細胞内ではPPARγと結合しユビキチン化を促進するユビキチンリガーゼPTRIMを同定していたが、直接結合することでユビキチン化を促進しているかは明らかではなかった。リコンビナントPTRIM、PPARγを作製し、In vitroユビキチン化アッセイを行ったところ、PTRIMによりPPARγを直接ユビキチン化することを明らかにした。
②免疫沈降法と質量分析器を用いた新たなTRIM23相互作用タンパク質の探索
FLAG-TRIM23タンパク質を細胞内で発現させ、抗FLAG抗体にてプルダウンし、質量分析器にて相互作用分子を探索し、複数の結合タンパク質を得た。このうち、メディエーター複合体サブユニットのMed24が含まれていた。PTRIMがMed24のリクルートを介してPPARγの活性化を調節している可能性が示唆された。
文部科学省, 研究活動スタート支援, 北海道大学, Principal investigator, Competitive research funding, 24890002 - 疾患関連TRIMファミリーユビキチンリガーゼ群の網羅的解析
科学研究費助成事業(特別研究員奨励費)
2009 - 2011
渡部昌
文部科学省, Principal investigator, Competitive research funding