Updated on 2024/11/10

写真a

 
KAKIHARA Yoshito
 
Organization
Academic Assembly Institute of Medicine and Dentistry SHIGAKU KEIRETU Assistant Professor
Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction Assistant Professor
Title
Assistant Professor
External link

Degree

  • 博士(医学) ( 2003.5   大阪大学 )

Research Interests

  • 骨代謝

  • 分子シャペロン

  • Hsp90

  • R2TP complex

  • 口腔癌

Research Areas

  • Life Science / Pharmacology

Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction   Assistant Professor

    2014.7

Studying abroad experiences

  • トロント大学医学部生化学講座   博士研究員

    2005.6 - 2014.6

 

Papers

  • Cell-cell interaction determines cell fate of mesoderm-derived cell in tongue development through Hh signaling. International journal

    Maiko Kawasaki, Katsushige Kawasaki, Finsa Tisna Sari, Takehisa Kudo, Jun Nihara, Madoka Kitamura, Takahiro Nagai, Vanessa Utama, Yoko Ishida, Fumiya Meguro, Alex Kesuma, Akira Fujita, Takayuki Nishimura, Yuan Kogure, Satoshi Maruyama, Jun-Ichi Tanuma, Yoshito Kakihara, Takeyasu Maeda, Sarah Ghafoor, Roman H Khonsari, Pierre Corre, Paul T Sharpe, Martyn Cobourne, Brunella Franco, Atsushi Ohazama

    eLife   13   2024.10

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    Dysfunction of primary cilia leads to genetic disorder, ciliopathies, which shows various malformations in many vital organs such as brain. Multiple tongue deformities including cleft, hamartoma, and ankyloglossia are also seen in ciliopathies, which yield difficulties in fundamental functions such as mastication and vocalization. Here, we found these tongue anomalies in mice with mutation of ciliary protein. Abnormal cranial neural crest-derived cells (CNCC) failed to evoke Hh signal for differentiation of mesoderm-derived cells into myoblasts, which resulted in abnormal differentiation of mesoderm-derived cells into adipocytes. The ectopic adipose subsequently arrested tongue swelling formation. Ankyloglossia was caused by aberrant cell migration due to lack of non-canonical Wnt signaling. In addition to ciliopathies, these tongue anomalies are often observed as non-familial condition in human. We found that these tongue deformities could be reproduced in wild-type mice by simple mechanical manipulations to disturb cellular processes which were disrupted in mutant mice. Our results provide hints for possible future treatment in ciliopathies.

    DOI: 10.7554/eLife.85042

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  • Nutritional Strategies for Chronic Craniofacial Pain and Temporomandibular Disorders: Current Clinical and Preclinical Insights

    Kajita Piriyaprasath, Yoshito Kakihara, Mana Hasegawa, Yuya Iwamoto, Yoko Hasegawa, Noritaka Fujii, Kensuke Yamamura, Keiichiro Okamoto

    Nutrients   16 ( 17 )   2868 - 2868   2024.8

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    This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.

    DOI: 10.3390/nu16172868

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  • Multiomics analysis of cultured mouse periodontal ligament cell-derived extracellular matrix. Reviewed International journal

    Masaru Kaku, Lay Thant, Azusa Dobashi, Yoshiki Ono, Megumi Kitami, Masaru Mizukoshi, Moe Arai, Hajime Iwama, Kohei Kitami, Yoshito Kakihara, Masaki Matsumoto, Isao Saito, Katsumi Uoshima

    Scientific reports   14 ( 1 )   354 - 354   2024.1

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    A comprehensive understanding of the extracellular matrix (ECM) is essential for developing biomimetic ECM scaffolds for tissue regeneration. As the periodontal ligament cell (PDLC)-derived ECM has shown potential for periodontal tissue regeneration, it is vital to gain a deeper understanding of its comprehensive profile. Although the PDLC-derived ECM exhibits extracellular environment similar to that of periodontal ligament (PDL) tissue, details of its molecular composition are lacking. Thus, using a multiomics approach, we systematically analyzed cultured mouse PDLC-derived ECM and compared it to mouse PDL tissue as a reference. Proteomic analysis revealed that, compared to PDL tissue, the cultured PDLC-derived ECM had a lower proportion of fibrillar collagens with increased levels of glycoprotein, corresponding to an immature ECM status. The gene expression signature was maintained in cultured PDLCs and was similar to that in cells from PDL tissues, with additional characteristics representative of naturally occurring progenitor cells. A combination of proteomic and transcriptomic analyses revealed that the cultured mouse PDLC-derived ECM has multiple advantages in tissue regeneration, providing an extracellular environment that closely mimics the environment in the native PDL tissue. These findings provide valuable insights for understanding PDLC-derived ECM and should contribute to the development of biomimetic ECM scaffolds for reliable periodontal tissue regeneration.

    DOI: 10.1038/s41598-023-51054-8

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  • Preventive Roles of Rice-koji Extracts and Ergothioneine on Anxiety- and Pain-like Responses under Psychophysical Stress Conditions in Male Mice. Reviewed International journal

    Kajita Piriyaprasath, Yoshito Kakihara, Atsushi Kurahashi, Mayumi Taiyoji, Kazuya Kodaira, Kotaro Aihara, Mana Hasegawa, Kensuke Yamamura, Keiichiro Okamoto

    Nutrients   15 ( 18 )   2023.9

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    This study determined the effect of daily administration of Rice-koji on anxiety and nociception in mice subjected to repeated forced swim stress (FST). In a parallel experiment, it was determined whether ergothioneine (EGT) contained in Rice-koji displayed similar effects. Anxiety and nociception were assessed behaviorally using multiple procedures. c-Fos and FosB immunoreactivities were quantified to assess the effect of both treatments on neural responses in the paraventricular nucleus of the hypothalamus (PVN), nucleus raphe magnus (NRM), and lumbar spinal dorsal horn (DH). FST increased anxiety- and pain-like behaviors in the hindpaw. Rice-koji or EGT significantly prevented these behaviors after FST. In the absence of formalin, both treatments prevented decreased FosB expressions in the PVN after FST, while no effect was seen in the NRM and DH. In the presence of formalin, both treatments prevented changes in c-Fos and FosB expressions in all areas in FST mice. Further, in vitro experiments using SH-SY5Y cells were conducted. Rice-koji and EGT did not affect cell viability but changed the level of brain-derived neurotrophic factor. In conclusion, Rice-koji could reduce anxiety and pain associated with psychophysical stress, possibly mediated by the modulatory effects of EGT on neural functions in the brain.

    DOI: 10.3390/nu15183989

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  • ストレス伝染は吻側延髄腹側部を変調させる

    Kajita Piriyaprasath, 長谷川 真奈, 柿原 嘉人, 藤井 規孝, 山村 健介, 岡本 圭一郎

    Journal of Oral Biosciences Supplement   2023   [P2 - 08]   2023.9

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  • Effects of stress contagion on anxiogenic- and orofacial inflammatory pain-like behaviors with brain activation in mice. Reviewed International journal

    Kajita Piriyaprasath, Mana Hasegawa, Yoshito Kakihara, Yuya Iwamoto, Rantaro Kamimura, Isao Saito, Noritaka Fujii, Kensuke Yamamura, Keiichiro Okamoto

    European journal of oral sciences   e12942   2023.6

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    The conditions of stress contagion are induced in bystanders without direct experiences of stressful events. This study determined the effects of stress contagion on masseter muscle nociception in mice. Stress contagion was developed in the bystanders after cohabitating with a conspecific mouse subjected to social defeat stress for 10 days. On Day 11, stress contagion increased anxiety- and orofacial inflammatory pain-like behaviors. The c-Fos and FosB immunoreactivities evoked by masseter muscle stimulation were increased in the upper cervical spinal cord, while c-Fos expressions were increased in the rostral ventromedial medulla, including the lateral paragigantocellular reticular nucleus and nucleus raphe magnus in stress contagion mice. The level of serotonin in the rostral ventromedial medulla was increased under stress contagion, while the number of serotonin positive cells was increased in the lateral paragigantocellular reticular nucleus. Stress contagion increased c-Fos and FosB expressions in the anterior cingulate cortex and insular cortex, both of which were positively correlated with orofacial inflammatory pain-like behaviors. The level of brain-derived neurotrophic factor was increased in the insular cortex under stress contagion. These results indicate that stress contagion can cause neural changes in the brain, resulting in increased masseter muscle nociception, as seen in social defeat stress mice.

    DOI: 10.1111/eos.12942

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  • Involvement of Rab11 in osteoblastic differentiation: Its up-regulation during the differentiation and by tensile stress. Reviewed International journal

    Lay Thant, Yoshito Kakihara, Masaru Kaku, Megumi Kitami, Kohei Kitami, Masaru Mizukoshi, Takeyasu Maeda, Isao Saito, Makio Saeki

    Biochemical and biophysical research communications   624   16 - 22   2022.7

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    Rab GTPases, the largest group of small monomeric GTPases, have been shown to participate in membrane trafficking involving many cellular processes. However, their roles during osteoblastic differentiation remain to be elucidated. In this study, we investigated Rab GTPase involvement in osteoblastic differentiation. Protein levels of a series of Rabs (Rab4, Rab5, Rab7, Rab9a, Rab11a/b, and Rab27) were increased during osteoblastic differentiation of MC3T3-E1 cells, and the Rab11a/b levels were particularly pronounced in the presence of Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, an activator of osteoblastogenesis. We subsequently investigated the functional contribution of Rab11a and Rab11b during osteoblastic differentiation. The alkaline phosphatase (ALP) levels were reduced by Rab11b depletion but not by Rab11a depletion. Because our result suggested that Rab11a and Rab11b could be regulated downstream of Runx2 (Runt-related transcription factor 2), a key transcription factor for osteoblastic differentiation, we investigated the effects of the double knockdown of Runx2 and Rab11a or Rab11b on osteoblastic phenotypes. The double knockdown significantly reduced ALP activity as well as collagen deposition compared with single Runx2 knockdown. Furthermore, the Rab11a and Rab11b response to mechanical stress in vivo was investigated using a mouse orthodontic tooth movement model. Rab11a and Rab11b expression was enhanced in the periodontal ligament, where bone formation is activated by tensile stress. This study shows that Rab11a and Rab11b are regulated downstream of Runx2 in osteoblastic differentiation, and their expressions are also controlled by tensile stress.

    DOI: 10.1016/j.bbrc.2022.07.061

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  • Extracellular Matrix-Oriented Proteomic Analysis of Periodontal Ligament Under Mechanical Stress Reviewed

    Lay Thant, Masaru Kaku, Yoshito Kakihara, Masaru Mizukoshi, Megumi Kitami, Moe Arai, Kohei Kitami, Daiki Kobayashi, Yutaka Yoshida, Takeyasu Maeda, Isao Saito, Katsumi Uoshima, Makio Saeki

    Frontiers in Physiology   13   2022.5

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    The periodontal ligament (PDL) is a specialized connective tissue that provides structural support to the tooth and is crucial for oral functions. The mechanical properties of the PDL are mainly derived from the tissue-specific composition and structural characteristics of the extracellular matrix (ECM). The ECM also plays key roles in determining cell fate in the cellular microenvironment thus crucial in the PDL tissue homeostasis. In the present study, we determined the comprehensive ECM profile of mouse molar PDL using laser microdissection and mass spectrometry-based proteomic analysis with ECM-oriented data curation. Additionally, we evaluated changes in the ECM proteome under mechanical loading using a mouse orthodontic tooth movement (OTM) model and analyzed potential regulatory networks using a bioinformatics approach. Proteomic changes were evaluated in reference to the novel second harmonic generation (SHG)-based fiber characterization. Our ECM-oriented proteomics approach succeeded in illustrating the comprehensive ECM profile of the mouse molar PDL. We revealed the presence of type II collagen in PDL, possibly associated with the load-bearing function upon occlusal force. Mechanical loading induced unique architectural changes in collagen fibers along with dynamic compositional changes in the matrisome profile, particularly involving ECM glycoproteins and matrisome-associated proteins. We identified several unique matrisome proteins which responded to the different modes of mechanical loading in PDL. Notably, the proportion of type VI collagen significantly increased at the mesial side, contributing to collagen fibrogenesis. On the other hand, type XII collagen increased at the PDL-cementum boundary of the distal side. Furthermore, a multifaceted bioinformatics approach illustrated the potential molecular cues, including PDGF signaling, that maintain ECM homeostasis under mechanical loading. Our findings provide fundamental insights into the molecular network underlying ECM homeostasis in PDL, which is vital for clinical diagnosis and development of biomimetic tissue-regeneration strategies.

    DOI: 10.3389/fphys.2022.899699

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  • Preclinical models of deep craniofacial nociception and temporomandibular disorder pain Reviewed

    Keiichiro Okamoto, Mana Hasegawa, Kajita Piriyaprasath, Yoshito Kakihara, Makio Saeki, Kensuke Yamamura

    Japanese Dental Science Review   57   231 - 241   2021.11

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    DOI: 10.1016/j.jdsr.2021.10.002

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  • Effects of rice fermented extracts, "Sake Lees", on the functional activity of odontoblast-like cells (KN-3 cells). Reviewed

    Keiichiro Okamoto, Yoshito Kakihara, Naoto Ohkura, Aiko Tohma, Ayako Washio, Chiaki Kitamura, Yuichiro Noiri, Kensuke Yamamura, Makio Saeki

    Odontology   110 ( 2 )   254 - 261   2021.9

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    This study was designed to investigate the effects of Sake Lees extracts (SLE, Sake Kasu) on the functional activity of odontoblastic cells and tooth pulp of the rats. For in vitro studies, a rat clonal odontoblast-like cell line, KN-3 cells were cultured. SLE significantly decreased KN-3 cell proliferation, but showed no significant cytotoxicity. SLE effects on several protein productions of KN-3 cells were compared with PBS. SLE and PBS increased alkaline phosphatase (ALP), dentin sialoprotein (DSP), and osterix in a day-course dependent manner, while SLE increased the induction of ALP on day 9-21 and DSP on day 15-21. SLE also increased Runx2 expression on day 3 and 9 compared to PBS. Alizarin Red stainings revealed that SLE showed a subtle increase in mineralization of KN-3 cells on day 15 and 21. A histological investigation was conducted to assess if SLE induced reparative dentin formation after direct capping at the exposed tooth pulp in rats, suggesting that SLE could increase the reparative dentin formation more than PBS. These findings suggest that Sake Lees could have functional roles in the alterations of odontoblastic activity, which might influence the physiology of the tooth pulp.

    DOI: 10.1007/s10266-021-00654-9

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  • HEATR1, a novel interactor of Pontin/Reptin, stabilizes Pontin/Reptin and promotes cell proliferation of oral squamous cell carcinoma Reviewed

    Akihiko Nakamura, Yoshito Kakihara, Akinori Funayama, Kenta Haga, Toshihiko Mikami, Daiki Kobayashi, Yutaka Yoshida, Kenji Izumi, Tadaharu Kobayashi, Makio Saeki

    Biochemical and Biophysical Research Communications   557   294 - 301   2021.6

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    DOI: 10.1016/j.bbrc.2021.04.021

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  • Identification and characterization of R2TP in the development of oral squamous cell carcinoma Reviewed

    Tetsuo Kiguchi, Yoshito Kakihara, Manabu Yamazaki, Kouji Katsura, Kenji Izumi, Jun-ichi Tanuma, Takashi Saku, Ritsuo Takagi, Makio Saeki

    Biochemical and Biophysical Research Communications   548   161 - 166   2021.4

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    DOI: 10.1016/j.bbrc.2021.02.074

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  • Reptinは胎仔上皮におけるDNA損傷応答を介して器官形成を制御する

    目黒 史也, 柿原 嘉人, 川崎 真依子, 川崎 勝盛, 丹原 惇, トゥラカナン・スッパラック, 工藤 武久, 山田 茜, 前田 健康, 多部田 康一, 佐伯 万騎男, 大峡 淳

    新潟歯学会雑誌   50 ( 2 )   115 - 116   2020.12

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  • HEATR1はPontin/Reptinを安定化させmTORシグナル経路を介してOSCC細胞の増殖を正に制御する

    中村 彬彦, 柿原 嘉人, 船山 昭典, 小林 正治, 佐伯 万騎男

    新潟歯学会雑誌   50 ( 2 )   111 - 111   2020.12

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  • Construction of an artificial system for ambrein biosynthesis and investigation of some biological activities of ambrein. Reviewed International journal

    Yota Yamabe, Yukina Kawagoe, Kotone Okuno, Mao Inoue, Kanako Chikaoka, Daijiro Ueda, Yuko Tajima, Tadasu K Yamada, Yoshito Kakihara, Takashi Hara, Tsutomu Sato

    Scientific reports   10 ( 1 )   19643 - 19643   2020.11

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    Ambergris, a sperm whale metabolite, has long been used as a fragrance and traditional medication, but it is now rarely available. The odor components of ambergris result from the photooxidative degradation of the major component, ambrein. The pharmacological activities of ambergris have also been attributed to ambrein. However, efficient production of ambrein and odor compounds has not been achieved. Here, we constructed a system for the synthesis of ambrein and odor components. First, we created a new triterpene synthase, "ambrein synthase," for mass production of ambrein by redesigning a bacterial enzyme. The ambrein yields were approximately 20 times greater than those reported previously. Next, an efficient photooxidative conversion system from ambrein to a range of volatiles of ambergris was established. The yield of volatiles was 8-15%. Finally, two biological activities, promotion of osteoclast differentiation and prevention of amyloid β-induced apoptosis, were discovered using the synthesized ambrein.

    DOI: 10.1038/s41598-020-76624-y

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  • リボソーム合成関連因子HEATR1は、Pontin/Reptin complexと共に口腔扁平上皮癌進展に寄与する

    中村 彬彦, 木口 哲郎, 高木 律男, 船山 昭典, 小林 正治, 柿原 嘉人, 佐伯 万騎男

    日本口腔科学会雑誌   69 ( 2 )   132 - 132   2020.7

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  • ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation. Reviewed International journal

    Juri Nakata, Yosuke Akiba, Jun Nihara, Lay Thant, Kaori Eguchi, Hiroko Kato, Kenji Izumi, Mariko Ohkura, Masanori Otake, Yoshito Kakihara, Isao Saito, Makio Saeki

    Biochemical and biophysical research communications   526 ( 3 )   547 - 552   2020.6

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    Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chemical compounds that enhance turnover of bone metabolism for promoting bone healing. First, we screen a chemical library which includes 378 compounds by using murine pre-osteoclastic RAW264.7 cells to identify compounds that promote osteoclastic differentiation. We find that two ROCK (Rho-associated coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compounds also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo experiment shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.

    DOI: 10.1016/j.bbrc.2020.03.033

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  • Daily administration of Sake Lees (Sake Kasu) reduced psychophysical stress-induced hyperalgesia and Fos responses in the lumbar spinal dorsal horn evoked by noxious stimulation to the hindpaw in the rats. Reviewed

    Shimizu S, Nakatani Y, Kakihara Y, Taiyoji M, Saeki M, Takagi R, Yamamura K, Okamoto K

    Bioscience, biotechnology, and biochemistry   84 ( 1 )   159 - 170   2020.1

  • R2TP/PAQosome as a promising chemotherapeutic target in cancer Invited Reviewed

    Kakihara Y, Kiguchi T, Ohazama A, Saeki M

    Japanese Dental Science Review   56 ( 1 )   38 - 42   2019.12

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  • 口腔扁平上皮癌における新規分子シャペロンR2TPの機能解析

    柿原 嘉人, 木口 哲郎, 高木 律男, 佐伯 万騎男

    有病者歯科医療   28 ( 6 )   424 - 424   2019.12

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  • Pontin-Reptin complexは、リボソーム合成関連因子HEATR1を安定化することで口腔扁平上皮癌進展に寄与する

    中村 彬彦, 木口 哲郎, 船山 昭典, 柿原 嘉人, 佐伯 万騎男

    Journal of Oral Biosciences Supplement   2019   161 - 161   2019.10

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  • Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. Reviewed

    El Bakkouri M, Kouidmi I, Wernimont AK, Amani M, Hutchinson A, Loppnau P, Kim JJ, Flueck C, Walker JR, Seitova A, Senisterra G, Kakihara Y, Kim C, Blackman MJ, Calmettes C, Baker DA, Hui R

    Proceedings of the National Academy of Sciences of the United States of America   116 ( 28 )   14164 - 14173   2019.7

  • Bmp signaling in molar cusp formation. Reviewed International journal

    Fumiya Meguro, Thantrira Porntaveetus, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Yoshito Kakihara, Makio Saeki, Koichi Tabeta, John A Kessler, Takeyasu Maeda, Atsushi Ohazama

    Gene expression patterns : GEP   32   67 - 71   2019.6

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    Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.

    DOI: 10.1016/j.gep.2019.04.002

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  • Fusaspirols A-D, novel oxaspirol derivatives isolated from Fusarium solani B-18 Reviewed

    Ariefta Nanang Rudianto, Nikmawahda, Hasna Tazkia, Aboshi Takako, Murayama Tetsuya, Tawaraya Keitaro, Koseki Takuya, Katagi Genta, Kakihara Yoshito, Shiono Yoshihito

    TETRAHEDRON   75 ( 10 )   1371 - 1377   2019.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    Four novel compounds with gamma-methylidene-spirobutanolide core, fusaspirols A-D, were isolated from the brown rice culture of Fusarium solani B-18. Their structures were established by extensive spectroscopic analyses of 1D/2D-NMR, HRESITOFMS, and chemical derivatization. The absolute configurations of secondary alcohols in fusaspirols A and D were determined using modified Mosher's ester method. Fusaspirol A and 4,9-di-O-acetylfusaspirol A activated a signaling pathway in osteoclastic differentiation of murine macrophage derived RAW264.7 cells. (C) 2019 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2019.01.052

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  • 口腔扁平上皮癌における新規分子シャペロンR2TPの機能解析

    柿原 嘉人, 木口 哲郎, 高木 律男, 佐伯 万騎男

    歯科薬物療法   38 ( 2 )   121 - 121   2019.3

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  • 分子シャペロンR2TP complexの口腔扁平上皮癌進展における作用機序の解析

    木口 哲郎, 柿原 嘉人, 永田 昌毅, 佐伯 万騎男, 高木 律男

    新潟歯学会雑誌   48 ( 2 )   119 - 120   2018.12

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  • Japanese Rice Wine can reduce psychophysical stress-induced depression-like behaviors and Fos expression in the trigeminal subnucleus caudalis evoked by masseter muscle injury in the rats. Reviewed

    Nakatani Y, Kakihara Y, Shimizu S, Kurose M, Sato T, Kaneoke M, Saeki M, Takagi R, Yamamura K, Okamoto K

    Bioscience, biotechnology, and biochemistry   83 ( 1 )   1 - 11   2018.10

  • 分子シャペロンR2TPの口腔扁平上皮癌(OSCC)進展における作用機序の解析

    木口 哲郎, 柿原 嘉人, 高木 律男, 佐伯 万騎男

    Journal of Oral Biosciences Supplement   2018   141 - 141   2018.9

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  • Systems analysis of the genetic interaction network of yeast molecular chaperones Reviewed

    Rizzolo Kamran, Kumar Ashwani, Kakihara Yoshito, Phanse Sadhna, Minic Zoran, Snider Jamie, Stagljar Igor, Zilles Sandra, Babu Mohan, Houry Walid A

    MOLECULAR OMICS   14 ( 2 )   82 - 94   2018.4

  • The effect of ROCK inhibitor on bone remodeling Reviewed

    Juri Nakata, Yosuke Akiba, Kaori Eguchi, Jun Nihara, Isao Saito, Yoshito Kakihara, Makio Saeki

    JOURNAL OF BONE AND MINERAL RESEARCH   32   S229 - S229   2017.12

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  • Features of the Chaperone Cellular Network Revealed through Systematic Interaction Mapping Reviewed

    Kamran Rizzolo, Jennifer Huen, Ashwani Kumar, Sadhna Phanse, James Vlasblom, Yoshito Kakihara, Hussein A. Zeineddine, Zoran Minic, Jamie Snider, Wen Wang, Carles Pons, Thiago V. Seraphim, Edgar Erik Boczek, Simon Alberti, Michael Costanzo, Chad L. Myers, Igor Stagljar, Charles Boone, Mohan Babu, Walid A. Houry

    CELL REPORTS   20 ( 11 )   2735 - 2748   2017.9

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    A comprehensive view of molecular chaperone function in the cell was obtained through a systematic global integrative network approach based on physical (protein-protein) and genetic (gene-gene or epistatic) interaction mapping. This allowed us to decipher interactions involving all core chaperones (67) and cochaperones (15) of Saccharomyces cerevisiae. Our analysis revealed the presence of a large chaperone functional supercomplex, which we named the naturally joined (NAJ) chaperone complex, encompassing Hsp40, Hsp70, Hsp90, AAA+, CCT, and small Hsps. We further found that many chaperones interact with proteins that form foci or condensates under stress conditions. Using an in vitro reconstitution approach, we demonstrate condensate formation for the highly conserved AAA+ ATPases Rvb1 and Rvb2, which are part of the R2TP complex that interacts with Hsp90. This expanded view of the chaperone network in the cell clearly demonstrates the distinction between chaperones having broad versus narrow substrate specificities in protein homeostasis.

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  • GSK-3 beta inhibitory activities of novel dichroloresorcinol derivatives from Cosmospora vilior isolated from a mangrove plant Reviewed

    Yoshihito Shiono, Nozomi Miyazaki, Tetsuya Murayama, Takuya Koseki, Harizon, Dewa Gede Katja, Unang Supratman, Juri Nakata, Yoshito Kakihara, Makio Saeki, Jun Yoshida, Shota Uesugi, Ken-ichi Kimura

    PHYTOCHEMISTRY LETTERS   18   122 - 127   2016.12

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    Cosmochlorins A (1), B (2), and C (3) were isolated from the endophytic fungus Cosmospora vilior IM2-155. The structures of 1, 2, and 3 were elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR, HRESITOFMS, and chemical reactions. Compounds 1, 2, and 3 were evaluated for their biological activity. Compounds 1 and 2 partially restored the growth inhibition caused by hyperactivated Ca2+-signaling in mutant yeast and showed glycogen synthase kinase (GSK)-3b inhibition activity at IC50 values of 62.5 and 60.6 mu M, respectively. Further, compound 2 significantly increased osteoclast formation by more than 1.5-fold in RAW264.7 cells compared to receptor activator of nuclear factor-kB ligand (RANKL) alone. (C) 2016 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved.

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  • The inhibitors of cyclin-dependent kinases and GSK-3β enhance osteoclastogenesis Reviewed

    Yosuke Akiba, Akiko Mizuta, Yoshito Kakihara, Juri Nakata, Jun Nihara, Isao Saito, Hiroshi Egusa, Makio Saeki

    Biochemistry and Biophysics Reports   5   253 - 258   2016.3

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    © 2016 The Authors. Published by Elsevier B.V. Osteoclasts are multinucleated cells with bone resorption activity that is crucial for bone remodeling. RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling has been shown as a main signal pathway for osteoclast differentiation. However, the molecular mechanism and the factors regulating osteoclastogenesis remain to be fully understood. In this study, we performed a chemical genetic screen, and identified a Cdks/GSK-3β (cyclin-dependent kinases/glycogen synthase kinase 3β) inhibitor, kenpaullone, and two Cdks inhibitors, olomoucine and roscovitine, all of which significantly enhance osteoclastogenesis of RAW264.7 cells by upregulating NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) levels. We also determined that the all three compounds increase the number of osteoclast differentiated from murine bone marrow cells. Furthermore, the three inhibitors, especially kenpaullone, promoted maturation of cathepsin K, suggesting that the resorption activity of the resultant osteoclasts is also activated. Our findings indicate that inhibition of GSK-3β and/or Cdks enhance osteoclastogenesis by modulating the RANK-RANKL signaling pathway.

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  • Discovering novel drugs for modulating osteoclastogenesis Reviewed

    Kakihara Yoshito, Nakata Juni, Kiyokawa Yuki, Yamashita Naoyuki, Shiono Yoshihito, Saeki Makio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   130 ( 3 )   S208   2016.3

  • The effect of CDK inhibitors on osteoclast differentiation Reviewed

    Yoshito Kakihara, Juri Nakata, Yosuke Akiba, Hiroshi Egusa, Makio Saeki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   128 ( 3 )   S242 - S242   2015.7

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  • The R2TP chaperone complex: Its involvement in snoRNP assembly and tumorigenesis Reviewed

    Yoshito Kakihara, Makio Saeki

    Biomolecular Concepts   5 ( 6 )   513 - 520   2014.12

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    R2TP was originally identified in yeast Saccharomyces cerevisiae as Hsp90 interacting complex, and is composed of four different proteins: Rvb1, Rvb2, Tah1, and Pih1. This complex is well-conserved in eukaryotes, and is involved in many cellular processes such as snoRNP biogenesis, RNA polymerase assembly, PIKK signaling, and apoptosis. An increasing number of research related to R2TP suggests a linkage of its function with tumorigenesis. In this review, we provide an overview of several recent studies on R2TP that are related to cell proliferation and carcinogenesis, and propose a possible role of R2TP in tumorigenesis through regulating snoRNA/snoRNP biogenesis.

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  • Nutritional status modulates box C/D snoRNP biogenesis by regulated subcellular relocalization of the R2TP complex. Reviewed

    Kakihara Y, Makhnevych T, Zhao L, Tang W, Houry WA

    Genome biology   15 ( 7 )   404   2014.7

  • Nutritional status modulates box C/D snoRNP biogenesis by regulated subcellular relocalization of the R2TP complex Reviewed

    Yoshito Kakihara, Taras Makhnevych, Liang Zhao, Weiwen Tang, Walid A. Houry

    GENOME BIOLOGY   15 ( 7 )   2014

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    Background: Box C/D snoRNPs, which are typically composed of box C/D snoRNA and the four core protein components Nop1, Nop56, Nop58, and Snu13, play an essential role in the modification and processing of pre-ribosomal RNA. The highly conserved R2TP complex, comprising the proteins Rvb1, Rvb2, Tah1, and Pih1, has been shown to be required for box C/D snoRNP biogenesis and assembly; however, the molecular basis of R2TP chaperone-like activity is not yet known.
    Results: Here, we describe an unexpected finding in which the activity of the R2TP complex is required for Nop58 protein stability and is controlled by the dynamic subcellular redistribution of the complex in response to growth conditions and nutrient availability. In growing cells, the complex localizes to the nucleus and interacts with box C/D snoRNPs. This interaction is significantly reduced in poorly growing cells as R2TP predominantly relocalizes to the cytoplasm. The R2TP-snoRNP interaction is mainly mediated by Pih1.
    Conclusions: The R2TP complex exerts a novel regulation on box C/D snoRNP biogenesis that affects their assembly and consequently pre-rRNA maturation in response to different growth conditions.

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  • PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription Reviewed

    Yuya Kamano, Makio Saeki, Hiroshi Egusa, Yoshito Kakihara, Walid A. Houry, Hirofumi Yatani, Yoshinori Kamisaki

    FEBS Letters   587 ( 20 )   3303 - 3308   2013.10

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    PIH1D1 is the defining component of the R2TP complex. Recently, R2TP has been reported to stabilize mTOR (mammalian target of rapamycin), an important regulator of cell growth and protein synthesis. Two complexes of mTOR, mTORC1 and mTORC2, have been identified. We demonstrate that immunoprecipitation (IP) of PIH1D1 results in the co-IP of Raptor (mTORC1 specific), but not Rictor (mTORC2 specific), and that knockdown of PIH1D1 decreases mTORC1 assembly, S6 kinase phosphorylation (indicator of mTORC1 activity), and rRNA transcription without affecting mTORC2 in human breast cancer MCF-7 cells. In addition, we provide evidence that PIH1D1 is overexpressed in various breast cancer cell lines. These findings collectively suggest that PIH1D1 may have an important role in mTORC1 regulation in breast cancers. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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  • Exosome-Bound WD Repeat Protein Monad Inhibits Breast Cancer Cell Invasion by Degrading Amphiregulin mRNA Reviewed

    Makio Saeki, Hiroshi Egusa, Yuya Kamano, Yoshito Kakihara, Walid A. Houry, Hirofumi Yatani, Shinzaburo Noguchi, Yoshinori Kamisaki

    PLOS ONE   8 ( 7 )   e67326   2013.7

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    Increased stabilization of mRNA coding for key cancer genes can contribute to invasiveness. This is achieved by down-regulation of exosome cofactors, which bind to 3'-UTR in cancer-related genes. Here, we identified amphiregulin, an EGFR ligand, as a target of WD repeat protein Monad, a component of R2TP/prefoldin-like complex, in MDA-MB-231 breast cancer cells. Monad specifically interacted with both the 3'-UTR of amphiregulin mRNA and the RNA degrading exosome, and enhanced decay of amphiregulin transcripts. Knockdown of Monad increased invasion and this effect was abolished with anti-amphiregulin neutralizing antibody. These results suggest that Monad could prevent amphiregulin-mediated invasion by degrading amphiregulin mRNA.

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  • The R2TP complex: discovery and functions. Reviewed

    Kakihara Y, Houry WA

    Biochimica et biophysica acta   1823 ( 1 )   101 - 107   2012.1

  • Alternative Oligomeric States of the Yeast Rvb1/Rvb2 Complex Induced by Histidine Tags Reviewed

    Kevin L. Y. Cheung, Jennifer Huen, Yoshito Kakihara, Walid A. Houry, Joaquin Ortega

    JOURNAL OF MOLECULAR BIOLOGY   404 ( 3 )   478 - 492   2010.12

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    Rvb1 and Rvb2 are essential AAA(+) (ATPases associated with diverse cellular activities) helicases, which are important components of critical complexes such as chromatin remodeling and telomerase complexes. The oligomeric state of the Rvb proteins has been controversial. Independent studies from several groups have described the yeast and human Rvb1/Rvb2 complex both as a single and as a double hexameric ring complex. We found that histidine-tagged constructs of yeast Rvb proteins employed in some of these studies induced the assembly of double hexameric ring Rvb1/Rvb2 complexes. Instead, untagged versions of these proteins assemble into single hexameric rings. Furthermore, purified endogenous untagged Rvb1/Rvb2 complexes from Saccharomyces cerevisiae were also found as single hexameric rings, similar to the complexes assembled in vitro from the purified untagged components. These results demonstrate that some of the differences between the reported structures are caused by histidine tags and imply that further studies on the purified proteins should be carried out using untagged constructs. (c) 2010 Elsevier Ltd. All rights reserved.

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  • Rvb1-Rvb2: essential ATP-dependent helicases for critical complexes Reviewed

    Jennifer Huen, Yoshito Kakihara, Francisca Ugwu, Kevin L. Y. Cheung, Joaquin Ortega, Walid A. Houry

    BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE   88 ( 1 )   29 - 40   2010.2

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  • An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell Reviewed

    Yunchen Gong, Yoshito Kakihara, Nevan Krogan, Jack Greenblatt, Andrew Emili, Zhaolei Zhang, Walid A. Houry

    MOLECULAR SYSTEMS BIOLOGY   5   2009.6

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    Molecular chaperones are known to be involved in many cellular functions, however, a detailed and comprehensive overview of the interactions between chaperones and their cofactors and substrates is still absent. Systematic analysis of physical TAP-tag based protein-protein interactions of all known 63 chaperones in Saccharomyces cerevisiae has been carried out. These chaperones include seven small heat-shock proteins, three members of the AAA+ family, eight members of the CCT/TRiC complex, six members of the prefoldin/GimC complex, 22 Hsp40s, 1 Hsp60, 14 Hsp70s, and 2 Hsp90s. Our analysis provides a clear distinction between chaperones that are functionally promiscuous and chaperones that are functionally specific. We found that a given protein can interact with up to 25 different chaperones during its lifetime in the cell. The number of interacting chaperones was found to increase with the average number of hydrophobic stretches of length between one and five in a given protein. Importantly, cellular hot spots of chaperone interactions are elucidated. Our data suggest the presence of endogenous multicomponent chaperone modules in the cell. Molecular Systems Biology 5: 275; published online 16 June 2009; doi: 10.1038/msb.2009.26

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  • Molecular chaperone Hsp90 stabilizes Pih1/Nop 17 to maintain R2TP complex activity that regulates snoRNA accumulation Reviewed

    Rongmin Zhao, Yoshito Kakihara, Anna Gribun, Jennifer Huen, Guocheng Yang, May Khanna, Michael Costanzo, Renee L. Brost, Charles Boone, Timothy R. Hughes, Christopher M. Yip, Walid A. Houry

    JOURNAL OF CELL BIOLOGY   180 ( 3 )   563 - 578   2008.2

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    Hsp90 is a highly conserved molecular chaperone that is involved in modulating a multitude of cellular processes. In this study, we identify a function for the chaperone in RNA processing and maintenance. This functionality of Hsp90 involves two recently identified interactors of the chaperone: Tah 1 and Pih1/Nop17. Tah1 is a small protein containing tetra tricopeptide repeats, whereas Pih1 is found to be an unstable protein. Tah1 and Pih1 bind to the essential helicases Rvb1 and Rvb2 to form the R2TP complex, which we demonstrate is required for the correct accumulation of box C/D small nucleolar ribonucleoproteins. Together with the Tah1 cofactor, Hsp90 functions to stabilize Pih1. As a consequence, the chaperone is shown to affect box C/D accumulation and maintenance, especially under stress conditions. Hsp90 and R2TP proteins are also involved in the proper accumulation of box H/ACA small nucleolar RNAs.

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  • Screening of drugs that suppress Ste11 MAPKKK activation in yeast identified a c-Abl tyrosine kinase inhibitor Reviewed

    Takao Kitagawa, Yuko Hashizume, Tatsuhiko Murakane, Emi Koga, Yuki Nomura, Yoshito Kakihara, Ayako Fujieda, Motoyuki Uchida, Hidetoshi Takahashi, Hisashi Hoshida, Rinji Akada

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   71 ( 3 )   772 - 782   2007.3

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    The yeast MAPKKK Ste11 activates three MAP kinase pathways, including pheromone signaling, osmo-sensing, and pseudohyphal/invasive growth pathways. We identified two chemical compounds, BTB03006 and GK03225, that suppress growth defects induced by Ste11 activation in diploid yeast cells. BTB03006, but not GK03225, was found to suppress growth defects induced by both a-factor and Ste4 G(beta) overexpression in the pheromone signaling pathway, suggesting that GK03225 is an osmosensing pathway-specific inhibitor. We also performed genome-wide suppressor analysis for Ste11 activation, using a yeast deletion strains collection, and identified PBS2 and HOG1, and several genes associated with chaperone functions, which represent potential target proteins of the drugs screened from Ste11 activation. GK03225 possesses an Iressa-like quinazoline ring structure, and its chemical analog, 11N-078, suppresses c-Abl human tyrosine kinase activity. These results suggest that drug screening in yeast can identify human tyrosine kinase inhibitors and other drugs for human diseases.

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  • PCR-mediated seamless gene deletion and marker recycling in Saccharomyces cerevisiae Reviewed

    R Akada, T Kitagawa, S Kaneko, D Toyonaga, S Ito, Y Kakihara, H Hoshida, S Morimura, A Kondo, K Kida

    YEAST   23 ( 5 )   399 - 405   2006.4

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    Repeated gene manipulations can be performed in yeast by excision of an introduced marker. Cassette modules containing a marker flanked by two direct repeat sequences of hisG or loxP have often been used for marker recycling, but these leave one copy of the repeats in the chromosome after excision. Genomic copies of a repeat can cause increased mistargeting of constructs containing the same repeats or unexpected chromosomal rearrangements via intra- or interchromosomal recombi nations. Here, we describe a novel marker recycling procedure that leaves no scar in the genome, which we have designated seamless gene deletion. A 40 base sequence derived from an adjacent region to the targeted locus was placed in an integrating construct to generate direct repeats after integration. Seamless HIS3 deletion was achieved via a PCR fragment that consisted of a URA3 marker attached to a 40 base repeat-generating sequence flanked by HIS3 targeting sequences at both ends. Transformation of the designed construct resulted in his3 disruption and the generation of 40 base direct repeats on both sides of URA3 in the targeted locus. The resulting his3::URA3 disruptants were plated on 5-fluoroorotic acid medium to select for URA3 loss. All the selected colonies had lost URA3 precisely by recombination between the repeats, resulting in his3 deletion without any extraneous sequences left behind in the chromosome. Copyright (c) 2006 John Wiley & Sons, Ltd.

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  • Cost-saving design of PCR primers containing additional sequences Reviewed

    Y. Kakihara

    ITE letters   6 ( 2 )   135 - 139   2005

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  • Overlapping omt1(+) and omt2(+) genes are required for spore wall maturation in Schizosaccharomyces pombe Reviewed

    Y Kakihara, K Nabeshima, A Hirata, H Nojima

    GENES TO CELLS   8 ( 6 )   547 - 558   2003.6

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    Background: Overlapping genes that are transcribed from the same genomic regions are rare in eukaryotes and to date few detailed functional analyses have been reported.
    Results: We report here three novel overlapping transcripts that are specifically expressed during meiosis of Schizosaccharomyces pombe . They are denoted as omt1 (+) , omt2 (+) and omt3 (+) after o verlapping m eiotic transcripts. omt1 (+) encodes a 12-kDa protein and omt2 (+) encodes a 11-kDa protein with homology to the bifunctional mammalian protein DCoH/PCBD. omt3 (+) does not have a significant open reading frame. The omt2 (+) transcript overlaps with both the omt1 (+) and omt3 (+) transcripts but the latter two transcripts do not overlap. omt1Delta and omt2Delta but not omt3Delta failed to form mature spore walls. The Omt1-GFP and Omt2-GFP fusion proteins localized to the outside and the inside of the spore walls, respectively. The sporulation-specific protein Meu10 and the spore wall components were abnormally localized in the spore walls of omt1Delta and omt2Delta .
    Conclusion: The overlapping genes omt1 (+) and omt2 (+) express functional proteins that participate in spore wall maturation, indicating that gene overlap does not affect the physiological functions of the proteins encoded by these genes. Generation of overlapped RNA may be due to loose regulation of transcription termination during meiosis of S. pombe .

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  • Meu10 is required for spore wall maturation in Schizosaccharomyces pombe Reviewed

    T Tougan, Y Chiba, Y Kakihara, A Hirata, H Nojima

    GENES TO CELLS   7 ( 2 )   217 - 231   2002.2

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    Background: Many genes are meiosis and/or sporulation-specifically transcribed during this process. Isolation and analysis of these genes might help us to understand how meiosis and sporulation are regulated. For this purpose, we have isolated a large number of cDNA clones from Schizosaccharomyces pombe whose expression is up-regulated during meiosis.
    Results: We have isolated meu10(+) gene, which encodes 416 amino acids and bears homology to SPS2 of Saccharomyces cerevisiae. A strain whose meu10(+) gene has been deleted forms no viable spores. Thin-section electron micrographs showed that the meu10Delta strain has abnormally formed spore walls, and then they disrupt, allowing cytoplasmic material to escape. The Meu10-GFP fusion protein is localized to the spore periphery, thereafter returned to the cytoplasm after sporulation. Meu10-GFP localization to the spore wall was almost normal in the bgs2Delta or chs1Delta mutants that lack 1,3-beta-glucan or chitin, respectively. In contrast, 1,3-beta-glucan is abnormally localized in meu10Delta cells. Meu10 has an N-terminal domain with homology to the mammalian insulin receptor and a C-terminal domain with a transmembrane motif. Mutants whose N-terminal or C-terminal domain was truncated were severely defective for sporulation.
    Conclusions: Meu10 is a spore wall component and plays a pivotal role in the formation of the mature spore wall structure.

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  • A novel meiosis-specific protein of fission yeast, Meu13p, promotes homologous pairing independently of homologous recombination Reviewed

    K Nabeshima, Y Kakihara, Y Hiraoka, H Nojima

    EMBO JOURNAL   20 ( 14 )   3871 - 3881   2001.7

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    Meiotic homologous pairing is crucial to proper homologous recombination, which secures subsequent reductional chromosome segregation. We have identified a novel meiosis-specific protein of fission yeast Schizosaccharomyces pombe, Meu13p, to be a molecule that is required for proper homologous pairing and recombination. Rec12p (homologue of Saccharomyces cerevisiae Spo11p), which is essential for the initiation of meiotic recombination, is also shown for the first time to participate in the pairing process of S. pombe. Meu13p, however, contributes to pairing through a recombination-independent mechanism, as disruption of the meu13(+) gene reduces pairing whether the rec12(+) gene is deleted or not. We also demonstrate a dynamic nature of homologous pairing in living meiotic cells, which is markedly affected by meu13 deletion. Meu13p is not required for telomere clustering and the nuclear movement process, which are well known requirements for efficient pairing in S. pombe. Based on these results, together with the localization of Meu13p on meiotic chromatin, we propose that Meu13p directly promotes proper homologous pairing and recombination.

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  • Comprehensive isolation of meiosis-specific genes identifies novel proteins and unusual non-coding transcripts in Schizosaccharomyces pombe Reviewed

    T Watanabe, K Miyashita, TT Saito, T Yoneki, Y Kakihara, K Nabeshima, YA Kishi, C Shimoda, H Nojima

    NUCLEIC ACIDS RESEARCH   29 ( 11 )   2327 - 2337   2001.6

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    In order to isolate meiosis-specific genes in Schizosaccharomyces pombe, we have constructed a subtracted cDNA library enriched in clones whose expression is enhanced during meiosis induced by nitrogen starvation. Using northern blot analysis, we isolated 31 kinds of clones whose expression was induced in a meiosis/sporulation-specific manner. We comprehensively named them meu after meiotic expression upregulated, The transcription of 20 meu genes was found to be dependent on the mei4+ gene, which encodes a transcription factor required for the progression of meiosis, DNA sequencing indicated that most of the meu genes encode novel proteins, Notably, five of the meu genes harbor no apparent protein coding sequences, and the transcripts form stable hairpin structures, suggesting that they may generate non-coding RNAs or antisense RNAs, The results presented here imply that RNAs are also important for the comprehensive characterization of genomic expression.

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  • Characterization of rec7, an early meiotic recombination gene in Schizosaccharomyces pombe Reviewed

    M Molnar, S Parisi, Y Kakihara, H Nojima, A Yamamoto, Y Hiraoka, A Bozsik, M Sipiczki, J Kohli

    GENETICS   157 ( 2 )   519 - 532   2001.2

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    rec7 is involved in intra- and intergenic meiotic recombination in all tested regions of the genome of the fission yeast Schizosaccharomyces pombe. Segregational analysis in a rec7 gene disruption mutant revealed frequent occurrence of two-spored asci. Spores giving rise to diploid colonies were shown to derive from skipping of the second meiotic division. Nondisjunction of homologous chromosomes at the first meiotic division was also frequent. The cytological structures and processes, such as formation of linear elements, pairing of homologous chromosomes, and clustering of telomeres and centromeres, are regular in the mutant. Northern blot experiments revealed meiosis-specific expression of rec7. Screening of a meiotic cDNA library also identified transcripts from the opposite strand in the rec7 region. A Rec7-GFP fusion protein was localized in the nucleus of whole cells before karyogamy, during prophase, and after meiosis I. On spreads of prophase nuclei approximately 50 foci of Rec7-GFP were counted. Some of the observed phenotypes of the disruption mutant and the N-terminal sequence homology suggest that Rec7p is a functional homolog of Rec114p of Saccharomyces cerevisae. The observed phenotypes of the disruption and the appearance of Rec7-GFP in mating haploid cells and after meiosis I are consistent with Rec7p functions before, during, and after meiotic prophase.

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  • 骨代謝に対する酒粕の調節機能の解析

    柿原嘉人, 岡本圭一郎, 山村健介

    Journal of Oral Biosciences Supplement (Web)   2023   2023

  • ストレス伝染は吻側延髄腹側部を変調させる

    KAJITA Piriyaprasath, 長谷川真奈, 長谷川真奈, 柿原嘉人, 藤井規孝, 山村健介, 岡本圭一郎

    Journal of Oral Biosciences Supplement (Web)   2023   2023

  • Reptinは胎仔上皮におけるDNA損傷応答を介して器官形成を制御する

    目黒史也, 目黒史也, 目黒史也, 柿原嘉人, 川崎真依子, 川崎勝盛, 川崎勝盛, 丹原惇, 丹原惇, トゥラカナン スッパラック, 工藤武久, 工藤武久, 山田茜, 山田茜, 前田健康, 多部田康一, 佐伯万騎男, 大峡淳

    新潟歯学会雑誌   50 ( 2 )   2020

  • 日本酒によるストレス誘発性の咬筋侵害応答の軽減効果は日本酒含有エタノールの直接作用ではない

    中谷 暢佑, 柿原 嘉人, 清水 志保, 黒瀬 雅之, 佐伯 万騎男, 高木 律男, 山村 健介, 岡本 圭一郎

    Journal of Oral Biosciences Supplement   2018   260 - 260   2018.9

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    Language:Japanese   Publisher:(一社)歯科基礎医学会  

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  • ROCK阻害剤の骨代謝および矯正学的歯の移動への影響

    中田 樹里, 柿原 嘉人, 秋葉 陽介, 江口 香里, 丹原 惇, 大倉 麻里子, 加藤 寛子, 泉 健次, 佐伯 万騎男, 齋藤 功

    新潟歯学会雑誌   47 ( 2 )   120 - 120   2017.12

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  • ROCK阻害剤による骨形成促進メカニズムの解析

    中田 樹里, 柿原 嘉人, 丹原 惇, 佐伯 万騎男, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   76回   184 - 184   2017.10

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  • 『酒は百薬の長』の根拠を科学的に解明するストレス誘発性の咬筋侵害受容反応に対する日本酒の影響について

    岡本 圭一郎, 中谷 暢佑, 黒瀬 雅之, 柿原 嘉人, 木口 哲郎, 長谷川 真奈, 藤井 規孝, 佐伯 万騎男, 高木 律男, 山村 健介

    Journal of Oral Biosciences Supplement   2017   462 - 462   2017.9

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  • セロトニン再取り込み阻害薬は繰り返しストレスによる咬筋の侵害受容反応の増強を抑制する

    中谷 暢佑, 黒瀬 雅之, 清水 志保, 柿原 嘉人, 木口 哲郎, 長谷川 真奈, 佐伯 万騎男, 高木 律男, 山村 健介, 岡本 圭一郎

    Journal of Oral Biosciences Supplement   2017   463 - 463   2017.9

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  • 分子シャペロンR2TPの口腔扁平上皮癌進展における作用機序の解析

    木口 哲郎, 柿原 嘉人, 山崎 学, 高木 律男, 佐伯 万騎男

    Journal of Oral Biosciences Supplement   2017   256 - 256   2017.9

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  • ROCK阻害剤の骨代謝への影響とその作用機序の解析

    中田 樹里, 秋葉 陽介, 江口 香里, 丹原 惇, 齋藤 功, 柿原 嘉人, 佐伯 万騎男

    日本骨代謝学会学術集会プログラム抄録集   35回   184 - 184   2017.7

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  • 破骨細胞分化に影響を与える薬剤のスクリーニングとその作用機序の解析

    中田 樹里, 柿原 嘉人, 秋葉 陽介, 丹原 惇, 齋藤 功, 佐伯 万騎男

    日本骨代謝学会学術集会プログラム抄録集   34回   207 - 207   2016.7

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  • リボソーム合成制御因子R2TPの口腔扁平上皮癌進展における作用機序の解析

    木口哲郎, 木口哲郎, 柿原嘉人, 山崎学, 永田昌毅, 高木律男, 佐伯万騎男

    日本薬理学会北部会プログラム・抄録集   67th   64   2016

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  • 破骨細胞の分化を誘導する小分子化合物の探索

    西川 実沙, 柿原 嘉人, 秋葉 陽介, 江草 宏, 佐伯 万騎男

    Journal of Oral Biosciences Supplement   2015   546 - 546   2015.9

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  • 破骨細胞分化に影響を与える薬剤の探索

    中田 樹里, 柿原 嘉人, 丹原 惇, 齋藤 功, 江草 宏, 佐伯 万騎男

    日本骨代謝学会学術集会プログラム抄録集   33回   196 - 196   2015.7

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  • 破骨細胞分化に影響を与える薬剤のケミカルライブラリースクリーニング

    中田樹里, 中田樹里, 柿原嘉人, 秋葉陽介, 丹原惇, 齋藤功, 江草宏, 佐伯万騎男

    日本薬理学会北部会プログラム・抄録集   66th   53   2015

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  • 破骨細胞の分化を誘導する小分子化合物の探索

    西川実沙, 柿原嘉人, 秋葉陽介, 江草宏, 佐伯万騎男

    Journal of Oral Biosciences Supplement (Web)   2015   2015

  • The R2TP complex: Discovery and functions

    Yoshito Kakihara, Walid A. Houry

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH   1823 ( 1 )   101 - 107   2012.1

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    Language:English   Publishing type:Book review, literature introduction, etc.   Publisher:ELSEVIER SCIENCE BV  

    The two closely related AAA + family ATPases Rvb1 and Rvb2 are part of several critical multiprotein complexes, and, thus, are involved in a wide range of cellular processes including chromatin remodelling, telomerase assembly, and snoRNP biogenesis. It was found that Rvb1 and Rvb2 form a tight functional complex with Pih1 (Protein interacting with Hsp90) and Tah1 (TPR-containing protein associated with Hsp90), which are two Hsp90 interactors. We named the complex R2TP. The complex was originally isolated from Saccharomyces cerevisiae and was, subsequently, identified in mammalian cells. R2TP was found to be required for box C/D snoRNP biogenesis in yeast and mammalian cells. More recently, several studies revealed that the complex is also involved in multiple biological processes including apoptosis, phosphatidylinositol-3 kinase-related protein kinase (PIKK) signalling, and RNA polymerase II assembly. In this review, we describe the discovery of the complex and discuss the emerging critical roles that R2TP plays in distinct cellular processes. This article is part of a Special Issue entitled: AAA ATPases: structure and function. (C) 2011 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.bbamcr.2011.08.016

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  • Comprehensive isolation of meiosis-specific genes identifies novel proteins and unusual non-coding transcripts in Schizosaccharomyces pombe.

    T Watanabe, K Miyashita, T Saito, T Yoneki, Y Kakihara, K Nabeshima, C Shimoda, H Nojima

    YEAST   18   S58 - S58   2001.8

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  • 分裂酵母Meu13は減数分裂特異的に発現し,減数分裂前期の相同染色体の秩序立った空間的配置を促進する

    鍋島建太郎, 柿原嘉人, 平岡泰, 野島博

    日本分子生物学会年会プログラム・講演要旨集   23rd   270   2000.11

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Research Projects

  • Elucidation of the central nervous system mechanism by which stress-induced modulation of higher brain function increases orofacial pain

    Grant number:24K13111

    2024.4 - 2027.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

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  • Extracellular matrix controlled stem cell differentiation and its application toward the regeneration of periodontal ligament

    Grant number:24K02630

    2024.4 - 2027.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\18590000 ( Direct Cost: \14300000 、 Indirect Cost:\4290000 )

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  • 骨芽細胞のⅠ型コラーゲンと基質小胞の分泌経路におけるRabタンパク質の機能解明

    Grant number:23K09117

    2023.4 - 2026.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    柿原 嘉人, 加来 賢, 三上 剛和

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

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  • Effects of treadmil running on masseter muscle pain under psychological stress conditions.

    Grant number:23K09391

    2023.4 - 2026.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

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  • Analysis of TGF-beta signaling in cancer-associated fibroblasts (CAFs) for invasion of oral squamous cell carcinoma

    Grant number:22K10143

    2022.4 - 2026.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

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  • The clarification of the pulp generation mechanism to improve the odontoblast differentiation by the transporter of ascorbic acid.

    Grant number:19K10147

    2022.1 - 2025.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • 低酸素微小環境を標的としたコルジセピン誘導体による口腔がん治療の検討

    Grant number:21K10087

    2021.4 - 2024.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    佐伯 万騎男, 柿原 嘉人, 小林 正治

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

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  • Proteome analysis of periodontal ligament matrix and development of regenerative material

    Grant number:21H03127

    2021.4 - 2024.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

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  • 口腔扁平上皮癌におけるR2TPのターゲット解析と治療標的としての可能性の検討

    Grant number:20K10155

    2020.4 - 2023.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    柿原 嘉人, 佐伯 万騎男, 荒井 雅吉, 船山 昭典

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    本研究では、真核生物において広く保存される分子シャペロンR2TPの口腔癌細胞における作用機序を明らかにすることを目的とする。R2TPは、Pontin, Reptin, PIH1D1, RPAP3の四種類の異なるタンパク質から構成されており、mTORC1、RNAポリメラーゼII、snoRNP巨大なタンパク質複合体 やタンパク質-RNA複合体形成をサポートすることが見出されてきた。我々はこれまでに、R2TPが口腔癌の9割を占める口腔扁平上皮癌の悪性進展にどのように関与しているのかについて解析を行ってきた。分子シャペロンであるR2TPの機能を探るためには、その標的因子の同定が必要である。そこで、R2TPの各因子に対する特異的抗体を用いて標的因子の網羅的解析を行ったところ、様々な新規因子が同定された。特に興味深いものとしてHEATR1が挙げられる。HEATリピートと呼ばれるタンパク質相互作用に関与するドメインを持っており、他にもいくつかのHEATリピートを持つタンパク質が同定されたことから、R2TPとHEATリピートドメインに結合親和性があることが予想された。HEATR1ノックダウンは、細胞増殖が顕著に低下したことから、R2TPと同様に癌細胞増殖に寄与する遺伝子であることが明らかになった。また、HEATR1のノックダウンによってR2TPの構成因子であるPontin/Reptinのタンパク質レベルの低下が見られた。HEATR1のmRNAレベルに変化は見られなかったため、HEATR1がPontin/Reptinのタンパク質安定性に関与していることが示唆された。

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  • Elucidation of mechanism on congenital abnormality in the maxillofacial region focusing on DNA repair mechanism

    Grant number:19H03849

    2019.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    MAEDA TAKEYASU

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    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    DNA repair is essential process for cell survive. It remains unclear whether DNA repair system is required for development. We generated mice with epithelial conditional deletions of DNA repair-related molecule, Reptin. Reptin cKO showed the arrest of epidermis development. The anomalies of epidermis were found to be caused by DNA damages and subsequent inhibition of cell proliferation due to aberrant activation of p53/p21 signals. We found that oxidative stress damage DNA during normal skin development. DNA damage caused by oxidative stress is repaired by Reptin, which lead to normal skin development.

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  • Neural basis for inhibitory effects of exercises on enhanced nociception in the orofacial region under psychological stress conditions

    Grant number:19K10353

    2019.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Okamoto Keiichiro

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    Stress controls are critical to alleviate stress-induced pain in human. However, 亜as we cannot avoid stressful events in our life, it could be appropriate to control adverse stress responses by means of convenient ways, like exercise. This study determined the effect of daily treadmill running on masseter muscle nociception under psychological stress conditions. The results indicated that enhanced masseter muscle nociception indicated by orofacial nocifensive behaviors and neural activities (c-Fos and FosB) in the upper cervical dorsal horn were inhibited by daily treadmill running exercise.These findings supported our hypothesis that daily exercise could have therapeutic and preventive roles on deep craniofacial nociception associated with psychological stress conditions.

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  • Oral squamous cell carcinoma and cetuximab loop theory

    Grant number:18K09504

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Saeki Makio

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    R2TP/PAQosome (particle for arrangement of quaternary structure) is a novel multisubunit chaperone specialized in the assembly/maturation of protein complexes that are involved in essential cellular processes such as PIKKs (phosphatidylinositol 3-kinase-like kinases) signaling, snoRNP (small nucleolar ribonucleoprotein) biogenesis, and RNAP II (RNA polymerase II) complex formation. In this review article, we describe the current understanding of R2TP/PAQosome functions and characteristics as well as how the chaperone complex is involved in oncogenesis, highlighting DNA damage response, mTOR (mammalian target of rapamycin) pathway as well as snoRNP biogenesis. Also, we discuss its possible involvement in HNSCC (head and neck squamous cell carcinoma) including OSCC (oral squamous cell carcinoma). Finally, we provide an overview of current anti-cancer drug development efforts targeting R2TP/PAQosome.

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  • Molecular regulation of actin polymerization and arrangement in the lateral front between oral squamous cell carcinoma and non-cancerous epithelium

    Grant number:18K09550

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Abe Tatsuya

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    We have reported that ladinin-1 (LAD1) was highly expressed in cancer tissues adjacent to non-cancerous tissues by proteomic analysis of histopathological specimens of oral squamous cell carcinoma (OSCC). In a present study, we investigated the role of LAD1 in cancer development. LAD1-knockdown OSCC cells by siRNA method showed decreased cell proliferation, decreased planar cell migration, and enhanced three-dimensional cell migration. LAD1 localized to actin fibers in intracellular actin arcs, and inhibition of LAD1 expression resulted in decreased expansion of lamella and loss of epithelial-like cell morphology. These results suggested that LAD1 involved in cell migration through regulation of actin molecule and related to the expression of epithelial morphology and properties.

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  • Osteoclast activator: a promising therapeutic target for osteoporosis

    Grant number:15K15683

    2015.4 - 2017.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    SAEKI Makio, YOSHIZAWA Michiko, AKIBA Yosuke

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    Small molecule compounds that potently affect osteoclastogenesis could be useful as chemical probes for elucidating the mechanisms of various biological phenomena, and as effective therapeutic strategies against bone resorption. An osteoclast progenitor cell-based high-throughput screening system was designed to target activation of nuclear factor of activated T cells (NFAT), which is a key event for osteoclastogenesis. Chemical compound library screening using this system identified kenpaullone, to be an NFAT regulator in osteoclasts. Kenpaullone promoted receptor activator for NF-κB ligand (RANKL)-induced NFAT activity in RAW264.7 cells and also promoted the formation of TRAP-positive multinucleated osteoclasts from RAW264.7 cells and mouse primary bone marrow macrophages (BMMs) in a concentration-dependent manner.

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Teaching Experience

  • 日本酒学概論V(医歯学・保健学)

    2023
    Institution name:新潟大学

  • 日本酒学A

    2022
    Institution name:新潟大学

  • 疾病とその病態

    2022
    Institution name:新潟大学

  • 「食べる」

    2022
    Institution name:新潟大学

  • 日本酒学A-2

    2021
    Institution name:新潟大学

  • 日本酒学A-1

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(ベーシック歯科薬理学コースワークI)

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(ベーシック歯科薬理学コースワークII)

    2021
    Institution name:新潟大学

  • 人体のしくみ

    2020
    Institution name:新潟大学

  • 日本酒学B

    2020
    Institution name:新潟大学

  • 歯科薬理学

    2018
    Institution name:新潟大学

  • 薬理学

    2015
    Institution name:新潟大学

  • 基礎科学演習

    2015
    -
    2016
    Institution name:新潟大学

  • 組織工学実習

    2015
    -
    2016
    Institution name:新潟大学

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